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Jin F, Wei X, Liu Y, Tang L, Ren J, Yang J, Lin C, Hu J, Sun M, Li G, Yuan Z, Zhao W, Wang X, Yang Z, Zhang L. Engineered cell membrane vesicles loaded with lysosomophilic drug for acute myeloid leukemia therapy via organ-cell-organelle cascade-targeting. Biomaterials 2025; 317:123091. [PMID: 39778270 DOI: 10.1016/j.biomaterials.2025.123091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 12/07/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025]
Abstract
Acute myeloid leukemia (AML) presents significant treatment challenges due to the severe toxicities and limited efficacy of conventional therapies, highlighting the urgency for innovative approaches. Organelle-targeting therapies offer a promising avenue to enhance therapeutic outcomes while minimizing adverse effects. Herein, inspired that primary AML cells are enriched with lysosomes and sensitive to lysosomophilic drugs (e.g., LLOMe), we developed a smart nanodrug (Cas-CMV@LM) including the engineered cell membrane vesicles (CMVs) nanocarrier and the encapsulated drug cargo LLOMe (LM). Briefly, the nanodrug with organ-cell-organelle cascade-targeting function could firstly home to the bone marrow guided by CMVs derived from CXCR4-overexpressing bone marrow mesenchymal stem cells (BMSC), subsequently target leukemia cells via CD33 and CD123 aptamers anchored on the vesicles, eventually precisely attack the lysosomes of leukemia cells. Consequently, Cas-CMV@LM specifically inhibited leukemia cell proliferation and triggered necroptosis in vitro. Importantly, the cascade-targeting nanodrug displayed high biosafety and significantly impeded leukemia progression in AML patient-derived xenograft (PDX) model. Collectively, this study provides a paradigm for precision leukemia treatment from the perspective of targeting organelle-lysosome.
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Affiliation(s)
- Fangfang Jin
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Xingyu Wei
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Yongcan Liu
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Lisha Tang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jun Ren
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jing Yang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Can Lin
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jiayuan Hu
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Minghui Sun
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Genyou Li
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Zihao Yuan
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Wen Zhao
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Xiaozhong Wang
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Zesong Yang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Ling Zhang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
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Liang A, Tao T, Chen J, Yang Y, Zhou X, Zhu X, Yu G. Immunocompetent tumor-on-a-chip: A translational tool for drug screening and cancer therapy. Crit Rev Oncol Hematol 2025; 210:104716. [PMID: 40194716 DOI: 10.1016/j.critrevonc.2025.104716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 04/09/2025] Open
Abstract
Tumor is one of the major diseases endangering human health while establishing an efficient in vitro tumor microenvironment (TME) model, which is an effective way to reveal the nature of the tumor and develop therapeutic methods. In recent years, due to the continuous development of lab-on-a-chip technology and tumor biology, various tumor-on-a-chip models applied to oncology research have emerged. Among them, the Immunotherapy-on-a-chip (ITOC) platform stands out with its ability to reflect immunological behavior in the TME. It is a class of in vitro tumor-on-a-chip with immune activity, which has good performance and the ability to reproduce TME. It can highly simulate the complex pathophysiological characteristics of tumors and be used to study various features related to tumor biological behavior. Currently, many advantageous functions and application values of ITOC platforms have been discovered and applied to tumor drug screening and development, tumor immunotherapy, and personalized therapy. In conclusion, the tumor-on-a-chip platform is a highly promising model for medical oncology research. In this review, the background of the ITOC platform, key factors for constructing an ideal ITOC platform, and the specific applications of ITOC platforms in tumor research and treatment are introduced.
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Affiliation(s)
- Anqi Liang
- Department of Cardiothoracic Surgery, Jiangyin People's Hospital Affiliated to Nantong University, Jiangyin, China; The Second Affiliated Hospital, Guangdong Medical University, Zhanjiang, China
| | - Tao Tao
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Jiahui Chen
- The Second Affiliated Hospital, Guangdong Medical University, Zhanjiang, China
| | - Yucong Yang
- The Second Affiliated Hospital, Guangdong Medical University, Zhanjiang, China
| | - Xiaorong Zhou
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Xiao Zhu
- The Second Affiliated Hospital, Guangdong Medical University, Zhanjiang, China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, China.
| | - Guiping Yu
- Department of Cardiothoracic Surgery, Jiangyin People's Hospital Affiliated to Nantong University, Jiangyin, China.
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3
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Liu W, Liu Q, Li Z, Zhang C, Li Z, Ke H, Xu X, Wang X, Du H, Talifu Z, Pan Y, Wang X, Mao J, Gao F, Yang D, Yu Y, Liu X, Li J. Multifunctional magneto-electric and exosome-loaded hydrogel enhances neuronal differentiation and immunoregulation through remote non-invasive electrical stimulation for neurological recovery after spinal cord injury. Bioact Mater 2025; 48:510-528. [PMID: 40104021 PMCID: PMC11919302 DOI: 10.1016/j.bioactmat.2025.02.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/22/2025] [Accepted: 02/23/2025] [Indexed: 03/20/2025] Open
Abstract
Intervention in the differentiation of neural stem cells (NSCs) is emerging as a highly promising approach for the treatment of spinal cord injury (SCI). However, NSCs at the injury site often suffer from low survival and uncontrolled differentiation. Whereas electrical stimulation has proven effective in regulating the fate of NSCs and promoting tissue repair, however, conventional electrical stimulation therapy has failed to be widely applied due to challenges such as invasiveness and technical complexity. To overcome these limitations, we developed a biomimetic magneto-electric hydrogel incorporating Fe3O4@BaTiO3 core-shell nanoparticles and human umbilical mesenchymal stem cell exosomes (HUMSC-Exos) around the concept of constructing remote noninvasive electrical stimulation for the synergistic treatment of SCI. The Fe3O4@BaTiO3 is activated by the peripheral magnetic field to generate electrical stimulation, which, in conjunction with the synergistic effects of HUMSC-Exos, significantly alleviates the early inflammatory response associated with SCI and enhances the regeneration of newborn neurons and axons, thereby creating favorable conditions for functional recovery post-SCI. Our findings indicate that applying this magneto-exosome hydrogel in a rat model of SCI leads to substantial functional recovery. This innovative combination represents a promising therapeutic strategy for SCI repair.
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Affiliation(s)
- Wubo Liu
- Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266100, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
| | - Qiang Liu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Zeqin Li
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- Ganan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Chunjia Zhang
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing, 100096, PR China
| | - Zehui Li
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
| | - Han Ke
- Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266100, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- Department of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100013, PR China
| | - Xin Xu
- Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
| | - Xiaoxin Wang
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
| | - Huayong Du
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
| | - Zuliyaer Talifu
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266100, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, 100005, PR China
| | - Yunzhu Pan
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266100, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
- Rehabilitation Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100005, PR China
| | - Xiaoxiong Wang
- Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
- University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266100, PR China
| | - Jingyun Mao
- College of Environmental and Resource Sciences, College of Carbon Neutral Modern Industry, Fujian Normal University, Fuzhou, 350007, PR China
| | - Feng Gao
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
| | - Degang Yang
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
| | - Yan Yu
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
| | - Xinyu Liu
- Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
- University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266100, PR China
| | - Jianjun Li
- Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
- China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, 100068, PR China
- University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266100, PR China
- China Rehabilitation Science Institute, Beijing, 100068, PR China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, 100068, PR China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100068, PR China
- School of Rehabilitation, Capital Medical University, Beijing, 100069, PR China
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4
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Kang H, Huang Y, Peng H, Zhang X, Liu Y, Liu Y, Xia Y, Liu S, Wu Y, Wang S, Lei T, Zhang H. Mesenchymal Stem Cell-Loaded Hydrogel Improves Surgical Treatment for Chronic Cerebral Ischemia. Transl Stroke Res 2025; 16:896-913. [PMID: 38977638 DOI: 10.1007/s12975-024-01274-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/11/2024] [Accepted: 06/25/2024] [Indexed: 07/10/2024]
Abstract
Chronic cerebral ischemia (CCI) results in a prolonged insufficient blood supply to the brain tissue, leading to impaired neuronal function and subsequent impairment of cognitive and motor abilities. Our previous research showed that in mice with bilateral carotid artery stenosis, the collateral neovascularization post Encephalo-myo-synangiosis (EMS) treatment could be facilitated by bone marrow mesenchymal stem cells (MSCs) transplantation. Considering the advantages of biomaterials, we synthesized and modified a gelatin hydrogel for MSCs encapsulation. We then applied this hydrogel on the brain surface during EMS operation in rats with CCI, and evaluated its impact on cognitive performance and collateral circulation. Consequently, MSCs encapsulated in hydrogel significantly augment the therapeutic effects of EMS, potentially by promoting neovascularization, facilitating neuronal differentiation, and suppressing neuroinflammation. Furthermore, taking advantage of multi-RNA-sequencing and in silico analysis, we revealed that MSCs loaded in hydrogel regulate PDCD4 and CASP2 through the overexpression of miR-183-5p and miR-96-5p, thereby downregulating the expression of apoptosis-related proteins and inhibiting early apoptosis. In conclusion, a gelatin hydrogel to enhance the functionality of MSCs has been developed, and its combination with EMS treatment can improve the therapeutic effect in rats with CCI, suggesting its potential clinical benefit.
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Affiliation(s)
- Huayu Kang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yimin Huang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huan Peng
- Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Xincheng Zhang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuan Liu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yanchao Liu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuze Xia
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shengwen Liu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yaqi Wu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sheng Wang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ting Lei
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huaqiu Zhang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China.
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Tang S, Zhang Y, Wang P, Tang Q, Liu Y, Lu F, Han M, Zhou M, Hu Q, Feng M, Liang D. NKG2D-CAR-targeted iPSC-derived MSCs efficiently target solid tumors expressing NKG2D ligand. iScience 2025; 28:112343. [PMID: 40276759 PMCID: PMC12020857 DOI: 10.1016/j.isci.2025.112343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/28/2025] [Accepted: 03/31/2025] [Indexed: 04/26/2025] Open
Abstract
Mesenchymal stem cells (MSCs) hold potential in cancer therapy; however, insufficient tumor homing ability and heterogeneity limit their therapeutic benefits. Obviously, the homogeneous induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) with enhanced ability of tumor targeting could be the solution. In this study, a CAR containing the NKG2D extracellular domain was targeted at the B2M locus of iPSCs to generate NKG2D-CAR-iPSCs, which were subsequently differentiated into NKG2D-CAR-iMSCs. In vitro, NKG2D-CAR significantly enhanced migration and adhesion of iMSCs to a variety of solid tumor cells expressing NKG2D ligands. RNA sequencing (RNA-seq) revealed significant upregulation of genes related to cell adhesion, migration, and binding in NKG2D-CAR-iMSCs. In A549 xenograft model, NKG2D-CAR-iMSCs demonstrated a 57% improvement in tumor-homing ability compared with iMSCs. In conclusion, our findings demonstrate enhanced targeting specificity of NKG2D-CAR-iMSCs to tumor cells expressing NKG2D ligands in vitro and in vivo, facilitating future investigation of iMSCs as an off-the-shelf living carrier for targeted delivery of anti-tumor agents.
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Affiliation(s)
- Shuqing Tang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Yusang Zhang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Peiyun Wang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Qiyu Tang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Yating Liu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Fan Lu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Mengting Han
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Miaojin Zhou
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Qian Hu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Mai Feng
- Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha 410078, China
| | - Desheng Liang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
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Wang Y, Zhu N, Liu J, Chen F, Song Y, Ma Y, Yang Z, Wang D. Role of tumor microenvironment in ovarian cancer metastasis and clinical advancements. J Transl Med 2025; 23:539. [PMID: 40369674 PMCID: PMC12079989 DOI: 10.1186/s12967-025-06508-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 04/16/2025] [Indexed: 05/16/2025] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide, characterized by heterogeneity at the molecular, cellular and anatomical levels. Most patients are diagnosed at an advanced stage, characterized by widespread peritoneal metastasis. Despite optimal cytoreductive surgery and platinum-based chemotherapy, peritoneal spread and recurrence of OC are common, resulting in poor prognoses. The overall survival of patients with OC has not substantially improved over the past few decades, highlighting the urgent necessity of new treatment options. Unlike the classical lymphatic and hematogenous metastasis observed in other malignancies, OC primarily metastasizes through widespread peritoneal seeding. Tumor cells (the "seeds") exhibit specific affinities for certain organ microenvironments (the "soil"), and metastatic foci can only form when there is compatibility between the "seeds" and "soil." Recent studies have highlighted the tumor microenvironment (TME) as a critical factor influencing the interactions between the "seeds" and "soil," with ascites and the local peritoneal microenvironment playing pivotal roles in the initiation and progression of OC. Prior to metastasis, the interplay among tumor cells, immunosuppressive cells, and stromal cells leads to the formation of an immunosuppressive pre-metastatic niche in specific sites. This includes characteristic alterations in tumor cells, recruitment and functional anomalies of immune cells, and dysregulation of stromal cell distribution and function. TME-mediated crosstalk between cancer and stromal cells drives tumor progression, therapy resistance, and metastasis. In this review, we summarize the current knowledge on the onset and metastatic progression of OC. We provide a comprehensive discussion of the characteristics and functions of TME related to OC metastasis, as well as its association with peritoneal spread. We also outline ongoing relevant clinical trials, aiming to offer new insights for identifying potential effective biomarkers and therapeutic targets in future clinical practice.
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Affiliation(s)
- Yang Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China
| | - Na Zhu
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China
| | - Jing Liu
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China
| | - Fang Chen
- Department of Gynecology, People's Hospital of Liaoning Province, Shenyang, Liaoning Province, 110016, People's Republic of China
| | - Yang Song
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People's Republic of China
| | - Yue Ma
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China.
| | - Zhuo Yang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China.
| | - Danbo Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China.
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Hu H, Fan Y, Wang J, Zhang J, Lyu Y, Hou X, Cui J, Zhang Y, Gao J, Zhang T, Nan K. Single-cell technology for cell-based drug delivery and pharmaceutical research. J Control Release 2025; 381:113587. [PMID: 40032008 DOI: 10.1016/j.jconrel.2025.113587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/05/2025]
Abstract
Leveraging the capacity to precisely manipulate and analyze individual cells, single-cell technology has rapidly become an indispensable tool in the advancement of cell-based drug delivery systems and innovative cell therapies. This technology offers powerful means to address cellular heterogeneity and significantly enhance therapeutic efficacy. Recent breakthroughs in techniques such as single-cell electroporation, mechanical perforation, and encapsulation, particularly when integrated with microfluidics and bioelectronics, have led to remarkable improvements in drug delivery efficiency, reductions in cytotoxicity, and more precise targeting of therapeutic effects. Moreover, single-cell analyses, including advanced sequencing and high-resolution sensing, offer profound insights into complex disease mechanisms, the development of drug resistance, and the intricate processes of stem cell differentiation. This review summarizes the most significant applications of these single-cell technologies, highlighting their impact on the landscape of modern biomedicine. Furthermore, it provides a forward-looking perspective on future research directions aimed at further optimizing drug delivery strategies and enhancing therapeutic outcomes in the treatment of various diseases.
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Affiliation(s)
- Huihui Hu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Yunlong Fan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China; MicroTech Medical (Hangzhou) Co., Hangzhou 311100, China
| | - Jiawen Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Jialu Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Yidan Lyu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Xiaoqi Hou
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Jizhai Cui
- Department of Materials Science, Fudan University, Shanghai 200438, China; International Institute of Intelligent Nanorobots and Nanosystems, Fudan University, Shanghai 200438, China
| | - Yamin Zhang
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 117585, Singapore
| | - Jianqing Gao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Tianyuan Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China.
| | - Kewang Nan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China.
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Wu J, Ge Y, Huang W, Zhang L, Huang J, Huang N, Luo Y. Natural bioactive compounds modified with mesenchymal stem cells: new hope for regenerative medicine. Front Bioeng Biotechnol 2025; 13:1446537. [PMID: 40416310 PMCID: PMC12098461 DOI: 10.3389/fbioe.2025.1446537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 04/25/2025] [Indexed: 05/27/2025] Open
Abstract
Mesenchymal stem cells (MSCs) have the potential to differentiate into various cell types, providing important sources of cells for the development of regenerative medicine. Although MSCs have various advantages, there are also various problems, such as the low survival rate of transplanted cells and poor migration and homing; therefore, determining how to reform MSCs to improve their utilization is particularly important. Although many natural bioactive compounds have shown great potential for improving MSCs, many mechanisms and pathways are involved; however, in the final analysis, natural bioactive compounds promoted MSC proliferation, migration and homing and promoted differentiation and antiaging. This article reviews the regulatory effects of natural bioactive compounds on MSCs to provide new ideas for the therapeutic effects of modified MSCs on diseases.
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Affiliation(s)
- Jingjing Wu
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
| | - Ying Ge
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
| | - Wendi Huang
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
| | - Li Zhang
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
| | - Juan Huang
- Key Laboratory of Basic Pharmacology and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nanqu Huang
- National Drug Clinical Trial Institution, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
- Department of Gerontology, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
| | - Yong Luo
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
- Department of Gerontology, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
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9
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Johor A, Mahadiuzzaman ASM, Alqusayer AA, Alkarim SA, Opo FADM. In vivo and in vitro therapeutic evaluation of bone marrow-derived mesenchymal stem cells in liver cancer treatment. Front Cell Dev Biol 2025; 13:1521809. [PMID: 40406417 PMCID: PMC12095274 DOI: 10.3389/fcell.2025.1521809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 03/31/2025] [Indexed: 05/26/2025] Open
Abstract
Hepatocellular carcinoma is the seventh most common kind of cancer worldwide and the second largest cause of cancer-related deaths in males, behind lung cancer. Globally, 866,000 people were diagnosed with hepatocellular carcinoma (HCC) in 2022, and nearly 42,240 new cases will be identified in 2025 in the United States. Using stem cells obtained from bone marrow can effectively reduce the number of malignant tumor cells through the induction of an epigenetic impact. We obtained bone marrow-derived mesenchymal stem cells (BM-MSCs) from mice and collected the conditioned medium (CM) from cultured cells with 90% confluency. The effect of the CM was identified using both 2D and 3D sphere cultures of wild-type human liver cancer cell line (HepG2), considering variations in sphere size and percentage. A cell death study was conducted using the cell cytotoxicity (MTT) kit, while the quantity of stem cells was determined by immunohistochemistry and gene expression analysis. The effectiveness of our therapy was demonstrated by an in vivo assessment of BM-MSCs through intravenous injection and the currently available anticancer drug cisplatin. In vitro, the combination treatment resulted in a synergetic effect, leading to 74% cell death in both adherent and spherical cultures when treated with 25 µM of cisplatin and 90%CM. In vivo, the histological study indicated a decrease in tumor size and number following treatment with cisplatin and BM-MSCs. The study lasted 18 weeks and revealed that the body weight of mice improved across all treatment groups, with the combination group exhibiting the most significant improvement. Both in vitro and in vivo studies showed the synergetic effect of cisplatin and isolated conditioned medium. Our study aimed to identify more efficient therapeutic approaches utilizing stem cells and existing marketed medications to minimize adverse effects with better efficacy.
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Affiliation(s)
- Abdulrahman Johor
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - A. S. M. Mahadiuzzaman
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdulaziz Abdullah Alqusayer
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh Abdulaziz Alkarim
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - F. A. Dain Md Opo
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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Tang Y, Shen Y, Zang X, Wu P, Li L, Qian H, Zhang X, Xu W, Jiang J. Neutrophil membrane engineered human umbilical cord MSC-derived sEVs enhance anti-tumor efficacy for gastric cancer via delivering pentraxin 3. J Control Release 2025; 383:113828. [PMID: 40345624 DOI: 10.1016/j.jconrel.2025.113828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 05/02/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
Gastric cancer poses a significant global health challenge, promoting ongoing updates and exploration of treatment strategies. In this study, we proposed the naïve human umbilical cord mesenchymal stem cell derived small extracellular vesicles (hucMSC-sEVs) effectively inhibit gastric cancer proliferation and migration, presenting a promising bioactive agent for gastric cancer therapy. To address the issues of shortage in circulation time, limited targeting efficiency, suboptimal therapeutic outcomes associated with hucMSC-sEVs, we engineered a membrane fusion between hucMSC-sEVs with human neutrophil membrane, creating Neu/MSC-sEVs. This modification enhanced tumor cell targeting, reduced clearance by the mononuclear macrophage system, prolonged circulation time, and improved therapeutic efficacy. Furthermore, inhibiting the tumor suppressor protein pentraxin 3 (PTX3) in hucMSC-sEVs attenuated their anti-tumor effects, indicating that enrichment with PTX3 enhances the tumor-inhibiting potential of hucMSC-sEVs. Overall, our findings shed light on the mechanism by which hucMSC-sEVs exert their therapeutic effects on gastric cancer and underscore the importance of vesicle modification in enhancing targeting precision and therapeutic outcomes. These findings provide new insights for clinical application of modified vesicles in cancer treatment.
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Affiliation(s)
- Yuting Tang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 jingang Road,Suzhou, Jiangsu 215600, China; Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Ye Shen
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 jingang Road,Suzhou, Jiangsu 215600, China; Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Xueyan Zang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 jingang Road,Suzhou, Jiangsu 215600, China; Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Peipei Wu
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Linli Li
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Hui Qian
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Xu Zhang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 jingang Road,Suzhou, Jiangsu 215600, China; Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Wenrong Xu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 jingang Road,Suzhou, Jiangsu 215600, China; Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China.
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 jingang Road,Suzhou, Jiangsu 215600, China; Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang 212013, China.
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11
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Liu X, Bian H, Zhou T, Zhao C. Protective Effects of Rat Bone Marrow Mesenchymal Stem Cells-Derived Fusogenic Plasma Membrane Vesicles Containing VSVG Protein Mediated Mitochondrial Transfer on Myocardial Injury In Vitro. FASEB Bioadv 2025; 7:e70010. [PMID: 40330432 PMCID: PMC12050952 DOI: 10.1096/fba.2024-00235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/19/2025] [Accepted: 03/28/2025] [Indexed: 05/08/2025] Open
Abstract
Overexpression of spike glycoprotein G of vesicular stomatitis virus (VSVG) can induce the release of fusogenic plasma membrane vesicles (fPMVs), which can transport cytoplasmic, nuclear, and surface proteins directly to target cells. This study aimed to investigate the roles of rat bone marrow mesenchymal stem cells (rBMSCs)-derived fPMVs containing VSVG protein in myocardial injury and their related mechanisms. The plasmids of pLP-VSVG were used to transfect rBMSCs, and then fPMVs were obtained by mechanical extrusion. After that, H9c2 cells were first treated with hypoxia reoxygenation (HR) to establish a cardiomyocyte injury model, and then were treated with fPMVs to evaluate the rescue of rBMSCs-derived fPMVs on HR-induced cardiomyocyte injury. FPMVs containing VSVG protein were successfully prepared from rBMSCs with VSVG overexpression. Compared with control fPMVs, ACTB, HDAC1, VSVG, CD81, MTCO1, and TOMM20 were significantly up-regulated (p < 0.05), while eEF2 was significantly down-regulated (p < 0.05) in the fPMVs containing VSVG protein. Additionally, it was obvious fPMVs could carry mitochondria into H9c2 cells, and HR treatment significantly inhibited viability and induced apoptosis of H9c2 cells, as well as significantly increased the contents of TNF-α and IL-1β, and ROS levels both in cells and cellular mitochondria, while evidently reducing the levels of ATP, MRCC IV, and MT-ND1 (p < 0.05). However, fPVMs could remarkably reverse the changes in these indexes caused by HR (p < 0.05). RBMSCs-derived fPMVs containing VSVG protein may have protective effects on myocardial injury by mediating mitochondrial transfer and regulating mitochondrial functions.
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Affiliation(s)
- Xin Liu
- Biochemistry and Molecular BiologyBasic Medical Institute of Ningxia Medical UniversityYinchunNingxiaChina
| | - Hong Bian
- Cardiothoracic SurgerySouthern University of Science and Technology HospitalShenzhen and GuangzhouGuangdongChina
| | - Tingyuan Zhou
- Biochemistry and Molecular BiologyBasic Medical Institute of Ningxia Medical UniversityYinchunNingxiaChina
| | - Chunjuan Zhao
- Rehabilitation MedicineGeneral Hospital of Ningxia Medical UniversityYinchunNingxiaChina
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Wang T, Gong Y, Lin H, Li X, Liang J, Yuan X, Li C, Hu Z, Chen H, Xiao J, Zhang J, Liu Y, Yan X, Jiang C, Yao J, Zhang Q, Li R, Zheng J. Heat Shock Strengthens the Protective Potential of MSCs in Liver Injury by Promoting EV Release Through Upregulated Autophagosome Formation. J Extracell Vesicles 2025; 14:e70084. [PMID: 40326673 PMCID: PMC12053880 DOI: 10.1002/jev2.70084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/18/2025] [Accepted: 03/28/2025] [Indexed: 05/07/2025] Open
Abstract
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show powerful potential in the treatment of multiple diseases. However, the low yield of MSC-EVs severely restricts their clinical application. Here, heat shock (HS), a moderate external stimulus, can enhance EVs release of MSCs by upregulating autophagosome formation. Mechanistically, HS elevates TRPV2 expression to induce Ca2+ influx and then promotes the activity of two succinylases, SUCLG2 and OXCT1, followed by increasing the succinylation of YWHAZ (a 14-3-3 protein) at lysine 11 (K11). Acting as an adaptor protein, YWHAZ's succinylation at K11 inhibits its degradation, reinforcing YWHAZ-ULK1 binding, which upregulates ULK1 S555 phosphorylation to promote autophagosome formation and enhance EV release of MSCs. Additionally, the improved therapeutic efficacy of HS-treated MSCs via EV release has been shown in two liver injury models-hepatic ischemia/reperfusion injury (HIRI) and acetaminophen-induced liver injury. These findings proved that HS, an easily implementable and cost-effective method, can be used to elevate MSC-EV yield in mass production.
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Affiliation(s)
- Tingting Wang
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yihang Gong
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Huizhu Lin
- Biological Treatment CenterThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Xuejiao Li
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jinliang Liang
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Biological Treatment CenterThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Xiaofeng Yuan
- Department of General Intensive Care UnitLingnan Hospital, The Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Cuiping Li
- Biological Treatment CenterThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Zhongying Hu
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Haitian Chen
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jiaqi Xiao
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jiebin Zhang
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yasong Liu
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Xijing Yan
- Department of Breast and Thyroid SurgeryLingnan Hospital, The Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Chenhao Jiang
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jia Yao
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Qi Zhang
- Biotherapy Centre & Cell‐gene Therapy Translational Medicine Research CentreThe Third Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Rong Li
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jun Zheng
- Organ Transplantation Research Center of Guangdong Province, Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat‐sen UniversityGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Liver Disease ResearchThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
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Wang H, Bai Z, Qiu Y, Kou J, Zhu Y, Tan Q, Chen C, Mo R. Empagliflozin-Pretreated MSC-Derived Exosomes Enhance Angiogenesis and Wound Healing via PTEN/AKT/VEGF Pathway. Int J Nanomedicine 2025; 20:5119-5136. [PMID: 40297404 PMCID: PMC12035755 DOI: 10.2147/ijn.s512074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 04/08/2025] [Indexed: 04/30/2025] Open
Abstract
Background Diabetic wounds are a common and challenging complication of diabetes, characterized by delayed healing and increased risk of infection. Current treatment methods are limited and often ineffective in promoting wound repair. Mesenchymal stem cell (MSC)-derived exosomes have shown promise in regenerative medicine, but enhancing their therapeutic potential remains a key area of research. Methods In this study, MSCs were pretreated with empagliflozin (EMPA), and exosomes were isolated using ultracentrifugation. The morphology, size, and protein markers of EMPA-Exos were characterized. Their effects on human umbilical vein endothelial cells (HUVECs) were assessed using EdU assays, CCK-8 assays, scratch assays, Transwell assays, and Matrigel tube formation assays. The PTEN/AKT/VEGF signaling pathway was analyzed through Western blotting. In vivo, diabetic mouse wound models were used to evaluate the healing efficacy of EMPA-Exos. Results EMPA pretreatment enhanced the functional properties of MSC-derived exosomes, significantly improving HUVECs' proliferation, migration, invasion, and angiogenesis compared to non-pretreated exosomes (P < 0.05). Transcriptomic analysis and pathway activation studies revealed that EMPA-Exos promoted angiogenesis through the PTEN/AKT/VEGF signaling pathway. In vivo experiments demonstrated accelerated wound healing and increased vascularization in diabetic mice treated with EMPA-Exos (P < 0.05). Conclusion EMPA-pretreated MSC-derived exosomes effectively enhance angiogenesis and accelerate diabetic wound healing by activating the PTEN/AKT/VEGF signaling pathway. This strategy offers a promising approach for improving diabetic wound repair and provides a potential new therapeutic avenue in regenerative medicine.
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Affiliation(s)
- Hao Wang
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Cardiothoracic Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Zihao Bai
- Nanjing Children’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing, Jiangsu, People’s Republic of China
| | - Yan Qiu
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Jiaxi Kou
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Yanqing Zhu
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Qian Tan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Chen Chen
- Department of Nutrition, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Ran Mo
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
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Zare S, Jafarzadeh A, Zare S, Shamloo A. Exploring the dermatological applications of human mesenchymal stem cell secretome: a comprehensive review. Stem Cell Res Ther 2025; 16:177. [PMID: 40221781 PMCID: PMC11993991 DOI: 10.1186/s13287-025-04311-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
INTRODUCTION Mesenchymal stem cell (MSC)-derived conditioned media is emerging as a promising alternative to stem cell therapy, owing to its abundant content of growth factors and cytokines. OBJECTIVE This review evaluates the clinical applications of MSC-conditioned media in improving scars, promoting wound healing, stimulating hair growth, and rejuvenating the skin. MATERIALS AND METHODS A thorough search of relevant databases was performed to identify studies meeting the inclusion criteria. From an initial pool of 75 articles, 16 studies published up to 2024 were selected based on their relevance, focus, and alignment with the research objectives. RESULTS Among the 17 selected studies, 5 examined the role of conditioned media in skin rejuvenation, 3 investigated its effects on hair growth, 5 assessed its efficacy in scar treatment, 2 assessed its efficacy in Inflammatory Dermatologic Disease and 2 explored its role in wound healing. All studies reported favorable outcomes, demonstrating significant improvements in scars, hair regrowth, and skin rejuvenation with the application of conditioned media. CONCLUSION This review underscores the potential of MSC-derived conditioned media in dermatology. Several studies also highlighted its enhanced therapeutic effects when combined with adjunctive treatments, such as laser therapy and microneedling, showcasing improved outcomes in dermatological care.
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Affiliation(s)
- Sona Zare
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Persian Bio-Based Production (PBBP) Company, Sharif University of Technology, Tehran, Iran
- Stem Cell and Regenerative Medicine Institute, Sharif University of Technology, Azadi Street, Tarasht Avenue, Tehran, 1445613131, Iran
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
| | - Alireza Jafarzadeh
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Solmaz Zare
- Persian Bio-Based Production (PBBP) Company, Sharif University of Technology, Tehran, Iran
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Shamloo
- Stem Cell and Regenerative Medicine Institute, Sharif University of Technology, Azadi Street, Tarasht Avenue, Tehran, 1445613131, Iran.
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.
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15
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Wang J, Xu S, Chen B, Qin Y. Advances in cell therapy for orthopedic diseases: bridging immune modulation and regeneration. Front Immunol 2025; 16:1567640. [PMID: 40276505 PMCID: PMC12018241 DOI: 10.3389/fimmu.2025.1567640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Orthopedic diseases pose significant challenges to public health due to their high prevalence, debilitating effects, and limited treatment options. Additionally, orthopedic tumors, such as osteosarcoma, chondrosarcoma, and Ewing sarcoma, further complicate the treatment landscape. Current therapies, including pharmacological treatments and joint replacement, address symptoms but fail to promote true tissue regeneration. Cell-based therapies, which have shown successful clinical results in cancers and other diseases, have emerged as a promising solution to repair damaged tissues and restore function in orthopedic diseases and tumors. This review discusses the advances and potential application of cell therapy for orthopedic diseases, with a particular focus on osteoarthritis, bone fractures, cartilage degeneration, and the treatment of orthopedic tumors. We explore the potential of mesenchymal stromal cells (MSCs), chondrocyte transplantation, engineered immune cells and induced pluripotent stem cells to enhance tissue regeneration by modulating the immune response and addressing inflammation. Ultimately, the integration of cutting-edge cell therapy, immune modulation, and molecular targeting strategies could revolutionize the treatment of orthopedic diseases and tumors, providing hope for patients seeking long-term solutions to debilitating conditions.
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Affiliation(s)
- Jing Wang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Shenghao Xu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Bo Chen
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yanguo Qin
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin, China
- Joint International Research Laboratory of Ageing Active Strategy and Bionic Health in Northeast Asia of Ministry of Education, Jilin University, Changchun, Jilin, China
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Pan C, Zhou Z, Cao J, Zhang L, Cheng T, Li H, Jiang Z, Huang D, Zeng D, Luo Y, Wu J. MACC1 is a potential prognostic biomarker for cancer immunotherapy in lung adenocarcinoma. Carcinogenesis 2025; 46:bgaf015. [PMID: 40117327 DOI: 10.1093/carcin/bgaf015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/02/2025] [Accepted: 03/15/2025] [Indexed: 03/23/2025] Open
Abstract
Our team previously reported that MACC1 levels are closely related to a variety of tumors and the efficacy of immune checkpoint blockade (ICB) therapy. However, the predictive value of MACC1 levels for lung adenocarcinoma (LUAD) immunotherapy has not been studied. This study aimed to investigate the predictive effect of the oncogene MACC1 on ICB reactivity in patients with LUAD. First, the expression patterns and clinical features of MACC1 in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were comprehensively evaluated using R packages. We subsequently assessed the correlations between MACC1 and immunological characteristics in the LUAD tumor microenvironment (TME) using the CIBERSORT algorithm. The results revealed that MACC1 overexpression was significantly correlated with 3 immune checkpoints, 14 tumor-infiltrating immune cells (TIICs), 9 immunomodulators, 5 anticancer immune process activities, and 3 effector genes of TIICs in LUAD. Additionally, on the basis of the prognostic genes from LASSO analysis, we developed the MACC1-related Risk Score (MRRS), which can accurately predict the prognosis and response to cancer immunotherapy in LUAD patients (HR = 3.50, AUC at 1, 2, and 3 years = 0.737, 0.744, and 0.724, respectively). Finally, in vivo experiments revealed that the combination of MACC1 silencing and PD-L1 inhibitors significantly inhibits tumor progression. These findings increase our understanding of MACC1 as a potential prognostic biomarker and potential therapeutic target for cancer immunotherapy. The MRRS may play a critical role in predicting the response of LUAD patients to ICB therapy.
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Affiliation(s)
- Changqie Pan
- Thoracic Medicine Department 1, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283, Tongzipo Road, Yuelu District, Changsha, Hunan 410013, China
| | - Zhiyuan Zhou
- Department of Oncology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Baiyun District, Guangzhou, Guangdong 510515, China
| | - Jun Cao
- Thoracic Medicine Department 1, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283, Tongzipo Road, Yuelu District, Changsha, Hunan 410013, China
| | - Lemeng Zhang
- Thoracic Medicine Department 1, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283, Tongzipo Road, Yuelu District, Changsha, Hunan 410013, China
| | - Tianli Cheng
- Thoracic Medicine Department 1, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283, Tongzipo Road, Yuelu District, Changsha, Hunan 410013, China
| | - Haitao Li
- Thoracic Medicine Department 1, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283, Tongzipo Road, Yuelu District, Changsha, Hunan 410013, China
| | - Zhou Jiang
- Thoracic Medicine Department 1, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283, Tongzipo Road, Yuelu District, Changsha, Hunan 410013, China
| | - Danhui Huang
- Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Baiyun District, Guangzhou, Guangdong 510515, China
| | - Dongqiang Zeng
- Department of Oncology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Baiyun District, Guangzhou, Guangdong 510515, China
| | - Yongzhong Luo
- Thoracic Medicine Department 1, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283, Tongzipo Road, Yuelu District, Changsha, Hunan 410013, China
| | - Jianhua Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Baiyun District, Guangzhou, Guangdong 510515, China
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Luo L, Zhang S, Gong J, Zhang J, Xie P, Yin J, Zhang M, Zhang C, Chen H, Liu Y, Ni B, Li C, Tian Z. 3-D Sustained-Release Culture Carrier Alleviates Rat Intervertebral Disc Degeneration by Targeting STING in Transplanted Skeletal Stem Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410151. [PMID: 39985222 PMCID: PMC12005824 DOI: 10.1002/advs.202410151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 01/14/2025] [Indexed: 02/24/2025]
Abstract
The hypoxic and high-pressure microenvironment of the intervertebral discs poses a major challenge to the survival and therapeutic efficiency of exogenous stem cells. Therefore, improving the utilization efficiency and therapeutic effect of exogenous stem cells to delay intervertebral disc degeneration (IVDD) is of great importance. Here, hypoxic induction studies are conducted in vivo and in vitro using rat costal cartilage-derived skeletal stem cells (SSCs) and find that hypoxia activates the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway and increased reactive oxygen species (ROS) accumulation, triggering ferroptosis in SSCs through hypoxia-inducible factor-1 alpha-dependent mitophagy. Progressive hypoxia preconditioning reduce STING expression and ROS accumulation, inducing SSCs differentiation into nucleus pulposus-like cells via the Wnt signaling pathway. Considering this, a 3-D sustained-release culture carrier is generated by mixing SSCs with methacrylated hyaluronic acid and polydopamine nanoparticles coated with the STING inhibitor C-176 and evaluated its inhibitory effect on IVDD. This carrier is demonstrated to inhibit the cGAS/STING pathway and prevent ROS accumulation by continuously releasing C-176-coated polydopamine nanoparticles, thereby reducing ferroptosis, promoting differentiation, and ultimately attenuating IVDD, suggesting its potential as a novel treatment strategy.
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Affiliation(s)
- Liwen Luo
- Department of OrthopaedicsXinqiao HospitalArmy Medical University (Third Military Medical University)ChongqingP. R. China
- State Key Laboratory of Trauma and Chemical PoisoningArmy Medical University (Third Military Medical University)ChongqingP. R. China
| | - Shiyu Zhang
- Department of OrthopaedicsXinqiao HospitalArmy Medical University (Third Military Medical University)ChongqingP. R. China
| | - Junfeng Gong
- Department of General SurgeryThe Armed Police Corps Hospital of AnhuiHefeiP. R. China
| | - Ji Zhang
- Institute of ImmunologyPLAArmy Medical University (Third Military Medical University)ChongqingP. R. China
| | - Peng Xie
- Department of Military BiosafetyCollege of Basic MedicineArmy Medical UniversityChongqingP. R. China
| | - Jun Yin
- Department of PathophysiologyCollege of High Altitude Military MedicineArmy Military Medical UniversityChongqingP. R. China
| | - MengJie Zhang
- Department of PathophysiologyCollege of High Altitude Military MedicineArmy Military Medical UniversityChongqingP. R. China
| | - Cong Zhang
- Department of Laboratory Animal ScienceCollege of Basic MedicineArmy Medical UniversityChongqingP. R. China
| | - Hong Chen
- Department of Orthopedics903 Hospital of Joint Logistic Support Force of The People's Liberation ArmyHangzhouP. R. China
| | - Yao Liu
- Department of PharmacyDaping HospitalArmy Medical University (Third Military Medical University)ChongqingP. R. China
| | - Bing Ni
- Department of PathophysiologyCollege of High Altitude Military MedicineArmy Military Medical UniversityChongqingP. R. China
| | - Changqing Li
- Department of OrthopaedicsXinqiao HospitalArmy Medical University (Third Military Medical University)ChongqingP. R. China
- State Key Laboratory of Trauma and Chemical PoisoningArmy Medical University (Third Military Medical University)ChongqingP. R. China
| | - Zhiqiang Tian
- Institute of ImmunologyPLAArmy Medical University (Third Military Medical University)ChongqingP. R. China
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Feng Z, Zuo Y, Shen J, Zhao Q, Cao ZQ, Li X, Wang Z. Bioengineering microspheres regulating mesenchymal stem cell fate accelerate spinal cord injury therapeutics. NANO TODAY 2025; 61:102574. [DOI: 10.1016/j.nantod.2024.102574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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Kamrani S, Naseramini R, Khani P, Razavi ZS, Afkhami H, Atashzar MR, Nasri F, Alavimanesh S, Saeidi F, Ronaghi H. Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword. Cancer Cell Int 2025; 25:117. [PMID: 40140850 PMCID: PMC11948648 DOI: 10.1186/s12935-025-03741-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/08/2025] [Indexed: 03/28/2025] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy defined by the abnormal proliferation and accumulation of plasma cells (PC) within the bone marrow (BM). While multiple myeloma impacts the bone, it is not classified as a primary bone cancer. The bone marrow microenvironment significantly influences the progression of myeloma and its treatment response. Mesenchymal stromal cells (MSCs) in this environment engage with myeloma cells and other bone marrow components via direct contact and the secretion of soluble factors. This review examines the established roles of MSCs in multiple facets of MM pathology, encompassing their pro-inflammatory functions, contributions to tumor epigenetics, effects on immune checkpoint inhibitors (ICIs), influence on reprogramming, chemotherapy resistance, and senescence. This review investigates the role of MSCs in the development and progression of MM.
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Affiliation(s)
- Sina Kamrani
- Department of Orthopedic, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Reza Naseramini
- Department of Orthopedic, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Pouria Khani
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Mohammad Reza Atashzar
- Department of Immunology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzad Nasri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sajad Alavimanesh
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Farzane Saeidi
- Department of Medical Genetics, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Hossein Ronaghi
- Department of Orthopedic, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
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20
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Wang Y, Wang Z, Gao Y, Zheng T, Liu T. Healthcare Professionals' Knowledge, Attitudes, and Practices Towards Stem Cell Therapy for Sarcopenia: A Cross-Sectional Study in Beijing. J Multidiscip Healthc 2025; 18:1511-1522. [PMID: 40104762 PMCID: PMC11917437 DOI: 10.2147/jmdh.s496326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 02/28/2025] [Indexed: 03/20/2025] Open
Abstract
Background Sarcopenia significantly impacts the aging population, and this study investigates healthcare professionals' knowledge, attitudes, and practices (KAP) towards stem cell therapy for sarcopenia. Methods A cross-sectional study was conducted between January 1, 2024, and March 10, 2024, in medical institutions across Beijing. The study included healthcare professionals aged 18-70 years who completed a self-designed KAP questionnaire (Cronbach's α=0.917). Positive KAP was defined as scoring above 80% of the total score for each dimension. Results A total of 451 healthcare professionals participated in the study, with 66.7% female and 41.0% aged 40-49 years. The knowledge, attitude, and practice were 18.00 [10.00, 24.00] (possible range: 12-24), 25.00 [23.00, 30.00] (possible range: 6-30), and 21.00 [16.00, 30.00] (possible range: 7-35), respectively. Of these respondents, 13.7% were healthcare workers in the geriatrics department, who had a positive knowledge score of 22.00 [14.00, 24.00] and a positive attitude score of 29.50 [24.00, 30.00], but their practice scores remain moderate at 27.00 [20.00, 35.00]. Additionally, 140 (31.0%) had treated sarcopenia patients within six months and 277 (61.4%) were employed at public tertiary hospitals with positive knowledge. Multivariate logistic regression indicated that not having treated patients with sarcopenia in the past six months was independently associated with poor knowledge (OR = 0.30, 95% CI: [0.15, 0.62], p = 0.001). Mediating effect analysis showed that knowledge directly affected both attitude (β = 0.475, p < 0.001) and practice (β = 0.127, p = 0.004), and indirectly influenced practice through attitude (β = 0.296, p < 0.001). Conclusion Healthcare professionals exhibited inadequate knowledge, positive attitudes and inactive practices towards stem cell therapy for sarcopenia. Disease-related healthcare has positive knowledge, but moderate practice. Educational programs are essential to improve knowledge and foster proactive practices among healthcare professionals regarding stem cell therapy for sarcopenia.
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Affiliation(s)
- Yao Wang
- Geriatrics Department, Beijing Geriatric Hospital, Beijing, 100095, People's Republic of China
| | - Zhe Wang
- Rehabilitation and Geriatric Department, Beijing Tongren Hospital Mentougou Campus, Capital Medical University, Beijing, 102300, People's Republic of China
| | - Yanan Gao
- Rehabilitation Medicine Department, Beijing Geriatric Hospital, Beijing, 100095, People's Republic of China
| | - Tianru Zheng
- Geriatrics Department, Beijing Geriatric Hospital, Beijing, 100095, People's Republic of China
| | - Tingting Liu
- Geriatrics Department, Beijing Geriatric Hospital, Beijing, 100095, People's Republic of China
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21
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Liu L, Chen S, Song Y, Cui L, Chen Y, Xia J, Fan Y, Yang L, Yang L. Hydrogels empowered mesenchymal stem cells and the derived exosomes for regenerative medicine in age-related musculoskeletal diseases. Pharmacol Res 2025; 213:107618. [PMID: 39892438 DOI: 10.1016/j.phrs.2025.107618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 01/09/2025] [Accepted: 01/17/2025] [Indexed: 02/03/2025]
Abstract
As the population ages, musculoskeletal diseases (MSK) have emerged as a significant burden for individuals, healthcare systems, and social care systems. Recently, regenerative medicine has exhibited vast potential in age-related MSK, with mesenchymal stromal cells (MSCs) and their derived exosomes (Exos) therapies showing distinct advantages. However, these therapies face several limitations, including issues related to ensuring stability and effective distribution within the body. Hydrogels, acting as an ideal carrier, can enhance the therapeutic effects and application range of MSCs and Exos derived from MSCs (MSC-Exos). Therefore, this review comprehensively summarizes the application progress of MSCs and MSC-Exos combined with hydrogels in age-related MSK disease research. It aims to provide a detailed perspective, showcasing the functional enhancement of MSCs and MSC-Exos when incorporated into hydrogels. Additionally, this review explores their potential and challenges in treating age-related MSK diseases, offering references for future research directions and potential innovative strategies.
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Affiliation(s)
- Lixin Liu
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Siwen Chen
- Research Center for Biomedical Materials, Shenyang Key Laboratory of Biomedical Polymers, Engineering Research Center of Ministry of Education for Minimally Invasive Gastrointestinal Endoscopic Techniques, Shengjing Hospital of China Medical University, Shenyang 110004, PR China; Center for Molecular Science and Engineering, College of Science, Northeastern University, Shenyang 110819, PR China
| | - Yantao Song
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110002, PR China
| | - Longwei Cui
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110002, PR China
| | - Yiman Chen
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Jiangli Xia
- School of Pharmaceutical Science, Liaoning University, Shenyang 110036, PR China
| | - Yibo Fan
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Liqun Yang
- Research Center for Biomedical Materials, Shenyang Key Laboratory of Biomedical Polymers, Engineering Research Center of Ministry of Education for Minimally Invasive Gastrointestinal Endoscopic Techniques, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
| | - Lina Yang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China; Department of International Physical Examination Center, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
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22
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Wang Q, Tang X, Wang Y, Zhang D, Li X, Liu S. The role of extracellular vesicles in non-alcoholic steatohepatitis: Emerging mechanisms, potential therapeutics and biomarkers. J Adv Res 2025; 69:157-168. [PMID: 38494073 PMCID: PMC11954800 DOI: 10.1016/j.jare.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 03/19/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH), an emerging global healthcare problem, has become the leading cause of liver transplantation in recent decades. No effective therapies in the clinic have been proven due to the incomplete understanding of the pathogenesis of NASH, and further studies are expected to continue to delve into the mechanisms of NASH. Extracellular vesicles (EVs), which are small lipid membrane vesicles carrying proteins, microRNAs and other molecules, have been identified to play a vital role in cell-to-cell communication and are involved in the development and progression of various diseases. In recent years, there has been increasing interest in the role of EVs in NASH. Many studies have revealed that EVs mediate important pathological processes in NASH, and the role of EVs in NASH is distinct and variable depending on their origin cells and target cells. This review outlines the emerging mechanisms of EVs in the development of NASH and the preclinical evidence related to stem cell-derived EVs as a potential therapeutic strategy for NASH. Moreover, possible strategies involving EVs as clinical diagnostic, staging and prognostic biomarkers for NASH are summarized.
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Affiliation(s)
- Qianrong Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xiangning Tang
- Department of endocrinology, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Yu Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Danyi Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
| | - Shanshan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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23
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Rahimian S, Mirkazemi K, Kamalinejad A, Doroudian M. Exosome-based advances in pancreatic cancer: The potential of mesenchymal stem cells. Crit Rev Oncol Hematol 2025; 207:104594. [PMID: 39732301 DOI: 10.1016/j.critrevonc.2024.104594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/28/2024] [Accepted: 12/08/2024] [Indexed: 12/30/2024] Open
Abstract
Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), is one of the most challenging clinical conditions due to its late-stage diagnosis and poor survival rates. Mesenchymal stem cells (MSCs), used for targeted therapies, are being explored as a promising treatment because of their tumor-homing properties and potential contributions to the pancreatic cancer microenvironment. Understanding these interactions is crucial for developing effective treatments. In this study, we investigated how MSCs exhibit tropism towards tumors, influence the microenvironment through paracrine effects, and serve as potential drug delivery vehicles. We also examined their role in progression and therapeutic resistance in pancreatic cancer therapy. The cytotoxic effects of certain compounds on tumor cells, the use of genetically modified MSCs as drug carriers, and the potential of exosomal biomarkers like miRNAs and riRNAs for diagnosis and monitoring of pancreatic cancer were analyzed. Overall, MSC-based therapies, coupled with insights into tumor-stromal interactions, offer new avenues for improving outcomes in pancreatic cancer treatment. Additionally, the use of MSC-based therapies in clinical trials is discussed. While MSCs show promising potential for pancreatic cancer monitoring, diagnosis, and treatment, results so far have been limited.
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Affiliation(s)
- Sana Rahimian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Kimia Mirkazemi
- Faculty of Science, University of Amsterdam, Amsterdam, the Netherlands
| | - Armita Kamalinejad
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
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24
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Chiu A, Rutkowski JM, Zhang Q, Zhao F. Tissue-Engineered Therapeutics for Lymphatic Regeneration: Solutions for Myocardial Infarction and Secondary Lymphedema. Adv Healthc Mater 2025; 14:e2403551. [PMID: 39806804 PMCID: PMC11936459 DOI: 10.1002/adhm.202403551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/12/2024] [Indexed: 01/16/2025]
Abstract
The lymphatic system, which regulates inflammation and fluid homeostasis, is damaged in various diseases including myocardial infarction (MI) and breast-cancer-related lymphedema (BCRL). Mounting evidence suggests that restoring tissue fluid drainage and clearing excess immune cells by regenerating damaged lymphatic vessels can aid in cardiac repair and lymphedema amelioration. Current treatments primarily address symptoms rather than underlying causes due to a lack of regenerative therapies, highlighting the importance of the lymphatic system as a promising novel therapeutic target. Here cutting-edge research on engineered lymphatic tissues, growth factor therapies, and cell-based approaches designed to enhance lymphangiogenesis and restore lymphatic function is explored. Special focus is placed on how therapies with potential for immediate lymphatic reconstruction, originally designed for treating BCRL, can be applied to MI to augment cardiac repair and reduce heart failure risk. The integration of these novel treatments can significantly improve patient outcomes by promoting lymphatic repair, preventing pathological remodeling, and offering new avenues for managing lymphatic-associated diseases.
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Affiliation(s)
- Alvis Chiu
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, 5045 Emerging Technologies Building 3120 TAMU, College Station, TX 77843-3120
| | - Joseph M. Rutkowski
- Department of Medical Physiology, College of Medicine, Texas A&M University, Medical Research and Education Building, 8447 Riverside Pkwy, Bryan, TX 77807-3260
| | - Qixu Zhang
- Department of Plastic Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030
| | - Feng Zhao
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, 5045 Emerging Technologies Building 3120 TAMU, College Station, TX 77843-3120
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25
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Xia X, Zhou K, An LY, Zhao M, Tian BL, Zhao JY, Zhou ZG, Tong Y. Nicotinamide adenine dinucleotide rejuvenates septic bone marrow mesenchymal stem cells. World J Stem Cells 2025; 17:96893. [DOI: 10.4252/wjsc.v17.i2.96893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 11/19/2024] [Accepted: 01/16/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage. However, the impact of sepsis on the bone marrow, particularly on bone marrow mesenchymal stem cells (BMSCs), is less reported. BMSCs are critical stromal cells in the bone marrow microenvironment that maintain bone stability and hematopoietic homeostasis; however, the impairment caused by sepsis remains unknown.
AIM To investigate the effects of sepsis on BMSCs and the underlying mechanisms.
METHODS BMSCs were obtained from healthy donors and patients with sepsis. We compared the self-renewal capacity, differentiation potential, and hematopoietic supportive ability in vitro. Senescence of septic BMSCs was assessed using β-galactosidase staining, senescence-associated secretory phenotype, intracellular reactive oxygen species levels, and the expression of P16 and P21. Finally, the changes in septic BMSCs after nicotinamide adenine dinucleotide (NAD) treatment were evaluated.
RESULTS Septic BMSCs showed decreased proliferation and self-renewal, bias towards adipogenic differentiation, and weakened osteogenic differentiation. Additionally, hematopoietic supportive capacity declines in sepsis. The levels of aging markers were significantly higher in the septic BMSCs. After NAD treatment, the proliferation capacity of septic BMSCs showed a recovery trend, with increased osteogenic and hematopoietic supportive capacities. Sepsis resulted in decreased expression of sirtuin 3 (SIRT3) in BMSCs, whereas NAD treatment restored SIRT3 expression, enhanced superoxide dismutase enzyme activity, reduced intracellular reactive oxygen species levels, maintained mitochondrial stability and function, and ultimately rejuvenated septic BMSCs.
CONCLUSION Sepsis accelerates the aging of BMSCs, as evidenced by a decline in self-renewal and osteogenic capabilities, as well as weakened hematopoietic support functions. These deficiencies can be effectively reversed via the NAD/SIRT3/superoxide dismutase pathway.
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Affiliation(s)
- Xin Xia
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Kun Zhou
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Lin-Ying An
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Min Zhao
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Bin-Le Tian
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jin-Yan Zhao
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zhi-Gang Zhou
- Department of Critical Care Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China
| | - Yin Tong
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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Fang C, Zeng Z, Ye J, Ni B, Zou J, Zhang G. Progress of mesenchymal stem cells affecting extracellular matrix metabolism in the treatment of female stress urinary incontinence. Stem Cell Res Ther 2025; 16:95. [PMID: 40001265 PMCID: PMC11863768 DOI: 10.1186/s13287-025-04220-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Stress urinary incontinence (SUI) is a prevalent pelvic floor dysfunction in women post-pregnancy. Currently, conservative treatment options have low success rates, while surgical interventions often result in multiple complications. The altered state of the extracellular matrix (ECM) is a pivotal factor in the onset of various diseases and likely plays a significant role in the pathogenesis of SUI, particularly through changes in collagen and elastin levels. Recent advances in mesenchymal stem cells (MSCs) therapy have shown considerable promise in treating SUI by modulating ECM remodeling, thereby enhancing the supportive tissues of the female pelvic floor. MSCs exhibit substantial potential in enhancing urethral sphincter function, modulating connective tissue architecture, and stimulating fibroblast activity. They play a pivotal role in the reconstruction and functional recovery of the ECM by influencing various signaling pathways, including TGF-β/SMAD, JAK/STAT, Wnt/β-catenin, PI3K/AKT, and ERK/MAPK. We have reviewed the advancements in MSC-mediated ECM metabolism in SUI and, by integrating the functions of ECM in other diseases and how MSCs can ameliorate conditions through their impact on ECM metabolism, we have projected the future trajectory of SUI treatment development.
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Affiliation(s)
- Chunyun Fang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Zitao Zeng
- First Clinical College of Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Bin Ni
- Department of Pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Junrong Zou
- Department of Urology, Institute of Urology, First Affiliated Hospital of Gannan Medical University, Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, No. 128, Jinling Road, Zhanggong District, Ganzhou, Jiangxi, 341000, China
| | - Guoxi Zhang
- Department of Urology, Institute of Urology, First Affiliated Hospital of Gannan Medical University, Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, No. 128, Jinling Road, Zhanggong District, Ganzhou, Jiangxi, 341000, China.
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Wang R, Fu J, He J, Wang X, Xing W, Liu X, Yao J, Ye Q, He Y. Apoptotic mesenchymal stem cells and their secreted apoptotic extracellular vesicles: therapeutic applications and mechanisms. Stem Cell Res Ther 2025; 16:78. [PMID: 39985021 PMCID: PMC11846181 DOI: 10.1186/s13287-025-04211-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 01/30/2025] [Indexed: 02/23/2025] Open
Abstract
Mesenchymal stem cells (MSCs), an accessible and less ethically controversial class of adult stem cells, have demonstrated significant efficacy in treating a wide range of diseases in both the preclinical and clinical phases. However, we do not yet have a clear understanding of the mechanisms by which MSCs exert their therapeutic effects in vivo. We found that the transplanted MSCs go an apoptotic fate within 24 h in vivo irrespective of the route of administration. Still, the short-term survival of MSCs do not affect their long-term therapeutic efficacy. An increasing number of studies have demonstrated that transplantation of apoptotic MSCs (ApoMSCs) show similar or even better efficacy than viable MSCs, including a variety of preclinical disease models such as inflammatory diseases, skin damage, bone damage, organ damage, etc. Although the exact mechanism has yet to be explored, recent studies have shown that transplanted MSCs undergo apoptosis in vivo and are phagocytosed by phagocytes, thereby exerting immunomodulatory effects. The apoptotic extracellular vesicles secreted by ApoMSCs (MSC-ApoEVs) play a significant role in promoting immunomodulation, endogenous stem cell regeneration, and angiogenesis due to their apoptotic properties and inheritance of molecular characteristics from their parental MSCs. On this basis, this review aims to deeply explore the therapeutic applications and mechanisms of ApoMSCs and their secretion of MSC-ApoEVs, as well as the challenges they face.
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Affiliation(s)
- Ruoxuan Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Jiao Fu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Jihui He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Xinxin Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Wenbo Xing
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Xiaojing Liu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Juming Yao
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Qingsong Ye
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China.
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China.
- Department of Stomatology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China.
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Li L, He Y, Zhao J, Yin H, Feng X, Fan X, Wu W, Lu Q. Mesenchymal Stromal Cell-Based Therapy: A Promising Approach for Autoimmune Diseases. Clin Rev Allergy Immunol 2025; 68:21. [PMID: 39982546 DOI: 10.1007/s12016-025-09030-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
Autoimmune diseases are characterized by immune dysregulation, resulting in aberrant reactivity of T cells and antibodies to self-antigens, leading to various patterns of inflammation and organ dysfunction. However, current therapeutic agents exhibit broad-spectrum activity and lack disease-specific selectivity, leading to enduring adverse effects, notably severe infections, and malignancies, and patients often fail to achieve the intended clinical goals. Mesenchymal stromal cells (MSCs) are multipotent stromal cells that can be easily derived from various tissues, such as adipose tissue, umbilical cords, Wharton's jelly, placenta, and dental tissues. MSCs offer advantages due to their immunomodulatory and anti-inflammatory abilities, low immunogenicity, and a high capacity for proliferation and multipotent differentiation, making them excellent candidates for cell-based treatment in autoimmune disorders. This review will cover preclinical studies and clinical trials involving MSCs in autoimmune diseases, as well as the primary challenges associated with the clinical application of MSC therapies and strategies for maximizing their therapeutic potential.
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Affiliation(s)
- Liming Li
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yong He
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Junpeng Zhao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China
| | - Huiqi Yin
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xiwei Feng
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xinyu Fan
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Wei Wu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Qianjin Lu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
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Feng Z, Yang Y, Liu XZ, Sun HJ, Wen BY, Chen Z, Wei B. Application of cell therapy in rheumatoid Arthritis: Focusing on the immunomodulatory strategies of Mesenchymal stem cells. Int Immunopharmacol 2025; 147:114017. [PMID: 39778278 DOI: 10.1016/j.intimp.2025.114017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 12/24/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025]
Abstract
Rheumatoid arthritis (RA) is a common chronic autoimmune disease that primarily affects the joints, leading to synovial inflammation and hyperplasia, which subsequently causes joint pain, swelling, and damage. The microenvironment of RA is characterized by hypoxia, high reactive oxygen species (ROS), low pH, and levels of high inflammatory factors. Traditional treatments only partially alleviate symptoms and often cause various adverse reactions with long-term use. Therefore, there is an urgent need for safer and more effective treatments. In recent years, mesenchymal stem cells (MSCs) have shown significant potential in treating RA due to their diverse immunomodulatory mechanisms. MSCs paracrine a variety of soluble factors to improve the inflammatory microenvironment in RA patients by inhibiting T cell proliferation or inducing T cell differentiation to regulatory T cells (Tregs), inhibiting B cell proliferation and differentiation and immunoglobulin production, prompting macrophage polarization toward an anti-inflammatory phenotype, and inhibiting neutrophil recruitment and preventing the maturation of dendritic cells (DCs). This review summarizes the immunomodulatory effects of MSCs in RA and their application in animal models and clinical trials. Although the immunomodulatory mechanisms of MSCs are not yet fully elucidated, their significant potential in RA treatment has been widely recognized. Future research should further explore the immunomodulatory mechanisms of MSCs and optimize their functions in different pathological microenvironments to develop more effective and safer therapeutic strategies.
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Affiliation(s)
- Zhi Feng
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Ying Yang
- Department of Specialty Medicine, School of Public Health, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiang-Zhuo Liu
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Hui-Jiao Sun
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Bo-Ya Wen
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Zhi Chen
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Bo Wei
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China.
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Wang S, Shi G, Duan K, Yin Y, Li T. Extraembryonic mesoderm cells derived from human embryonic stem cells rely on Wnt pathway activation. Cell Prolif 2025; 58:e13761. [PMID: 39385268 PMCID: PMC11839190 DOI: 10.1111/cpr.13761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 10/12/2024] Open
Abstract
Extraembryonic mesoderm cells (EXMCs) are involved in the development of multiple embryonic lineages and umbilical cord formation, where they subsequently develop into mesenchymal stem cells (MSCs). Although EXMCs can be generated from human naïve embryonic stem cells (ESCs), it is unclear whether human primed ESCs (hpESCs) can differentiate into EXMCs that subsequently produce MSCs. The present report described a three-dimensional differentiation protocol to induce hpESCs into EXMCs by activating the Wnt pathway using CHIR99021. Single-cell transcriptome and immunostaining analyses revealed that the EXMC characteristics were similar to those of post-implantation embryonic EXMCs. Cell sorting was used to purify and expand the EXMCs. Importantly, these EXMCs secreted extracellular matrix proteins, including COL3A1 and differentiated into MSCs. Inconsistent with other MSC types, these MSCs exhibited a strong differentiation potential for chondrogenic and osteogenic cells and lacked adipocyte differentiation. Together, these findings provided a protocol to generate EXMCs and subsequent MSCs from hpESCs.
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Affiliation(s)
- Si‐Le Wang
- State Key Laboratory of Primate Biomedical Research; Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnanChina
- Yunnan Key Laboratory of Primate Biomedical ResearchKunmingYunnanChina
| | - Gao‐Hui Shi
- State Key Laboratory of Primate Biomedical Research; Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnanChina
- Yunnan Key Laboratory of Primate Biomedical ResearchKunmingYunnanChina
| | - Kui Duan
- Department of Anatomy, College of Preclinical MedicineDali UniversityDaliYunnanChina
| | - Yu Yin
- State Key Laboratory of Primate Biomedical Research; Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnanChina
- Yunnan Key Laboratory of Primate Biomedical ResearchKunmingYunnanChina
| | - Tianqing Li
- State Key Laboratory of Primate Biomedical Research; Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnanChina
- Yunnan Key Laboratory of Primate Biomedical ResearchKunmingYunnanChina
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Liu H, Ji M, Yang T, Zou S, Qiu X, Zhan F, Chen J, Yan F, Ding F, Li P. Regulation of fibroblast phenotype in osteoarthritis using CDKN1A-loaded copper sulfide nanoparticles delivered by mesenchymal stem cells. Am J Physiol Cell Physiol 2025; 328:C679-C698. [PMID: 39819042 DOI: 10.1152/ajpcell.00573.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/26/2024] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
This study aimed to investigate the regulation of fibroblast phenotypes by mesenchymal stem cells (MSCs) delivering copper sulfide (CuS) nanoparticles (NPs) loaded with CDKN1A plasmids and their role in cartilage repair during osteoarthritis (OA). Single-cell RNA sequencing data from the GEO database were analyzed to identify subpopulations within the OA immune microenvironment. Quality control, filtering, principal component analysis (PCA) dimensionality reduction, and tSNE clustering were performed to obtain detailed cell subtypes. Pseudotime analysis was used to understand the developmental trajectory of fibroblasts, and GO/KEGG enrichment analyses highlighted biological processes related to fibroblast function. Transcriptomic data and WGCNA identified CDKN1A as a key regulatory gene. A biomimetic CuS@CDKN1A nanosystem was constructed and loaded into MSCs to create MSCs@CuS@CDKN1A. The characterization of this system confirmed its efficient cellular uptake by fibroblasts. In vitro experiments demonstrated that MSCs@CuS@CDKN1A significantly modulated fibroblast phenotypes and improved the structure, proliferation, reduced apoptosis, and enhanced migration of IL-1β-stimulated chondrocytes. In vivo, an OA mouse model was treated with intra-articular injections of MSCs@CuS@CDKN1A. Micro-CT scans revealed a significant reduction in osteophyte formation and improved joint space compared with control groups. Histological analysis, including H&E, Safranin O-Fast Green, and toluidine blue staining, confirmed improved cartilage integrity, whereas the International Osteoarthritis Research Society (OARSI) scoring indicated reduced disease severity. Immunofluorescence showed upregulated CDKN1A expression, decreased MMP13, and reduced α-SMA expression in fibroblast subtypes. Major organs exhibited no signs of toxicity, confirming the biocompatibility and safety of the treatment. These findings suggest that MSCs@CuS@CDKN1A can effectively regulate fibroblast activity and promote cartilage repair, providing a promising therapeutic strategy for OA treatment.NEW & NOTEWORTHY This study introduces MSCs@CuS@CDKN1A, a nanoengineered MSC platform that targets fibroblast phenotypes in osteoarthritis (OA). By modulating CDKN1A expression, this innovative approach not only enhances cartilage repair but also effectively mitigates fibroblast-driven inflammation, marking a significant advancement in OA therapeutics with demonstrated efficacy and biocompatibility.
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Affiliation(s)
- Hong Liu
- Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing, People's Republic of China
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
| | - Ming Ji
- Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing, People's Republic of China
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
| | - Tao Yang
- Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing, People's Republic of China
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
| | - Shihua Zou
- Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing, People's Republic of China
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
| | - Xingan Qiu
- Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing, People's Republic of China
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
| | - Fangbiao Zhan
- Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing, People's Republic of China
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
- School of Medicine, Chongqing University, Chongqing, People's Republic of China
| | - Jian Chen
- Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing, People's Republic of China
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
- School of Medicine, Chongqing University, Chongqing, People's Republic of China
| | - Fei Yan
- Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, People's Republic of China
- School of Medicine, Chongqing University, Chongqing, People's Republic of China
| | - Fan Ding
- Department of Orthopedics, General Hospital of Central Theater Command, Wuhan, People's Republic of China
| | - Ping Li
- Division of Orthopedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
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Wang Y, Pang X, Li R, Chen J, Wen C, Zhu H, Long T, Li J, Zheng L, Deng Y, Zheng J, Xu B. Mesenchymal Stem Cells Carrying Viral Fusogenic Protein p14 to Treat Solid Tumors by Inducing Cell-Cell Fusion and Immune Activation. RESEARCH (WASHINGTON, D.C.) 2025; 8:0594. [PMID: 39872128 PMCID: PMC11770199 DOI: 10.34133/research.0594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/29/2025]
Abstract
Background: Chimeric antigen receptor (CAR)-based immune cell therapies attack neighboring cancer cells after receptor recognition but are unable to directly affect distant tumor cells. This limitation may contribute to their inefficiency in treating solid tumors, given the restricted intratumoral infiltration and immunosuppressive tumor microenvironment. Therefore, cell-cell fusion as a cell-killing mechanism might develop a novel cytotherapy aimed at improving the efficacy against solid tumors. Methods: We constructed a fusogenic protein, fusion-associated small transmembrane (FAST) p14 of reptilian reovirus, into cancer cells and mesenchymal stem cells (MSCs), which cocultured with various colon cancer cells and melenoma cells to validate its ability to induce cell fusion and syncytia formation. RNA sequencing, quantitative reverse transcription polymerase chain reaction, and Western blot were performed to elucidate the mechanism of syncytia death. Cell viability assay was employed to assess the killing effects of MSCs carrying the p14 protein (MSCs-p14), which was also identified in the subcutaneous tumor models. Subsequently, the Tet-On system was introduced to enhance the controllability and safety of therapy. Results: Cancer cells incorporated with fusogenic protein p14 FAST from reovirus fused together to form syncytia and subsequently died through apoptosis and pyroptosis. MSCs-p14 cocultured with different cancer cells and effienctly induced cancer cell fusion and caused widespread cancer cell death in vitro. In mouse tumor models, mMSCs-p14 treatment markedly suppressed tumor growth and also enhanced the activity of natural killer cells and macrophages. Controllability and safety of MSCs-p14 therapy were further improved by introducing the tetracycline-controlled transcriptional system. Conclusion: MSC-based cytotherapy carrying viral fusogenic protein in this study kills cancer cells by inducing cell-cell fusion. It has demonstrated definite efficacy in treating solid tumors and is worth considering for clinical development.
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Affiliation(s)
- Yao Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xunlei Pang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Department of Gastroenterology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Ruirui Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jiuzhou Chen
- Department of Radiation Oncology, the Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Chen Wen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Huihuang Zhu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Tingyu Long
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jianjie Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Lijun Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Youcai Deng
- Department of Clinical Hematology,
College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing 400038, China
| | - Junnian Zheng
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Bo Xu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
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Kareem RA, Sameer HN, Yaseen A, Athab ZH, Adil M, Ahmed HH. A review of the immunomodulatory properties of mesenchymal stem cells and their derived extracellular vesicles in small-cell and non-small-cell lung cancer cells. Int Immunopharmacol 2025; 146:113848. [PMID: 39689606 DOI: 10.1016/j.intimp.2024.113848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 12/19/2024]
Abstract
Among the most challenging diseases to treat is lung cancer (LC). While immunotherapy has a checkered history, it has lately shown great promise in the treatment of LC, and interest in this promising new approach is on the rise around the globe. Immunotherapy using mesenchymal stem cells (MSCs) is gaining popularity. Regenerative medicine, cell therapy, and immune modulation are three areas that have shown significant interest in MSCs. More than that, MSCs have recently attracted attention as potential anti-cancer drug delivery vehicles due to their inherent ability to go home to tumor locations. Making MSCs a double-edged sword in the fight against neoplastic illnesses, they are also known to impart pro-oncogenic properties. Additionally, multiple studies have proposed extracellular vesicles (EVs) secreted by MSCs as a potential therapeutic agent or method for delivering anti-cancer drugs. However, there has been conflicting evidence regarding the impact of MSCs or MSC-EV on the behavior of cancer cells, and the exact mechanism for this effect is still unknown. Our research has focused on MSCs and their key characteristics, such as their immunomodulatory capabilities for cancer therapy. Our research has also explored the potential of MSCs and their derivatives to treat small-cell and non-small-cell lung cancers (NSCLC and SCLC, respectively) by leveraging MSCs' immunomodulatory characteristics. At the end of this article, we covered the pros and cons of this therapy procedure, as well as what researchers want to do in the future to make it more suitable for clinical application in LC treatment.
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Affiliation(s)
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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Shao Y, Du Y, Chen Z, Xiang L, Tu S, Feng Y, Hou Y, Kou X, Ai H. Mesenchymal stem cell-mediated adipogenic transformation: a key driver of oral squamous cell carcinoma progression. Stem Cell Res Ther 2025; 16:12. [PMID: 39849541 PMCID: PMC11755832 DOI: 10.1186/s13287-025-04132-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/08/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Interaction between mesenchymal stem cells (MSCs) and oral squamous cell carcinoma (OSCC) cells plays a major role in OSCC progression. However, little is known about adipogenic differentiation alteration in OSCC-derived MSCs (OSCC-MSCs) and how these alterations affect OSCC growth. METHODS MSCs were successfully isolated and cultured from normal gingival tissue, OSCC peritumoral tissue, and OSCC tissue. This included gingiva-derived MSCs (GMSCs), OSCC adjacent noncancerous tissues-derived MSCs (OSCCN-MSCs), and OSCC-MSCs. The adipogenic and osteogenic differentiation capabilities of these cells were evaluated using Oil Red O and Alizarin Red S staining, respectively. OSCC cells were then co-cultured with either OSCC-MSCs or GMSCs to assess the impact on OSCC cell proliferation and migration. Subcutaneous xenograft experiments were conducted in BALB/c-nu mice to further investigate the effects in vivo. Additionally, immunohistochemical staining was performed on clinical samples to determine the expression levels of fatty acid synthase (FASN) and the proliferation marker Ki67. RESULTS OSCC-MSCs exhibited enhanced adipogenic differentiation and reduced osteogenic differentiation compared to GMSCs. OSCC-MSCs significantly increased the proliferation and migration of OSCC cells relative to GMSCs and promoted tumor growth in mouse xenografts. Lipid droplet accumulation in the stroma was significantly more pronounced in OSCC + OSCC-MSCs xenografts compared to OSCC + GMSCs xenografts. Free fatty acids (FFAs) levels were elevated in OSCC tissues compared to normal gingival tissues. Moreover, OSCC-MSCs consistently secreted higher levels of FFAs in condition medium than GMSCs. Knockdown of FASN in OSCC-MSCs reduced their adipogenic potential and inhibited their ability to promote OSCC cell proliferation and migration. Clinical sample analysis confirmed higher FASN expression in OSCC stroma, correlating with larger tumor size and increased Ki67 expression in cancer tissues, and was associated with poorer overall survival. CONCLUSIONS OSCC-MSCs promoted OSCC proliferation and migration by upregulating FASN expression and facilitating FFAs secretion. Our results provide new insight into the mechanism of OSCC progression and suggest that the FASN of OSCC-MSCs may be potential targets of OSCC in the future.
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Affiliation(s)
- Yiting Shao
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yu Du
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Zheng Chen
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Lei Xiang
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Shaoqin Tu
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yi Feng
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yuluan Hou
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaoxing Kou
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China.
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
| | - Hong Ai
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
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Zhang H, Wu B, Wang Y, Du H, Fang L. Extracellular Vesicles as Mediators and Potential Targets in Combating Cancer Drug Resistance. Molecules 2025; 30:498. [PMID: 39942602 PMCID: PMC11819960 DOI: 10.3390/molecules30030498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/12/2024] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Extracellular vesicles (EVs) are key mediators in the communication between cancer cells and their microenvironment, significantly influencing drug resistance. This review provides a comprehensive analysis of the roles of EVs in promoting drug resistance through mechanisms such as drug efflux, apoptosis resistance, autophagy imbalance, and tumor microenvironment modulation. Despite extensive research, details of EVs biogenesis, cargo selection, and specific pathways in EVs-mediated drug resistance are not fully understood. This review critically examines recent advancements, highlighting key studies that elucidate the molecular mechanisms of EVs functions. Additionally, innovative therapeutic strategies targeting EVs are explored, including inhibiting EVs biogenesis, engineering EVs for drug delivery, and identifying resistance-inhibiting molecules within EVs. By integrating insights from primary research and proposing new directions for future studies, this review aims to advance the understanding of EVs in cancer biology and foster effective interventions to mitigate drug resistance in cancer therapy.
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Affiliation(s)
- Haodong Zhang
- College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, China; (H.Z.); (H.D.)
| | - Bohan Wu
- Westa College, Southwest University, Chongqing 400715, China; (B.W.); (Y.W.)
| | - Yanheng Wang
- Westa College, Southwest University, Chongqing 400715, China; (B.W.); (Y.W.)
| | - Huamao Du
- College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, China; (H.Z.); (H.D.)
| | - Liaoqiong Fang
- College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, China; (H.Z.); (H.D.)
- National Engineering Research Center of Ultrasound Medicine, Chongqing 401121, China
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Gonzalez-Rubio J, Zeevaert K, Buhl EM, Schedel M, Jockenhoevel S, Cornelissen CG, Wagner W, Thiebes AL. iPSC-derived mesenchymal stromal cells stimulate neovascularization less than their primary counterparts. Life Sci 2025; 361:123298. [PMID: 39647809 DOI: 10.1016/j.lfs.2024.123298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/29/2024] [Accepted: 12/02/2024] [Indexed: 12/10/2024]
Abstract
AIMS Mesenchymal stromal cells (MSCs) are being tested and accepted as a source for cell therapy worldwide. However, the advanced age of the patients, together with the difficulties in achieving the required cell amounts, impede autologous treatments. Reprogramming of MSCs into induced pluripotent stem cells (iPSCs), followed by re-differentiation to MSCs has emerged as a promising and safe method to facilitate the cell expansion and the removal of aging-associated characteristics. However, the effect of reprogramming on the MSC's pro-angiogenicity is poorly understood. MATERIALS AND METHODS In this study, we use a microfluidic organ-on-a-chip platform designed for vascularization assays to study and compare the effects of bone marrow MSCs (BM-MSCs) and iPSC-derived MSCs (iMSCs) in stimulating the formation of vessels by endothelial cells. Cells were loaded in fibrin hydrogels, injected into the microfluidic channel, and grown for ten days. KEY FINDINGS Fluorescence microscopy revealed that BM-MSCs promote the formation of long and interconnected endothelial vessels, while iMSCs barely stimulate neoangiogenesis. This was further confirmed and explained by bulk RNA sequencing, showing a decrease of pro-angiogenic agents in both of the iMSCs co-cultures. Furthermore, transmission electron microscopy revealed that BM-MSCs closely associate with the new vessels as perivascular cells, while iMSCs just remain in proximity. SIGNIFICANCE These results highlight iMSCs as a promising substitute for BM-MSCs in the treatment of diseases with pernicious vascularization, such as osteoarthritis, ocular degeneration, and cancer.
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Affiliation(s)
- Julian Gonzalez-Rubio
- Department of Biohybrid & Medical Textiles (BioTex), AME - Institute of Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University, 52074 Aachen, Germany
| | - Kira Zeevaert
- Institute of Stem Cell Biology, Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, 52074 Aachen, Germany
| | - Eva Miriam Buhl
- Institute of Pathology, Electron Microscopy Facility, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Michaela Schedel
- Department of Pulmonary Medicine, University Medicine Essen-Ruhrlandklinik, 45239 Essen, Germany; Department of Pulmonary Medicine, University Medicine Essen, 45147 Essen, Germany
| | - Stefan Jockenhoevel
- Department of Biohybrid & Medical Textiles (BioTex), AME - Institute of Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University, 52074 Aachen, Germany
| | - Christian G Cornelissen
- Department of Biohybrid & Medical Textiles (BioTex), AME - Institute of Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University, 52074 Aachen, Germany; Clinic for Pneumology and Internal Intensive Care Medicine (Medical Clinic V), RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Wolfgang Wagner
- Institute of Stem Cell Biology, Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, 52074 Aachen, Germany
| | - Anja Lena Thiebes
- Department of Biohybrid & Medical Textiles (BioTex), AME - Institute of Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University, 52074 Aachen, Germany.
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Li J, Wang J, Chen Z. Emerging role of exosomes in cancer therapy: progress and challenges. Mol Cancer 2025; 24:13. [PMID: 39806451 PMCID: PMC11727182 DOI: 10.1186/s12943-024-02215-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 12/25/2024] [Indexed: 01/16/2025] Open
Abstract
This review highlights recent progress in exosome-based drug delivery for cancer therapy, covering exosome biogenesis, cargo selection mechanisms, and their application across multiple cancer types. As small extracellular vesicles, exosomes exhibit high biocompatibility and low immunogenicity, making them ideal drug delivery vehicles capable of efficiently targeting cancer cells, minimizing off-target damage and side effects. This review aims to explore the potential of exosomes in cancer therapy, with a focus on applications in chemotherapy, gene therapy, and immunomodulation. Additionally, challenges related to exosome production and standardization are analyzed, highlighting the importance of addressing these issues for their clinical application. In conclusion, exosome-based drug delivery systems offer promising potential for future cancer therapies. Further research should aim to enhance production efficiency and facilitate clinical translation, paving the way for innovative cancer treatment strategies.
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Affiliation(s)
- Jiale Li
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, 570208, China
| | - Jiachong Wang
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, 570208, China.
| | - Zigui Chen
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, 570208, China.
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Feng QS, Shan XF, Yau V, Cai ZG, Xie S. Facilitation of Tumor Stroma-Targeted Therapy: Model Difficulty and Co-Culture Organoid Method. Pharmaceuticals (Basel) 2025; 18:62. [PMID: 39861125 PMCID: PMC11769033 DOI: 10.3390/ph18010062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 12/28/2024] [Accepted: 01/05/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Tumors, as intricate ecosystems, comprise oncocytes and the highly dynamic tumor stroma. Tumor stroma, representing the non-cancerous and non-cellular composition of the tumor microenvironment (TME), plays a crucial role in oncogenesis and progression, through its interactions with biological, chemical, and mechanical signals. This review aims to analyze the challenges of stroma mimicry models, and highlight advanced personalized co-culture approaches for recapitulating tumor stroma using patient-derived tumor organoids (PDTOs). Methods: This review synthesizes findings from recent studies on tumor stroma composition, stromal remodeling, and the spatiotemporal heterogeneities of the TME. It explores popular stroma-related models, co-culture systems integrating PDTOs with stromal elements, and advanced techniques to improve stroma mimicry. Results: Stroma remodeling, driven by stromal cells, highlights the dynamism and heterogeneity of the TME. PDTOs, derived from tumor tissues or cancer-specific stem cells, accurately mimic the tissue-specific and genetic features of primary tumors, making them valuable for drug screening. Co-culture models combining PDTOs with stromal elements effectively recreate the dynamic TME, showing promise in personalized anti-cancer therapy. Advanced co-culture techniques and flexible combinations enhance the precision of tumor-stroma recapitulation. Conclusions: PDTO-based co-culture systems offer a promising platform for stroma mimicry and personalized anti-cancer therapy development. This review underscores the importance of refining these models to advance precision medicine and improve therapeutic outcomes.
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Affiliation(s)
- Qiu-Shi Feng
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Xiao-Feng Shan
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Vicky Yau
- Division of Oral and Maxillofacial Surgery, Columbia Irving Medical Center, New York City, NY 10027, USA;
| | - Zhi-Gang Cai
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Shang Xie
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
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Baran Z, Çetinkaya M, Baran Y. Mesenchymal Stem Cells in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:149-177. [PMID: 39470980 DOI: 10.1007/5584_2024_824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/01/2024]
Abstract
The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies.
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Affiliation(s)
- Züleyha Baran
- Laboratory of Molecular Pharmacology, Department of Pharmacology, Anadolu University, Eskişehir, Turkey
| | - Melisa Çetinkaya
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey
| | - Yusuf Baran
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
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Cao Y, Zhao X, Miao Y, Wang X, Deng D. How the Versatile Self-Assembly in Drug Delivery System to Afford Multimodal Cancer Therapy? Adv Healthc Mater 2025; 14:e2403715. [PMID: 39587000 DOI: 10.1002/adhm.202403715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/04/2024] [Indexed: 11/27/2024]
Abstract
The rapid development of self-assembly technology during the past few decades has effectively addressed plenty of the issues associated with carrier-based drug delivery systems, such as low loading efficiency, complex fabrication processes, and inherent toxicity of carriers. The integration of nanoscale delivery systems with self-assembly techniques has enabled efficient and targeted self-administration of drugs, enhanced bioavailability, prolonged circulation time, and controllable drug release. Concurrently, the limitations of single-mode cancer treatment, including low bioavailability, poor therapeutic outcomes, and significant side effects, have highlighted the urgent need for multimodal combined antitumor therapies. Set against the backdrop of multimodal cancer therapy, this review summarizes the research progress and applications of a large number of self-assembled drug delivery platforms, including natural small molecule self-assembled, carrier-free self-assembled, amphiphilic polymer-based self-assembled, peptide-based self-assembled, and metal-based self-assembled nano drug delivery systems. This review particularly analyzes the latest advances in the application of self-assembled nano drug delivery platforms in combined antitumor therapies mediated by chemotherapy, phototherapy, radiotherapy, sonodynamic therapy, and immunotherapy, providing innovative research insights for further optimization and expansion of self-assembled nano drug delivery systems in the clinical translation and development of antitumor combined therapy.
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Affiliation(s)
- Yuqi Cao
- Department of Pharmaceutical Engineering and Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, China
| | - Xiaomin Zhao
- Department of Pharmaceutical Engineering and Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, China
| | - Yuhang Miao
- Department of Pharmaceutical Engineering and Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Wang
- Department of Pharmaceutical Engineering and Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, China
| | - Dawei Deng
- Department of Pharmaceutical Engineering and Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, China
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Sadeghian F, Kazemi F, Pirsadeghi A, Asadi F, Tashakori M, Yousefi-Ahmadipour A. Adipose MSCs response to breast cancer cell-derived factors in conditioned media and extracts. Cell Tissue Bank 2024; 26:6. [PMID: 39733372 DOI: 10.1007/s10561-024-10156-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 12/15/2024] [Indexed: 12/31/2024]
Abstract
Interactions between MSCs and cancer cells are complex and multifaceted and have been shown to exhibit both pro-tumor and antitumor effects. This study investigated the effects of conditioned medium (CM) and cell extract (CE) from two different ERα statuses, MCF-7 and MDA-MB-231 breast cancer cell lines, on adipose-derived mesenchymal stem cells (ASCs). Findings showed that CM and CE increased cellular metabolic activity and viability of ASCs, upregulated angiogenic factors VEGF and HIF-1α, and cytokine TGF-β expression levels. However, CM and CE treatment did not significantly affect the clonogenicity of ASCs. In addition, apoptosis-related genes caspase-3 and 9 showed differential expression patterns among the treatment groups. The findings suggest that breast cancer cell-derived factors can modulate the behavior of ASCs, highlighting their potential as a therapeutic tool in breast cancer treatment and tissue regeneration. However, it is essential to consider the potential risks associated with CM and CE treatment on ASCs, as well as the potential recruitment of ASCs by cancer tumors and the risks associated with this recruitment. Further research is needed to elucidate these potential risks and benefits.
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Affiliation(s)
- Fatemeh Sadeghian
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Faezeh Kazemi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsadeghi
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fatemeh Asadi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mahnaz Tashakori
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Aliakbar Yousefi-Ahmadipour
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
- Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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Roy NS, Kumari M, Alam K, Bhattacharya A, Kaity S, Kaur K, Ravichandiran V, Roy S. Development of bioengineered 3D patient derived breast cancer organoid model focusing dynamic fibroblast-stem cell reciprocity. PROGRESS IN BIOMEDICAL ENGINEERING (BRISTOL, ENGLAND) 2024; 7:012007. [PMID: 39662055 DOI: 10.1088/2516-1091/ad9dcb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 12/11/2024] [Indexed: 12/13/2024]
Abstract
Three-dimensional (3D) models, such as tumor spheroids and organoids, are increasingly developed by integrating tissue engineering, regenerative medicine, and personalized therapy strategies. These advanced 3Din-vitromodels are not merely endpoint-driven but also offer the flexibility to be customized or modulated according to specific disease parameters. Unlike traditional 2D monolayer cultures, which inadequately capture the complexities of solid tumors, 3D co-culture systems provide a more accurate representation of the tumor microenvironment. This includes critical interactions with mesenchymal stem/stromal cells (MSCs) and induced pluripotent stem cells (iPSCs), which significantly modulate cancer cell behavior and therapeutic responses. Most of the findings from the co-culture of Michigan Cancer Foundation-7 breast cancer cells and MSC showed the formation of monolayers. Although changes in the plasticity of MSCs and iPSCs caused by other cells and extracellular matrix (ECM) have been extensively researched, the effect of MSCs on cancer stem cell (CSC) aggressiveness is still controversial and contradictory among different research communities. Some researchers have argued that CSCs proliferate more, while others have proposed that cancer spread occurs through dormancy. This highlights the need for further investigation into how these interactions shape cancer aggressiveness. The objective of this review is to explore changes in cancer cell behavior within a 3D microenvironment enriched with MSCs, iPSCs, and ECM components. By describing various MSC and iPSC-derived 3D breast cancer models that replicate tumor biology, we aim to elucidate potential therapeutic targets for breast cancer. A particular focus of this review is the Transwell system, which facilitates understanding how MSCs and iPSCs affect critical processes such as migration, invasion, and angiogenesis. The gradient formed between the two chambers is based on diffusion, as seen in the human body. Once optimized, this Transwell model can serve as a high-throughput screening platform for evaluating various anticancer agents. In the future, primary cell-based and patient-derived 3D organoid models hold promise for advancing personalized medicine and accelerating drug development processes.
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Affiliation(s)
- Nakka Sharmila Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Mamta Kumari
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Kamare Alam
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Anamitra Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Santanu Kaity
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Kulwinder Kaur
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine a Health Sciences, Dublin, Ireland
- Department of Anatomy & Regenerative Medicine, Tissue Engineering Research Group, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Velayutham Ravichandiran
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
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Afkhami H, Yarahmadi A, Bostani S, Yarian N, Haddad MS, Lesani SS, Aghaei SS, Zolfaghari MR. Converging frontiers in cancer treatment: the role of nanomaterials, mesenchymal stem cells, and microbial agents-challenges and limitations. Discov Oncol 2024; 15:818. [PMID: 39707033 DOI: 10.1007/s12672-024-01590-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/14/2024] [Indexed: 12/23/2024] Open
Abstract
Globally, people widely recognize cancer as one of the most lethal diseases due to its high mortality rates and lack of effective treatment options. Ongoing research into cancer therapies remains a critical area of inquiry, holding significant social relevance. Currently used treatment, such as chemotherapy, radiation, or surgery, often suffers from other problems like damaging side effects, inaccuracy, and the lack of ability to clear tumors. Conventional cancer therapies are usually imprecise and ineffective and usually develop resistance to treatments and cancer recurs. Cancer patients need fresh and innovative treatment that can reduce side effects while maximizing effectiveness. In recent decades several breakthroughs in these, and other areas of medical research, have paved the way for new avenues of fighting cancer including more focused and more effective alternatives. This study reviews exciting possibilities for mesenchymal stem cells (MSCs), nanomaterials, and microbial agents in the modern realm of cancer treatment. Nanoparticles (NPs) have demonstrated surprisingly high potential. They improve drug delivery systems (DDS) significantly, enhance imaging techniques remarkably, and target cancer cells selectively while protecting healthy tissues. MSCs play a double role in tissue repair and are a vehicle for novel cancer treatments such as gene treatments or NPs loaded with therapeutic agents. Additionally, therapies utilizing microbial agents, particularly those involving bacteria, offer an inventive approach to cancer treatment. This review investigates the potential of nanomaterials, MSCs, and microbial agents in addressing the shortcomings of conventional cancer therapies. We will also discuss the challenges and limitations of using these therapeutic approaches.
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Affiliation(s)
- Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Shoroq Bostani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | - Nahid Yarian
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | | | - Shima Sadat Lesani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
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Du P, Tao X, Harati J, Shi Y, Xiao L, Li X, Pan H, Wang PY. Human platelet lysate enhances small lipid droplet accumulation of human MSCs through MAPK phosphorylation. Stem Cell Res Ther 2024; 15:473. [PMID: 39696689 DOI: 10.1186/s13287-024-04085-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Human platelet lysate (hPL) has emerged as a promising serum substitute to enhance the self-renewal and multipotency of human mesenchymal stem cells (MSCs). Despite its potential, the specific biological mechanisms by which hPL influences MSC phenotypes remain inadequately understood. METHODS We investigated the biological signaling activated by hPL in two common types of human MSCs: bone marrow-derived MSCs (BMSCs) and adipose-derived MSCs (ASCs). Cell adhesion and cell-matrix interaction were assessed through immunofluorescence staining and western blotting. The impact of hPL on lipid droplet formation in MSCs was thoroughly examined using oil red O/BODIPY staining, semi-quantitative analysis, and qRT-PCR. RNA sequencing and intracellular inhibition assays were also performed to elucidate the mechanisms by which hPL modulates MSC behavior. RESULTS MSCs cultured in hPL medium demonstrated a reduction in cell size, spreading area, and vinculin puncta, while enhancing cell proliferation and lipid droplet accumulation compared to those cultured in control media. Notably, the lipid droplets in hPL-treated MSCs were significantly smaller than those in adipocyte-like cells differentiated from MSCs, highlighting hPL's distinctive role in lipid production. Gene and protein expression profiles of hPL-treated MSCs differed from those in adipocyte-like cells. An angiogenic factor array revealed that hPL-MSCs had a distinct angiogenic factor profile compared to FBS-MSCs, with VEGF expression closely linked to HIF-1α expression. RNA-seq data identified approximately 1,900 differentially expressed genes (DEGs) between hPL-MSCs and FBS-MSCs, with enrichment in focal adhesion, ECM-receptor interaction, and PI3K-Akt/MAPK signaling pathways. Inhibition of MAPK phosphorylation significantly hampered lipid formation in hPL-MSCs, underscoring the pivotal role of MAPK signaling in hPL-driven adipogenesis. CONCLUSION This study reveals the biological mechanisms by which hPL infleunces MSC behavior and differentiation, offering new insights into its potential application in regenerative medicine and tissue engineering.
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Affiliation(s)
- Ping Du
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Xuelian Tao
- Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Javad Harati
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yue Shi
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Liang Xiao
- Department of Surgery and Oncology, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518035, China
| | - Xian Li
- Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Haobo Pan
- Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
| | - Peng-Yuan Wang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
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Rehman A, Panda SK, Torsiello M, Marigliano M, Tufano CC, Nigam A, Parveen Z, Papaccio G, La Noce M. The crosstalk between primary MSCs and cancer cells in 2D and 3D cultures: potential therapeutic strategies and impact on drug resistance. Stem Cells Transl Med 2024; 13:1178-1185. [PMID: 39418131 PMCID: PMC11631265 DOI: 10.1093/stcltm/szae077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/23/2024] [Indexed: 10/19/2024] Open
Abstract
The tumor microenvironment (TME) significantly influences cancer progression, and mesenchymal stem cells (MSCs) play a crucial role in interacting with tumor cells via paracrine signaling, affecting behaviors such as proliferation, migration, and epithelial-mesenchymal transition. While conventional 2D culture models have provided valuable insights, they cannot fully replicate the complexity and diversity of the TME. Therefore, developing 3D culture systems that better mimic in vivo conditions is essential. This review delves into the heterogeneous nature of the TME, spotlighting MSC-tumor cellular signaling and advancements in 3D culture technologies. Utilizing MSCs in cancer therapy presents opportunities to enhance treatment effectiveness and overcome resistance mechanisms. Understanding MSC interactions within the TME and leveraging 3D culture models can advance novel cancer therapies and improve clinical outcomes. Additionally, this review underscores the therapeutic potential of engineered MSCs, emphasizing their role in targeted anti-cancer treatments.
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Affiliation(s)
- Ayesha Rehman
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Sameer Kumar Panda
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Martina Torsiello
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Martina Marigliano
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana,”Via Salvador Allende, 43, Baronissi, Salerno, Italy
| | - Camilla Carmela Tufano
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Aditya Nigam
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Zahida Parveen
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Gianpaolo Papaccio
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Marcella La Noce
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
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Zou X, Brigstock D. Extracellular Vesicles from Mesenchymal Stem Cells: Potential as Therapeutics in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Biomedicines 2024; 12:2848. [PMID: 39767754 PMCID: PMC11673942 DOI: 10.3390/biomedicines12122848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 01/03/2025] Open
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the accumulation of triglycerides within hepatocytes, which can progress to more severe conditions, such as metabolic dysfunction-associated steatohepatitis (MASH), which may include progressive fibrosis, leading to cirrhosis, cancer, and death. This goal of this review is to highlight recent research showing the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in reducing the key pathogenic pathways of MASLD or MASH. Methods: Relevant published studies were identified using PubMed with one or more of the following search terms: MASLD, MASH, NAFLD, NASH, exosome, extracellular vesicle (EV), therapy, and/or mesenchymal stem cells (MSC). The primary literature were subsequently downloaded and summarized. Results: Using in vitro or in vivo models, MSC-EVs have been found to counteract oxidative stress, a significant contributor to liver injury in MASH, and to suppress disease progression, including steatosis, inflammation, and, in a few instances, fibrosis. Some of these outcomes have been attributed to specific EV cargo components including microRNAs and proteins. Thus, MSC-EVs enriched with these types of molecules may have improved the therapeutic efficacy for MASLD/MASH and represent a novel approach to potentially halt or reverse the disease process. Conclusions: MSC-EVs are attractive therapeutic agents for treating MASLD/MASH. Further studies are necessary to validate the clinical applicability and efficacy of MSC-EVs in human MASH patients, focusing on optimizing delivery strategies and identifying the pathogenic pathways that are targeted by specific EV components.
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Affiliation(s)
- Xue Zou
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - David Brigstock
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212, USA
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Li D, Yang Y, Zheng G, Meng L, Shang L, Ren J, Wang L, Bao Y. The potential of cellular homing behavior in tumor immunotherapy: from basic discoveries to clinical applications of immune, mesenchymal stem, and cancer cell homing. Front Immunol 2024; 15:1495978. [PMID: 39726590 PMCID: PMC11669694 DOI: 10.3389/fimmu.2024.1495978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 11/28/2024] [Indexed: 12/28/2024] Open
Abstract
The efficacy of immunotherapy, a pivotal approach in the arsenal of cancer treatment strategies, is contingent on the capacity of effector cells to localize at the tumor site. The navigational capacity of these cells is intricately linked to the homing behaviors of specific cell types. Recent studies have focused on leveraging immune cells and mesenchymal stem cells (MSCs) homing for targeted tumor therapy and incorporating cancer cell homing properties into anti-tumor strategies. However, research and development of immunotherapy based on cancer cell homing remain in their preliminary stages. Enhancing the homing efficiency of effector cells is essential; therefore, understanding the underlying mechanisms and addressing immune resistance within the tumor microenvironment and challenges associated with in vivo therapeutic agent delivery are essential. This review firstly delineates the discovery and clinical translation of the three principal cell-homing behaviors. Secondly, we endeavor to conduct an in-depth analysis of existing research on the homing of immune and stem cells in cancer therapy, with the aim of identifying and understanding of the common applications, potential benefits, barriers, and critical success factors of cellular homing therapies. Finally, based on the understanding of the key factors of cellular homing therapies, we provide an overview and outlook on the enormous potential of harnessing cancer cells' self-homing to treat tumors. Although immunotherapy based on cell-homing behavior warrants further research, it remains a highly competitive treatment modality that can be combined with existing classic anti-cancer therapies. In general, combining the homing properties of cells to optimize their clinical effects is also one of the future research directions in the field of cell transplantation.
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Affiliation(s)
- Dongtao Li
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yixuan Yang
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Guangda Zheng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Linghan Meng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lu Shang
- First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Juanxia Ren
- First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Lingyun Wang
- First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Yanju Bao
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Zhu XY, Liu WT, Hou XJ, Zong C, Yu W, Shen ZM, Qu SP, Tao M, Xue MM, Zhou DY, Bai HR, Gao L, Jiang JH, Zhao QD, Wei LX, Yang X, Han ZP, Zhang L. CD34 +CLDN5 + tumor associated senescent endothelial cells through IGF2-IGF2R signaling increased cholangiocellular phenotype in hepatocellular carcinoma. J Adv Res 2024:S2090-1232(24)00564-2. [PMID: 39674501 DOI: 10.1016/j.jare.2024.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 11/02/2024] [Accepted: 12/05/2024] [Indexed: 12/16/2024] Open
Abstract
INTRODUCTION The heterogeneity of hepatocellular carcinoma (HCC) is linked to tumor malignancy and poor prognosis. Nevertheless, the precise mechanisms underlying the development of the cholangiocellular phenotype (CCA) within HCC remain unclear. Emerging studies support that the cross-talk among the host cells within tumor microenvironment (TME) sustains the cancer cell plasticity. OBJECTIVES This study sought to identify the specific cell types involved in the formation of CCA and to elucidate their functional roles in the progression of HCC. METHODS Single-cell RNA sequencing was employed to identify the specific cell types involved in the formation of CCA. Both in vitro and vivo analyses were used to identify the tumor-associated senescent ECs and investigate the function in TME. The diethylnitrosamine-induced model was utilized to investigate the interaction between senescent ECs and MSCs, aiming to elucidate their synergistic contributions to the progression of CCA. RESULTS Using single-cell RNA sequencing, we identified a distinct senescent-associated subset of endothelial cells (ECs), namely CD34+CLDN5+ ECs, which mainly enriched in tumor tissue. Further, the senescent ECs were observed to secrete IGF2, which recruited mesenchymal stem cells (MSCs) into the TME through IGF2R/MAPK signaling. In primary liver cancer model, MSCs exhibited a strong tumor-promoting effect, increasing the CCA and tumor malignancy after HCC formation. Interestingly, knockdown of IGF2R expression in MSCs inhibited the increase of CCA caused by MSCs in HCC. Meanwhile, it was revealed that MSCs released multiple inflammatory and trophic-related cytokines to enhance the cancer stem cell-like characteristics in HCC cells. Finally, we demonstrated that CEBPβ up-regulated IGF2 expression in tumor senescent ECs by combining with Igf2-promtor-sequence. CONCLUSIONS Together, our findings illustrated that tumor associated senescent ECs in HCC recruited the MSCs into TME, enhancing cancer stem cell (CSC)-like features of HCC cells and contributing to the CCA formation.
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Affiliation(s)
- Xin-Yu Zhu
- Changhai Clinical Research Unit, Changhai Hospital of Naval Medical University, Shanghai, China; Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Wen-Ting Liu
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiao-Juan Hou
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Chen Zong
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Wei Yu
- Changhai Clinical Research Unit, Changhai Hospital of Naval Medical University, Shanghai, China; Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Zhe-Min Shen
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Shu-Ping Qu
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Min Tao
- Changhai Clinical Research Unit, Changhai Hospital of Naval Medical University, Shanghai, China; Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Meng-Meng Xue
- Changhai Clinical Research Unit, Changhai Hospital of Naval Medical University, Shanghai, China; Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Dao-Yu Zhou
- Changhai Clinical Research Unit, Changhai Hospital of Naval Medical University, Shanghai, China; Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Hao-Ran Bai
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu Gao
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Jing-Hua Jiang
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Qiu-Dong Zhao
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Li-Xin Wei
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
| | - Xue Yang
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China.
| | - Zhi-Peng Han
- Tumor Immunology and Metabolism Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China; Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Li Zhang
- Changhai Clinical Research Unit, Changhai Hospital of Naval Medical University, Shanghai, China.
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Iida Y, Harada M. Local cell therapy using CCL19-expressing allogeneic mesenchymal stem cells exerts robust antitumor effects by accumulating CD103 + IL-12-producing dendritic cells and priming CD8 + T cells without involving draining lymph nodes. J Immunother Cancer 2024; 12:e009683. [PMID: 39672553 DOI: 10.1136/jitc-2024-009683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2024] [Indexed: 12/15/2024] Open
Abstract
BACKGROUND Immune checkpoint blockade is a promising anticancer therapy, whereas the presence of T cells in tumor sites is indispensable for its therapeutic efficacy. To promote the infiltration of T cells and dendritic cells (DCs) into the tumor, we previously proposed a local cell therapy using chemokine (C-C motif) ligand 19 (CCL19)-expressing immortalized syngeneic immortalized mesenchymal stem cells (syn-iMSC/CCL19). However, the preparation of syngeneic/autologous MSC from individual hosts limits the clinical application of this cell therapy. METHODS In this study, we further developed a new cell therapy using allogeneic iMSC/CCL19 (allo-iMSC/CCL19) using several tumor mice models. RESULTS The allo-iMSC/CCL19 therapy exerted drastic antitumor effects, in which the host's T cells were induced to respond to allogeneic MSC. In addition, the allo-iMSC/CCL19 therapy promoted the infiltration of CD103+ interleukin (IL)-12-producing DCs and priming of CD8+ T cells at tumor sites compared with that using syn-iMSC/CCL19. The antitumor effect of allo-iMSC/CCL19 therapy was not influenced by fingolimod, a sphingosine 1-phosphate receptor modulator, implying no involvement of draining lymph nodes in the priming of tumor-specific T cells. CONCLUSION These results suggest that allo-iMSC/CCL19 therapy exerts dramatic antitumor effects by promoting the infiltration of CD103+ IL-12-producing DCs and thereby priming tumor-specific CD8+ T cells at tumor sites. This local cell therapy could be a promising approach to anticancer therapy, particularly for overcoming dysfunction in the cancer-immunity cycle.
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Affiliation(s)
- Yuichi Iida
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
| | - Mamoru Harada
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
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Liu X, Hyun Kim J, Li X, Liu R. Application of mesenchymal stem cells exosomes as nanovesicles delivery system in the treatment of breast cancer. Int J Pharm 2024; 666:124732. [PMID: 39304093 DOI: 10.1016/j.ijpharm.2024.124732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
As people's living standards continue to improve and human life span expectancy increases, the incidence and mortality rates of breast cancer are continuously rising. Early detection of breast cancer and targeted therapy for different breast cancer subtypes can significantly reduce the mortality rate and alleviate the suffering of patients. Exosomes are extracellular vesicles secreted by various cells in the body. They participate in physiological and pathological responses by releasing active substances and play an important role in regulating intercellular communication. In recent years, research on exosomes has gradually expanded, and their special membrane structure and targetable characteristics are being increasingly applied in various clinical studies. Mesenchymal stem cells (MSCs)-derived exosomes play an important role in regulating the progression of breast cancer. In this review, we summarize the current treatment methods for breast cancer, the connection between MSCs, exosomes, and breast cancer, as well as the application of exosomes derived from MSCs from different sources in cancer treatment. We highlight how the rational design of modified MSCs-derived exosomes (MSCs-Exos) delivery systems can overcome the uncertainties of stem cell therapy and overcome the clinical translation challenges of nanomaterials. This work aims to promote future research on the application of MSCs-Exos in breast cancer treatment.
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Affiliation(s)
- Xiaofan Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - June Hyun Kim
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea
| | - Xuemei Li
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China.
| | - Rui Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea.
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