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Melendez-Miranda I, Fatanmi OO, Wise SY, Petrus SA, Carpenter AD, Olsen C, Serebrenik AA, Lugo-Roman LA, Seed TM, Kaytor MD, Singh VK. Lethality Assessments for Acutely Irradiated Cynomolgus Macaques Under Subject-based Care. Radiat Res 2025; 203:304-320. [PMID: 40114472 DOI: 10.1667/rade-24-00223.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/04/2025] [Indexed: 03/22/2025]
Abstract
Well-characterized animal models of acute radiation syndrome are needed for the development of radiation medical countermeasures to mitigate injury due to acute exposure to high doses of total- or partial-body radiation. Such animal models must reveal a radiation dose- and time-dependent relationship, pathogenesis of injury, and clinical presentation similar to humans. The focus of this study was to investigate clinical responses, principally lethality patterns, of cynomolgus macaques acutely exposed to relatively high doses of total-body radiation. Such investigations are currently relevant due to the limited availability of rhesus macaques, the dominant and preferred macaque subspecies, due to limited supply and their use in other high-priority areas. In this study employing cynomolgus macaques, a preliminary dose-response relationship was determined using three different radiation doses (4.7, 5.8 and 6.5 Gy, n = 24, n = 8/radiation dose) at a dose rate of 0.6 Gy/min. Animals were provided subject-based supportive care excluding blood products and were monitored for 60 days postirradiation for survival, which was the primary endpoint and the secondary endpoint was hematopoietic recovery. The lethality curve suggested LD30/60, LD50/60, and LD70/60 values as 4.8, 5.3, and 5.8 Gy, respectively. The initial results of this study are deemed critical for future efficacy assessments of newly developed medical countermeasures for acute radiation injuries by making use of an alternative subspecies of macaques, namely cynomolgus macaques (Macaca fascicularis).
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Affiliation(s)
- Issa Melendez-Miranda
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
| | - Oluseyi O Fatanmi
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
| | - Stephen Y Wise
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
| | - Sarah A Petrus
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
| | - Alana D Carpenter
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
| | - Cara Olsen
- Preventive Medicine and Biostatistics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
| | | | - Luis A Lugo-Roman
- Department of Laboratory Animal Resources, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
| | - Thomas M Seed
- Tech Micro Services, 4417 Maple Avenue, Bethesda, Maryland 20814
| | | | - Vijay K Singh
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
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Choi M, Al Fahad MA, Shanto PC, Park SS, Lee BT. Surface modification of decellularized kidney scaffold with chemokine and AKI-CKD cytokine juice to increase the recellularization efficiency of bio-engineered kidney. Biomaterials 2025; 316:123007. [PMID: 39674100 DOI: 10.1016/j.biomaterials.2024.123007] [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: 08/09/2024] [Revised: 12/10/2024] [Accepted: 12/10/2024] [Indexed: 12/16/2024]
Abstract
Chronic kidney disease (CKD) is a prevalent global health issue, primarily caused by glomerular dysfunction, diabetes, endovascular disorders, hypertensive nephrosclerosis, and other vascular diseases. Despite the increase in available organ sources, significant challenges remain in securing organ compatibility, prompting extensive research into creating a bio-artificial kidney free from immune rejection. In this study, a bio-engineered kidney was established using a stem cell chemoattractant within a bioreactor system; rBMSCs were used to recellularize the decellularized kidney scaffold coated with SDF-1α/AKI-CKD cytokine juice under mimic-hypoxic conditions as these chemokines and cytokines are crucial for the cell migration. LC-MS/MS proteomic analysis of the scaffold suggested that it contains various important proteins related to angiogenesis, cell migration, differentiation, etc. The in-silico binding simulation and Immunohistochemical (IHC) staining were utilized to detect the coated chemokines and cytokines. Cells were administered through both ureter and arterial routes of the kidney scaffold to differentiate into epithelial and endothelial cells. After 14 days of the recellularization process utilizing a mimic-hypoxia-induced bioreactor, the SDF-1α/AKI-CKD CJ-coated kidney scaffold exhibited high levels of cell attachment, migration, and proliferation in both the cortex and medulla. Additionally, the coating of the cytokines remarkably enhanced the expression of specific renal cell markers within the complex microfilter-like tubular structures. This study underscores a recellularization strategy that addresses the challenges associated with constructing bio-artificial kidneys and contributes to the growing field of bio-artificial organ research.
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Affiliation(s)
- Minji Choi
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Md Abdullah Al Fahad
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Prayas Chakma Shanto
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Seong-Su Park
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Byong-Taek Lee
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea; Institute of Tissue Regeneration, Soonchunhyang University, Cheonan, South Korea.
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Lin H, Zhou C, Li Q, Xie Q, Xia L, Liu L, Bao W, Xiong X, Zhang H, Zheng Z, Zhao J, Liang W. Nanotechnology-Assisted mesenchymal stem cells treatment for improved cartilage regeneration: A review of current practices. Biochem Pharmacol 2025; 237:116895. [PMID: 40154890 DOI: 10.1016/j.bcp.2025.116895] [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: 11/18/2024] [Revised: 02/26/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025]
Abstract
Cartilage tissue does not promptly elicit an inflammatory response upon injury, hence constraining its capacity for healing and self-regeneration. Mesenchymal Stem Cells (MSC) therapy, enhanced by nanotechnology, offers promising advancements in cartilage repair. Injuries to cartilage often cause chronic pain, where current treatments are inadequate. As MSCs can readily differentiate into chondrocytes and secrete soluble factors, they are essential components in tissue engineering of cartilage repair. Although, like other stem cell applications, clinical applications are restricted by poor post implantation survival and differentiation. Recent studies show that nanoparticles (NPs) can further improve MSC outcomes by promoting cell adhesion, and chondrogenic differentiation allowing for sustained growth factor release. In addition, nanomaterials can improve the biological activity of MSCs, by also facilitating the composition of a conducive microenvironment for cartilage repair. In this review, the application of nanofibrous scaffolds, hydrogels and nanoscale particulate matter to improve mechanical properties in cartilage tissue engineering, are discussed. Moreover, the MSCs and nanotechnology synergistic effects present hope of overcoming the limitations of conventional treatments. Nanotechnology greatly enhances the MSC based cartilage regeneration strategies and could provide better treatment for cartilage related diseases in the future. Future research should be aimed at standardizing MSC harvesting and culturing protocols and contrasting their long-term efficacy.
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Affiliation(s)
- Hongming Lin
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Chao Zhou
- Department of Orthopedics, Zhoushan Guanghua hospital, Zhoushan 316000 Zhejiang Province, China
| | - Qingping Li
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Qiong Xie
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Linying Xia
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Lu Liu
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Wenwen Bao
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Xiaochun Xiong
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Hao Zhang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Zeping Zheng
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China
| | - Jiayi Zhao
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China.
| | - Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000 Zhejiang Province, China.
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Wang YC, Cheng JB, Feng ML. Requirements for standardizing the assessment of mesenchymal stem cell therapy and its effects on osteoarthritis. World J Orthop 2025; 16:104451. [PMID: 40124721 PMCID: PMC11924026 DOI: 10.5312/wjo.v16.i3.104451] [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: 12/23/2024] [Revised: 02/06/2025] [Accepted: 02/27/2025] [Indexed: 03/12/2025] Open
Abstract
Publications of Soufan et al and Kristjánsson et al in the World Journal of Orthopedics on mesenchymal stem cell (MSC) therapy for osteoarthritis (OA) represent a significant exploration of regenerative medicine's potential in OA treatment. In their research, it is highlighted that MSCs can alleviate OA symptoms and even regenerate cartilage, potentially reversing the disease. They also compared the efficacy of three MSC subtypes, emphasizing the therapeutic advantages of adipose-derived MSCs. MSC injections, a novel and less invasive alternative to traditional treatments such as chondrocyte transplantation or arthroplasty, have a low cost, low risks, and favorable outcomes, presenting a promising approach for OA patients. Additionally, we stressed that the efficacy evaluation criteria, heterogeneity, safety, and other factors must be carefully considered to further advance the clinical translation of MSC therapy for OA.
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Affiliation(s)
- Yu-Chen Wang
- Department of Orthopaedic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Jing-Bo Cheng
- Department of Orthopaedic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Ming-Li Feng
- Department of Orthopaedic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
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Sun GC, Xu WD, Yao H, Chen J, Chai RN. Protective effects of autologous bone marrow-derived mesenchymal stem cell transplantation on acute radioactive enteritis in Beagle dogs. World J Gastroenterol 2025; 31:97599. [PMID: 39991676 PMCID: PMC11755250 DOI: 10.3748/wjg.v31.i7.97599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 11/25/2024] [Accepted: 12/18/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Radiation enteritis is a common complication of radiation therapy in which the surrounding normal intestinal tissue is damaged by ionising radiation, and there is no standard pharmacological prophylaxis or treatment regimen available. Mesenchymal stem cell transplantation can be used for radiation protection and the treatment of acute radiation injury, but its therapeutic mechanism of action remains unclear. AIM To investigate the protective effects of autologous bone marrow-derived mesenchymal stem cell (ABMSC) transplantation on radiation-induced intestinal injury. METHODS A model of acute radioactive enteritis was established in dogs by applying abdominal intensity-modulated radiation at a single X-ray dose of 12 Gy. ABMSCs were transplanted into the mesenteric artery with the technology of femoral artery puncture and DSA imaging two days after radiation. Visual and histopathological changes of the experimental dogs were observed. Different kinds of cytokines from intestinal samples were tested using Quantibody Canine Cytokine Array method. Enzyme-linked immunosorbent assay (ELISA) was also used to evaluate the cytokines changes in serum. RESULTS The ABMSCs group showed significant improvements in survival status compared with the blank and saline treatment groups. Histological observations revealed that the former had lower histological scores than the later after treatment (P < 0.05). Compared to the control groups, interleukin (IL)-10 and monocyte chemotactic protein (MCP)-1 from intestinal samples showed a remarkable increase and ELISA of serum samples proved higher secretion of the two target cytokines in the ABMSCs group (P < 0.05). CONCLUSION Our data suggest that transplantation of ABMSCs promotes intestinal recovery after acute radioactive injury in Beagle dogs. The cytokines of IL-10 and MCP-1 might play an important role in this process.
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Affiliation(s)
- Guang-Chen Sun
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110000, Liaoning Province, China
- Department of Respiratory Medicine, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Wen-Da Xu
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Hui Yao
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Ruo-Nan Chai
- Department of Respiratory Medicine, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
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Sajjad U, Ahmed M, Iqbal MZ, Riaz M, Mustafa M, Biedermann T, Klar AS. Exploring mesenchymal stem cells homing mechanisms and improvement strategies. Stem Cells Transl Med 2024; 13:1161-1177. [PMID: 39550211 PMCID: PMC11631218 DOI: 10.1093/stcltm/szae045] [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: 07/26/2023] [Accepted: 05/16/2024] [Indexed: 11/18/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells with high self-renewal and multilineage differentiation abilities, playing an important role in tissue healing. Recent advancements in stem cell-based technologies have offered new and promising therapeutic options in regenerative medicine. Upon tissue damage, MSCs are immediately mobilized from the bone marrow and move to the injury site via blood circulation. Notably, allogenically transplanted MSCs can also home to the damaged tissue site. Therefore, MSCs hold great therapeutic potential for curing various diseases. However, one major obstacle to this approach is attracting MSCs specifically to the injury site following systemic administration. In this review, we describe the molecular pathways governing the homing mechanism of MSCs and various strategies for improving this process, including targeted stem cell administration, target tissue modification, in vitro priming, cell surface engineering, genetic modifications, and magnetic guidance. These strategies are crucial for directing MSCs precisely to the injury site and, consequently, enhancing their migration and local tissue repair properties. Specifically, our review provides a guide to improving the therapeutic efficacy of clinical applications of MSCs through optimized in vivo administration and homing capacities.
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Affiliation(s)
- Umar Sajjad
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Ahmed
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - M Zohaib Iqbal
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Mahrukh Riaz
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Muhammad Mustafa
- KAM School of Life Sciences, Forman Christian College University, Lahore, Pakistan
| | - Thomas Biedermann
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Agnes S Klar
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
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Miura Y, Fujii S, Ichinohe T. Cell-based and extracellular vesicle-based MSC therapies for acute radiation syndrome affecting organ systems. JOURNAL OF RADIATION RESEARCH 2024; 65:i80-i87. [PMID: 39679884 DOI: 10.1093/jrr/rrae009] [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: 12/05/2023] [Revised: 01/28/2024] [Indexed: 12/17/2024]
Abstract
Exposure to ionizing radiation can induce harmful biological effects on the human body, particularly in cases of high-dose γ-irradiation affecting the gastrointestinal tract, bone marrow, skin and lung. Such exposures lead to lethal outcomes as individuals experience a breakdown in their immune system's ability to defend against pathogens, predisposing them to sepsis-induced multiple organ failures. Mesenchymal stromal/stem cells (MSCs) possess diverse biological characteristics, including immunomodulation, anti-inflammation and tissue regeneration. Off-the-shelf culture-expanded human bone marrow- or adipose tissue-derived MSCs are clinically available to treat graft-versus-host disease following hematopoietic cell transplantation and perianal fistulas in Crohn's disease in Japan. While preclinical studies showcase encouraging outcomes in radiation-induced injuries, the effectiveness of MSC transplantation in addressing acute radiation syndrome affecting organs in irradiated individuals is limited. Recent studies have highlighted MSC-releasing extracellular vesicles as nanoparticle substances responsible for outlining the mechanism of action and have identified various components, including proteins and microRNA, that serve as functional molecules. MSC-releasing extracellular vesicle-based therapy emerges as a promising avenue, offering a potential solution to the challenges posed by radiation-induced injuries. However, further investigation is required, especially regarding whether MSC-releasing extracellular vesicles have regenerative effects on tissue-resident stem cells. These unresolved issues represent key aspects that need to be addressed to optimize the therapeutic potential of cell-based and extracellular vesicle-based MSC therapies for interventions in the context of radiation-induced injuries.
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Affiliation(s)
- Yasuo Miura
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
- Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, 1-93 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192, Japan
| | - Sumie Fujii
- Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, 1-93 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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Strack M, Kückelhaus J, Diebold M, Wuchter P, Huber PE, Schnell O, Sankowski R, Prinz M, Grosu AL, Heiland DH, Nicolay NH, Rühle A. Effects of tumor treating fields (TTFields) on human mesenchymal stromal cells. J Neurooncol 2024; 169:329-340. [PMID: 38900237 PMCID: PMC11341748 DOI: 10.1007/s11060-024-04740-0] [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: 05/20/2024] [Accepted: 06/10/2024] [Indexed: 06/21/2024]
Abstract
PURPOSE Mesenchymal stromal cells (MSCs) within the glioblastoma microenvironment have been shown to promote tumor progression. Tumor Treating Fields (TTFields) are alternating electric fields with low intensity and intermediate frequency that exhibit anti-tumorigenic effects. While the effects of TTFields on glioblastoma cells have been studied previously, nothing is known about the influence of TTFields on MSCs. METHODS Single-cell RNA sequencing and immunofluorescence staining were employed to identify glioblastoma-associated MSCs in patient samples. Proliferation and clonogenic survival of human bone marrow-derived MSCs were assessed after TTFields in vitro. MSC' characteristic surface marker expression was determined using flow cytometry, while multi-lineage differentiation potential was examined with immunohistochemistry. Apoptosis was quantified based on caspase-3 and annexin-V/7-AAD levels in flow cytometry, and senescence was assessed with ß-galactosidase staining. MSCs' migratory potential was evaluated with Boyden chamber assays. RESULTS Single-cell RNA sequencing and immunofluorescence showed the presence of glioblastoma-associated MSCs in patient samples. TTFields significantly reduced proliferation and clonogenic survival of human bone marrow-derived MSCs by up to 60% and 90%, respectively. While the characteristic surface marker expression and differentiation capacity were intact after TTFields, treatment resulted in increased apoptosis and senescence. Furthermore, TTFields significantly reduced MSCs' migratory capacity. CONCLUSION We could demonstrate the presence of tumor-associated MSCs in glioblastoma patients, providing a rationale to study the impact of TTFields on MSCs. TTFields considerably increase apoptosis and senescence in MSCs, resulting in impaired survival and migration. The results provide a basis for further analyses on the role of MSCs in glioblastoma patients receiving TTFields.
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Affiliation(s)
- Maren Strack
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK), partner site DKTK-Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany
| | - Jan Kückelhaus
- Department of Neurosurgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Martin Diebold
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Neurology and Medical Oncology, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Patrick Wuchter
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, German Red Cross Blood Service Baden- Württemberg- Hessen, Heidelberg University, Mannheim, Germany
| | - Peter E Huber
- Department of Molecular Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany
- Department of Radiation Oncology, University Hospital Center Heidelberg, Heidelberg, Germany
| | - Oliver Schnell
- Department of Neurosurgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roman Sankowski
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK), partner site DKTK-Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany
| | - Dieter Henrik Heiland
- Department of Neurosurgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nils H Nicolay
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK), partner site DKTK-Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany
- Department of Molecular Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany
- Department of Radiation Oncology, University of Leipzig Medical Center, Leipzig, Germany
- Comprehensive Cancer Center Central (CCCG) Germany, Partner Site Leipzig, Leipzig, Germany
| | - Alexander Rühle
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK), partner site DKTK-Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany.
- Department of Molecular Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany.
- Department of Radiation Oncology, University of Leipzig Medical Center, Leipzig, Germany.
- Comprehensive Cancer Center Central (CCCG) Germany, Partner Site Leipzig, Leipzig, Germany.
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Gharib OA, Fahmy HA, Abdou FY. Role of Olive Leaf Extract, Mesenchymal Stem Cells or Low Radiation Dose in Alleviating Hepatic Injury in Rats. Dose Response 2024; 22:15593258241289301. [PMID: 39483141 PMCID: PMC11526167 DOI: 10.1177/15593258241289301] [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: 06/14/2024] [Accepted: 08/28/2024] [Indexed: 11/03/2024] Open
Abstract
Objectives This study was conducted to determine the efficacy of mesenchymal stem cells (MSCs) or low-dose gamma radiation (LDR) on liver injury compared to the effect of olive leaf extract as a hepatoprotective agent. Methods Rats were allocated into six groups; group I served as the negative control. Group II received 5% dextran sodium sulfate (DSS) in its drinking water for 1 week. Group III was injected with a single dose of 1 × 106 bone marrow-derived mesenchymal stem cells (BM-MSCs) intravenously. Group IV was treated as in group III after 5% DSS treatment. Group V was given 5% DSS, followed by olive leaf extract (OLE) (1000 mg/ kg, oral). Group VI: 5% DSS for 1 week, then was exposed to low-dose gamma radiation (LDR) (0.05 Gy). Results Rats treated with OLE, BM-MSCs, or exposed to LDR exerted significant alleviation in all hepatic biomarkers, significant enhancements in oxidative stress parameters, and improvements in inflammatory biomarkers Interleukin-1 beta (IL-1β) and Interferon gamma (INF-γ) hepatic contents compared with those of the DSS group. Histological pictures emphasized the biochemical findings. Conclusions BM-MSCs might be a valuable therapeutic approach to overcome hepatic injury. Exposure to LDR provided protective mechanisms that allow the body to survive better.
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Affiliation(s)
- Ola A. Gharib
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Hanan A. Fahmy
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Fatma Y. Abdou
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
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Moellerberndt J, Niebert S, Fey K, Hagen A, Burk J. Impact of platelet lysate on immunoregulatory characteristics of equine mesenchymal stromal cells. Front Vet Sci 2024; 11:1385395. [PMID: 38725585 PMCID: PMC11079816 DOI: 10.3389/fvets.2024.1385395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 03/29/2024] [Indexed: 05/12/2024] Open
Abstract
Multipotent mesenchymal stromal cells (MSC) play an increasing role in the treatment of immune-mediated diseases and inflammatory processes. They regulate immune cells via cell-cell contacts and by secreting various anti-inflammatory molecules but are in turn influenced by many factors such as cytokines. For MSC culture, platelet lysate (PL), which contains a variety of cytokines, is a promising alternative to fetal bovine serum (FBS). We aimed to analyze if PL with its cytokines improves MSC immunoregulatory characteristics, with the perspective that PL could be useful for priming the MSC prior to therapeutic application. MSC, activated peripheral blood mononuclear cells (PBMC) and indirect co-cultures of both were cultivated in media supplemented with either PL, FBS, FBS+INF-γ or FBS+IL-10. After incubation, cytokine concentrations were measured in supernatants and control media. MSC were analyzed regarding their expression of immunoregulatory genes and PBMC regarding their proliferation and percentage of FoxP3+ cells. Cytokines, particularly IFN-γ and IL-10, remained at high levels in PL control medium without cells but decreased in cytokine-supplemented control FBS media without cells during incubation. PBMC released IFN-γ and IL-10 in various culture conditions. MSC alone only released IFN-γ and overall, cytokine levels in media were lowest when MSC were cultured alone. Stimulation of MSC either by PBMC or by PL resulted in an altered expression of immunoregulatory genes. In co-culture with PBMC, the MSC gene expression of COX2, TNFAIP6, IDO1, CXCR4 and MHC2 was upregulated and VCAM1 was downregulated. In the presence of PL, COX2, TNFAIP6, VCAM1, CXCR4 and HIF1A were upregulated. Functionally, while no consistent changes were found regarding the percentage of FoxP3+ cells, MSC decreased PBMC proliferation in all media, with the strongest effect in FBS media supplemented with IL-10 or IFN-γ. This study provides further evidence that PL supports MSC functionality, including their immunoregulatory mechanisms. The results justify to investigate functional effects of MSC cultured in PL-supplemented medium on different types of immune cells in more detail.
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Affiliation(s)
- Julia Moellerberndt
- Equine Clinic (Surgery, Orthopedics), Justus-Liebig-University Giessen, Giessen, Germany
| | - Sabine Niebert
- Institute of Physiology, Pathophysiology, and Biophysics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Kerstin Fey
- Equine Clinic (Internal Medicine), Justus-Liebig-University Giessen, Giessen, Germany
| | - Alina Hagen
- Equine Clinic (Surgery, Orthopedics), Justus-Liebig-University Giessen, Giessen, Germany
| | - Janina Burk
- Institute of Physiology, Pathophysiology, and Biophysics, University of Veterinary Medicine Vienna, Vienna, Austria
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11
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Deng R, Wu J, Zhu B, Song G, Zhou T, Yang M, Pan L, Wang J, Zou X, Lv Z, Jin X, Xu Y, Lu X, Gui S. Engineered exosomes loaded with M1–8 peptide for targeted therapy of hepatocellular carcinoma. APPLIED MATERIALS TODAY 2024; 37:102071. [DOI: 10.1016/j.apmt.2024.102071] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Ramírez Idarraga JA, Restrepo Múnera LM. Mesenchymal Stem Cells: Their Role in the Tumor Microenvironment. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:681-691. [PMID: 37276173 DOI: 10.1089/ten.teb.2023.0048] [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: 06/07/2023]
Abstract
Mesenchymal stem cells (MSCs) have been seen for years as great candidates for treating different diseases and an alternative to embryonic stem cells due to their differentiation capacity in vitro. More recent research has focused on their ability to modulate the immune response and regeneration at sites associated with inflammation, activities attributable to the release of trophic factors into the extracellular medium, a set of components known as the secretome. It has been possible to demonstrate the presence of these cells within the tumor microenvironment, which is associated with their tropism for sites of inflammation; however, their role here needs to be clarified. In different investigations, the feasibility of using MSCs or their secretome to treat cancer has been sought, with these results being ambiguous. It has been described that MSCs can be activated and present various phenotypes, which could explain the divergence in their action; however, these activation mechanisms and the different phenotypes still need to be well known. This review explores MSCs and their use in regenerative medicine with a targeted approach to cancer. Impact Statement This text addresses the diverging findings on the role of mesenchymal stem cells in the tumor microenvironment and discrepancies on the use of these cells as cancer treatment, separating the direct use of the cells from the use of the secretome. Multiple authors refer equally to the cells and their secretome to conclude on the positive or negative outcome, without taking into consideration how the cells are affected by their surroundings.
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Affiliation(s)
- Jhon Alexander Ramírez Idarraga
- Corporación Académica Ciencias Básicas Biomédicas, Universidad de Antioquía, Medellín, Colombia
- Grupo Ingeniería de Tejidos y Terapias Celulares, Instituto de Investigaciones Médicas, Universidad de Antioquía, Medellín, Colombia
| | - Luz Marina Restrepo Múnera
- Grupo Ingeniería de Tejidos y Terapias Celulares, Instituto de Investigaciones Médicas, Universidad de Antioquía, Medellín, Colombia
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Zhang S, Zhang R, Yin X, Lu Y, Cheng H, Pan Y, Liu Y, Lin J. MenSCs Transplantation Improve the Viability of Injured Endometrial Cells Through Activating PI3K/Akt Pathway. Reprod Sci 2023; 30:3325-3338. [PMID: 37308799 DOI: 10.1007/s43032-023-01282-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/01/2023] [Indexed: 06/14/2023]
Abstract
Endometrial injury is one of the leading causes of female infertility and is caused by intrauterine surgery, endometrial infection, repeated abortion, or genital tuberculosis. Currently, there is little effective treatment to restore the fertility of patients with severe intrauterine adhesions and thin endometrium. Recent studies have confirmed the promising therapeutic effects of mesenchymal stem cell transplantation on various diseases with definite tissue injury. The aim of this study is to investigate the improvements of menstrual blood-derived endometrial stem cells (MenSCs) transplantation on functional restoration in the endometrium of mouse model. Therefore, ethanol-induced endometrial injury mouse models were randomly divided into two groups: the PBS-treated group, and the MenSCs-treated group. As expected, the endometrial thickness and gland number in the endometrium of MenSCs-treated mice were significantly improved compared to those of PBS-treated mice (P < 0.05), and fibrosis levels were significantly reduced (P < 0.05). Subsequent results revealed that MenSCs treatment significantly promoted angiogenesis in the injured endometrium. Simultaneously, MenSCs enhance the proliferation and antiapoptotic capacity of endometrial cells, which is likely contributed by activating the PI3K/Akt signaling pathway. Further tests also confirmed the chemotaxis of GFP-labeled MenSCs towards the injured uterus. Consequently, MenSCs treatment significantly improved the pregnant mice and the number of embryos in pregnant mice. This study confirmed the superior improvements of MenSCs transplantation on the injured endometrium and uncovered the potential therapeutic mechanism, which provides a promising alternative for patients with serious endometrial injury.
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Affiliation(s)
- Shenghui Zhang
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China
- Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Gelugor, Penang, Malaysia
| | - Ruiyun Zhang
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China
| | - Xiyao Yin
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453000, China
| | - Yuyu Lu
- The Third Affiliated Hospital of Xinxiang Medical University, Hualan Road, XinxiangHenan Province, 453100, China
| | - Hongbin Cheng
- College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
- The Third Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Ying Pan
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China.
- The Third Affiliated Hospital of Xinxiang Medical University, Hualan Road, XinxiangHenan Province, 453100, China.
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China.
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China
- College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
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Wang Y, Gao T, Wang B. Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Res Ther 2023; 14:260. [PMID: 37726805 PMCID: PMC10510299 DOI: 10.1186/s13287-023-03497-z] [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: 07/25/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
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Affiliation(s)
- Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Tianyun Gao
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China.
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15
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [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: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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16
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Park HS, Cetin E, Siblini H, Seok J, Alkelani H, Alkhrait S, Liakath Ali F, Mousaei Ghasroldasht M, Beckman A, Al-Hendy A. Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles to Treat PCOS. Int J Mol Sci 2023; 24:11151. [PMID: 37446328 DOI: 10.3390/ijms241311151] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 06/30/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in women. Previously, we suggested that human mesenchymal stem cells (MSCs) can reverse the PCOS condition by secreting factors. Here, we evaluated the therapeutic capability of MSC-derived extracellular vesicles (EVs), also known as exosomes, in both in vitro and in vivo PCOS models. Exosomes were used to treat androgen-producing H293R cells and injected in a mouse model through intraovarian and intravenous injection into a letrozole (LTZ)-induced PCOS mouse model. We assessed the effects of the exosomes on androgen-producing cells or the PCOS mouse model by analyzing steroidogenic gene expression (quantitative real-time polymerase chain reaction (qRT-PCR)), body weight change, serum hormone levels, and fertility by pup delivery. Our data show the therapeutic effect of MSC-derived EVs for reversing PCOS conditions, including fertility issues. Interestingly, intravenous injection was more effective for serum glucose regulation, and an intraovarian injection was more effective for ovary restoration. Our study suggests that MSC-derived exosomes can be promising biopharmaceutics for treating PCOS conditions as a novel therapeutic option. Despite the fact that we need more validation in human patients, we may evaluate this novel treatment option for PCOS with the following clinical trials.
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Affiliation(s)
- Hang-Soo Park
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Esra Cetin
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Hiba Siblini
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Jin Seok
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Hiba Alkelani
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Samar Alkhrait
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Farzana Liakath Ali
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | | | - Analea Beckman
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
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17
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Kahrizi MS, Mousavi E, Khosravi A, Rahnama S, Salehi A, Nasrabadi N, Ebrahimzadeh F, Jamali S. Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies. Stem Cell Res Ther 2023; 14:155. [PMID: 37287066 DOI: 10.1186/s13287-023-03374-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 05/10/2023] [Indexed: 06/09/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs)-based therapy brings the reassuring capability to regenerative medicine through their self-renewal and multilineage potency. Also, they secret a diversity of mediators, which are complicated in moderation of deregulated immune responses, and yielding angiogenesis in vivo. Nonetheless, MSCs may lose biological performance after procurement and prolonged expansion in vitro. Also, following transplantation and migration to target tissue, they encounter a harsh milieu accompanied by death signals because of the lack of proper tensegrity structure between the cells and matrix. Accordingly, pre-conditioning of MSCs is strongly suggested to upgrade their performances in vivo, leading to more favored transplantation efficacy in regenerative medicine. Indeed, MSCs ex vivo pre-conditioning by hypoxia, inflammatory stimulus, or other factors/conditions may stimulate their survival, proliferation, migration, exosome secretion, and pro-angiogenic and anti-inflammatory characteristics in vivo. In this review, we deliver an overview of the pre-conditioning methods that are considered a strategy for improving the therapeutic efficacy of MSCs in organ failures, in particular, renal, heart, lung, and liver.
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Affiliation(s)
| | - Elnaz Mousavi
- Department of Endodontics, School of Dentistry, Guilan University of Medical Sciences, Rasht, Iran
| | - Armin Khosravi
- Department of Periodontics, Dental School, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Sara Rahnama
- Department of Pediatric Dentistry, School of Dentistry, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Salehi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Navid Nasrabadi
- Department of Endodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Farnoosh Ebrahimzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Samira Jamali
- Department of Endodontics, Stomatological Hospital, College of Stomatology, Xi'an Jiaotong University, Shaanxi, People's Republic of China.
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18
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Subayyil AA, Basmaeil YS, Kulayb HB, Alrodayyan M, Alhaber LAA, Almanaa TN, Khatlani T. Preconditioned Chorionic Villus Mesenchymal Stem/Stromal Cells (CVMSCs) Minimize the Invasive Phenotypes of Breast Cancer Cell Line MDA231 In Vitro. Int J Mol Sci 2023; 24:ijms24119569. [PMID: 37298519 DOI: 10.3390/ijms24119569] [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: 03/05/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 06/12/2023] Open
Abstract
Among the newer choices of targeted therapies against cancer, stem cell therapy is gaining importance because of their antitumor properties. Stem cells suppress growth, metastasis, and angiogenesis, and induce apoptosis in cancer cells. In this study, we have examined the impact of the cellular component and the secretome of preconditioned and naïve placenta-derived Chorionic Villus Mesenchymal Stem Cells (CVMSCs) on the functional characteristics of the Human Breast Cancer cell line MDA231. MDA231 cells were treated with preconditioned CVMSCs and their conditioned media (CM), followed by an evaluation of their functional activities and modulation in gene and protein expression. Human Mammary Epithelial Cells (HMECs) were used as a control. CM obtained from the preconditioned CVMSCs significantly altered the proliferation of MDA231 cells, yet no change in other phenotypes, such as adhesion, migration, and invasion, were observed at various concentrations and time points tested. However, the cellular component of preconditioned CVMSCs significantly inhibited several phenotypes of MDA231 cells, including proliferation, migration, and invasion. CVMSCs-treated MDA231 cells exhibited modulation in the expression of various genes involved in apoptosis, oncogenesis, and Epithelial to Mesenchymal Transition (EMT), explaining the changes in the invasive behavior of MDA231 cells. These studies reveal that preconditioned CVMSCs may make useful candidate in a stem cell-based therapy against cancer.
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Affiliation(s)
- Abdullah Al Subayyil
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Yasser S Basmaeil
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Hayaa Bin Kulayb
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Maha Alrodayyan
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Lama Abdulaziz A Alhaber
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Taghreed N Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Tanvir Khatlani
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
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MacVittie TJ. Where are the medical countermeasures against the ARS and DEARE? A current topic relative to an animal model research platform, radiation exposure context, the acute and delayed effects of acute exposure, and the FDA animal rule. Int J Radiat Biol 2023:1-15. [PMID: 36811500 DOI: 10.1080/09553002.2023.2181999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
PURPOSE A question echoed by the National Biodefense Science Board (NBSB) in 2010, remains a reasonable question in 2023; 'Where are the Countermeasures?'. A critical path for development of medical countermeasures (MCM) against acute, radiation-induced organ-specific injury within the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE) requires the recognition of problems and solutions inherent in the path to FDA approval under the Animal Rule. Keep Rule number one in mind, It's not easy. CONSIDERATIONS The current topic herein is focused on defining the nonhuman primate model(s) for efficient MCM development relative to consideration of prompt and delayed exposure in the context of the nuclear scenario. The rhesus macaque is a predictive model for human exposure of partial-body irradiation with marginal bone marrow sparing that allows definition of the multiple organ injury in the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE). The continued definition of natural history is required to delineate an associative or causal interaction within the concurrent multi-organ injury characteristic of the ARS and DEARE. A more efficient development of organ specific MCM for both pre-exposure and post-exposure prophylaxis to include acute radiation-induced combined injury requires closing critical gaps in knowledge and urgent support to rectify the national shortage of nonhuman primates. The rhesus macaque is a validated, predictive model of the human response to prompt and delayed radiation exposure, medical management and MCM treatment. A rational approach to further development of the cynomolgus macaque as a comparable model is urgently required for continued development of MCM for FDA approval. CONCLUSION It is imperative to examine the key variables relative to animal model development and validation, The pharmacokinetics, pharmacodynamics and exposure profiles, of candidate MCM relative to route, administration schedule and optimal efficacy define the fully effective dose. The conduct of adequate and well-controlled pivotal efficacy studies as well as safety and toxicity studies support approval under the FDA Animal Rule and label definition for human use.
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Affiliation(s)
- Thomas J MacVittie
- Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD, USA
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Katiyar D, Singhal S, Bansal P, Nagarajan K, Grover P. Nutraceuticals and phytotherapeutics for holistic management of amyotrophic lateral sclerosis. 3 Biotech 2023; 13:62. [PMID: 36714551 PMCID: PMC9880136 DOI: 10.1007/s13205-023-03475-5] [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: 10/18/2022] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
Amyotrophic lateral sclerosis" (ALS) is a progressive neuronal disorder that affects sensory neurons in the brain and spinal cord, causing loss of muscle control. Moreover, additional neuronal subgroups as well as glial cells such as microglia, astrocytes, and oligodendrocytes are also thought to play a role in the aetiology. The disease affects upper motor neurons and lowers motor neurons and leads to that either lead to muscle weakness and wasting in the arms, legs, trunk and periventricular area. Oxidative stress, excitotoxicity, programmed cell death, altered neurofilament activity, anomalies in neurotransmission, abnormal protein processing and deterioration, increased inflammation, and mitochondrial dysfunction may all play a role in the progression of ALS. There are presently hardly FDA-approved drugs used to treat ALS, and they are only beneficial in slowing the progression of the disease and enhancing functions in certain individuals with ALS, not really in curing or preventing the illness. These days, researchers focus on understanding the pathogenesis of the disease by targeting several mechanisms aiming to develop successful treatments for ALS. This review discusses the epidemiology, risk factors, diagnosis, clinical features, pathophysiology, and disease management. The compilation focuses on alternative methods for the management of symptoms of ALS with nutraceuticals and phytotherapeutics.
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Affiliation(s)
- Deepti Katiyar
- KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh 201206 India
| | - Shipra Singhal
- KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh 201206 India
| | - Priya Bansal
- KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh 201206 India
| | - K. Nagarajan
- KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh 201206 India
| | - Parul Grover
- KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh 201206 India
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Leyden GM, Greenwood MP, Gaborieau V, Han Y, Amos CI, Brennan P, Murphy D, Davey Smith G, Richardson TG. Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation. Br J Cancer 2023; 128:618-625. [PMID: 36434155 PMCID: PMC9938133 DOI: 10.1038/s41416-022-02060-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 10/30/2022] [Accepted: 11/02/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents of this heterogenous risk factor are predominantly responsible for driving disease effects has proven difficult to establish. We have leveraged tissue-specific gene expression to separate the effects of distinct phenotypes underlying BMI on the risk of seven site-specific cancers. METHODS SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence for colocalization with subcutaneous adipose- and brain-tissue-derived gene expression using a recently developed methodology. RESULTS Our results provide evidence that brain-tissue-derived BMI variants are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer (OR: 1.17; 95% CI: 1.01-1.36; P = 0.03). Similar findings were identified when analysing cigarettes per day as an outcome (Beta = 0.44; 95% CI: 0.26-0.61; P = 1.62 × 10-6), highlighting a possible shared aetiology or mediator effect between brain-tissue BMI, smoking and lung cancer. Our results additionally suggest that adipose-tissue-derived BMI variants may predominantly drive the effect of BMI and increased risk for endometrial cancer (OR: 1.71; 95% CI: 1.07-2.74; P = 0.02), highlighting a putatively important role in the aetiology of endometrial cancer. CONCLUSIONS The study provides valuable insight into the divergent underlying pathways between BMI and the risk of site-specific cancers.
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Affiliation(s)
- Genevieve M Leyden
- MRC Integrative Epidemiology Unit, Bristol Population Health Science Institute, University of Bristol, Bristol, BS8 2BN, UK.
- Bristol Medical School: Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
| | - Michael P Greenwood
- Bristol Medical School: Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK
| | - Valérie Gaborieau
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Younghun Han
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Christopher I Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Paul Brennan
- Bristol Medical School: Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK
| | - David Murphy
- Bristol Medical School: Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, Bristol Population Health Science Institute, University of Bristol, Bristol, BS8 2BN, UK
| | - Tom G Richardson
- MRC Integrative Epidemiology Unit, Bristol Population Health Science Institute, University of Bristol, Bristol, BS8 2BN, UK.
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22
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Zhang L. The Role of Mesenchymal Stem Cells in Modulating the Breast Cancer Microenvironment. Cell Transplant 2023; 32:9636897231220073. [PMID: 38135917 DOI: 10.1177/09636897231220073] [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] [Indexed: 12/24/2023] Open
Abstract
The role of mesenchymal stem cells (MSCs) in the breast tumor microenvironment (TME) is significant and multifaceted. MSCs are recruited to breast tumor sites through molecular signals released by tumor sites. Once in the TME, MSCs undergo polarization and interact with various cell populations, including immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), and breast cancer cells. In most cases, MSCs play roles in breast cancer therapeutic resistance, but there is also evidence that indicates their abilities to sensitize cancer cells to chemotherapy and radiotherapy. MSCs possess inherent regenerative and homing properties, making them attractive candidates for cell-based therapies. Therefore, MSCs can be engineered to express therapeutic molecules or deliver anti-cancer agents directly to tumor sites. Unraveling the intricate relationship between MSCs and the breast TME has the potential to uncover novel therapeutic targets and advance our understanding of breast cancer biology.
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Affiliation(s)
- Luxiao Zhang
- Department of Surgical Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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23
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Martí‐Chillón G, Muntión S, Preciado S, Osugui L, Navarro‐Bailón A, González‐Robledo J, Sagredo V, Blanco JF, Sánchez‐Guijo F. Therapeutic potential of mesenchymal stromal/stem cells in critical-care patients with systemic inflammatory response syndrome. Clin Transl Med 2023; 13:e1163. [PMID: 36588089 PMCID: PMC9806020 DOI: 10.1002/ctm2.1163] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/15/2022] [Accepted: 12/19/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Despite notable advances in the support and treatment of patients admitted to the intensive care unit (ICU), the management of those who develop a systemic inflammatory response syndrome (SIRS) still constitutes an unmet medical need. MAIN BODY Both the initial injury (trauma, pancreatitis, infections) and the derived uncontrolled response promote a hyperinflammatory status that leads to systemic hypotension, tissue hypoperfusion and multiple organ failure. Mesenchymal stromal/stem cells (MSCs) are emerging as a potential therapy for severe ICU patients due to their potent immunomodulatory, anti-inflammatory, regenerative and systemic homeostasis-regulating properties. MSCs have demonstrated clinical benefits in several inflammatory-based diseases, but their role in SIRS needs to be further explored. CONCLUSION In the current review, after briefly overviewing SIRS physiopathology, we explore the potential mechanisms why MSC therapy could aid in the recovery of this condition and the pre-clinical and early clinical evidence generated to date.
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Affiliation(s)
| | - Sandra Muntión
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Silvia Preciado
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Lika Osugui
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Almudena Navarro‐Bailón
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Javier González‐Robledo
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Department of MedicineUniversity of SalamancaSalamancaSpain
| | | | - Juan F. Blanco
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
- Department of SurgeryUniversity of SalamancaSalamancaSpain
| | - Fermín Sánchez‐Guijo
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Department of MedicineUniversity of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
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24
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Huang J, Liu Q, Xia J, Chen X, Xiong J, Yang L, Liang Y. Modification of mesenchymal stem cells for cartilage-targeted therapy. J Transl Med 2022; 20:515. [PMID: 36348497 PMCID: PMC9644530 DOI: 10.1186/s12967-022-03726-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/24/2022] [Indexed: 11/10/2022] Open
Abstract
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the destruction of the articular cartilage, sclerosis of the subchondral bone, and joint dysfunction. Its pathogenesis is attributed to direct damage and mechanical destruction of joint tissues. Mesenchymal stem cells (MSCs), suggested as a potential strategy for the treatment of OA, have shown therapeutic effects on OA. However, the specific fate of MSCs after intraarticular injection, including cell attachment, proliferation, differentiation, and death, is still unclear, and there is no guarantee that stem cells can be retained in the cartilage tissue to enact repair. Direct homing of MSCs is an important determinant of the efficacy of MSC-based cartilage repair. Recent studies have revealed that the unique homing capacity of MSCs and targeted modification can improve their ability to promote tissue regeneration. Here, we comprehensively review the homing effect of stem cells in joints and highlight progress toward the targeted modification of MSCs. In the future, developments of this targeting system that accelerate tissue regeneration will benefit targeted tissue repair.
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25
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Siddiqui S, Mateen S, Ahmad R, Moin S. A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS). J Assist Reprod Genet 2022; 39:2439-2473. [PMID: 36190593 PMCID: PMC9723082 DOI: 10.1007/s10815-022-02625-7] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/19/2022] [Indexed: 10/10/2022] Open
Abstract
Polycystic ovarian syndrome (PCOS) is a prevailing endocrine and metabolic disorder occurring in about 6-20% of females in reproductive age. Most symptoms of PCOS arise early during puberty. Since PCOS involves a combination of signs and symptoms, thus it is considered as a heterogeneous disorderliness. The most accepted diagnostic criteria is Rotterdam criteria which involves two of the latter three features: (a) hyperandrogenism, (b) oligo- or an-ovulation, and (c) polycystic ovaries. The persistent hormonal imbalance leads to multiple small antral follicles formation and irregular menstrual cycle, ultimately causing infertility among females. Insulin resistance, cardiovascular diseases, abdominal obesity, psychological disorders, infertility, and cancer are also related to PCOS. These pathophysiologies associated with PCOS are interrelated with each other. Hyperandrogenism causes insulin resistance and hyperglycemia, leading to ROS formation, oxidative stress, and abdominal adiposity. In consequence, inflammation, ROS production, insulin resistance, and hyperandrogenemia also increase. Elevation of AGEs in the body either produced endogenously or consumed from diet exaggerates PCOS symptoms and is also related to ovarian dysfunction. This review summarizes how AGE formation, inflammation, and oxidative stress are significantly essential in PCOS progression. Alterations during prenatal development like exposure to excess AMH, androgens, or toxins (bisphenol-A, endocrine disruptors, etc.) may also be the etiologic mechanism behind PCOS. Although the etiology of this disorder is unclear, environmental and genetic factors are primarily involved. Physical inactivity, as well as unhealthy eating habits, has a vital role in the progression of PCOS. This review outlines a collection of specific genes phenotypically linked with PCOS. Furthermore, beneficial effect of metformin in maintaining endocrine abnormalities and ovarian function is also mentioned. Kisspeptin is a protein which helps in onset of puberty and increases GnRH pulsatile release during ovulation as well as role of KNDy neurons in GnRH pulsatile signal required for reproduction are also elaborated. This review also focuses on the immunology related to PCOS involving chronic low-grade inflammation, and how the alterations within the follicular microenvironment are intricated in the development of infertility in PCOS patients. How PCOS develops following antiepileptic and psychiatric medication is also expanded in this review. Initiation of antiandrogen treatment in early age (≤ 25 years) might be helpful in spontaneous conception in PCOS women. The role of BMP (bone morphogenetic proteins) in folliculogenesis and their expression in oocytes and granulosa cells are also explained. GDF8 and SERPINE1 expression in PCOS is given in detail.
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Affiliation(s)
- Sana Siddiqui
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar, Pradesh -202002, India
| | - Somaiya Mateen
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar, Pradesh -202002, India
| | - Rizwan Ahmad
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar, Pradesh -202002, India
| | - Shagufta Moin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar, Pradesh -202002, India.
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26
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Gong SC, Yoon Y, Jung PY, Kim MY, Baik SK, Ryu H, Eom YW. Antifibrotic TSG-6 Expression Is Synergistically Increased in Both Cells during Coculture of Mesenchymal Stem Cells and Macrophages via the JAK/STAT Signaling Pathway. Int J Mol Sci 2022; 23:13122. [PMID: 36361907 PMCID: PMC9656625 DOI: 10.3390/ijms232113122] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 12/28/2022] Open
Abstract
The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β upregulate TNF-α-stimulated gene 6 (TSG-6); however, current knowledge about the optimal conditions for TSG-6 expression in mesenchymal stem cells (MSCs) is limited. Here, we investigated whether TSG-6 expression varies depending on the polarization state of macrophages co-cultured with adipose tissue-derived stem cells (ASCs) and analyzed the optimal conditions for TSG-6 expression in ASCs. TSG-6 expression increased in ASCs co-cultured with M0, M1, and M2 macrophages indirectly; among them, M1 macrophages resulted in the highest increase in TSG-6 expression in ASCs. TSG-6 expression in ASCs dramatically increased by combination (but not single) treatment of TNF-α, IL-1β, interferon-gamma (IFN-γ), and lipopolysaccharide (LPS). In addition, phosphorylation of signal transducer and activator of transcription (STAT) 1/3 was observed in response to IFN-γ and LPS treatment but not TNF-α and/or IL-1β. STAT1/3 activation synergistically increased TNF-α/IL-1β-dependent TSG-6 expression, and JAK inhibitors suppressed TSG-6 expression both in ASCs and macrophages. In LX-2 hepatic stellate cells, TSG-6 inhibited TGF-β-induced Smad3 phosphorylation, resulting in decreased α-smooth muscle actin (SMA) expression. Moreover, fibrotic activities of LX-2 cells induced by TGF-β were dramatically decreased after indirect co-culture with ASCs and M1 macrophages. These results suggest that a comprehensive inflammatory microenvironment may play an important role in determining the therapeutic properties of ASCs by increasing TSG-6 expression through STAT1/3 activation.
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Affiliation(s)
- Seong Chan Gong
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
| | - Yongdae Yoon
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
| | - Pil Young Jung
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
| | - Moon Young Kim
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
| | - Hoon Ryu
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
| | - Young Woo Eom
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
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27
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Sarvar DP, Effatpanah H, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived extracellular vesicles: novel approach in hematopoietic stem cell transplantation. Stem Cell Res Ther 2022; 13:202. [PMID: 35578300 PMCID: PMC9109321 DOI: 10.1186/s13287-022-02875-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/24/2021] [Indexed: 11/24/2022] Open
Abstract
Bone marrow mesenchymal stromal cells (MSCs) play a crucial role in the regulation of hematopoiesis. These cells affect the process through direct cell–cell contact, as well as releasing various trophic factors and extracellular vehicles (EVs) into the bone marrow microenvironment. MSC-derived EVs (MSC-EVs) are prominent intercellular communication tolls enriched with broad-spectrum bioactive factors such as proteins, cytokines, lipids, miRNAs, and siRNAs. They mimic some effects of MSCs by direct fusion with hematopoietic stem cells (HSC) membranes in the bone marrow (BM), thereby affecting HSC fate. MSC-EVs are attractive scope in cell-free therapy because of their unique capacity to repair BM tissue and regulate proliferation and differentiation of HSCs. These vesicles modulate the immune system responses and inhibit graft-versus-host disease following hematopoietic stem cell transplantation (HSCT). Recent studies have demonstrated that MSC-EVs play an influential role in the BM niches because of their unprecedented capacity to regulate HSC fate. Therefore, the existing paper intends to speculate upon the preconditioned MSC-EVs as a novel approach in HSCT.
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Affiliation(s)
| | | | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Tabriz University of Medical Science, Tabriz, Iran
| | - Karim Shamsasenjan
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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28
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Shokravi S, Borisov V, Zaman BA, Niazvand F, Hazrati R, Khah MM, Thangavelu L, Marzban S, Sohrabi A, Zamani A. Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review. Stem Cell Res Ther 2022; 13:192. [PMID: 35527304 PMCID: PMC9080215 DOI: 10.1186/s13287-022-02825-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepatocytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes. Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF. Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs, genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
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Affiliation(s)
- Samin Shokravi
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Vitaliy Borisov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Burhan Abdullah Zaman
- Basic Sciences Department, College of Pharmacy, University of Duhok, Duhok, Kurdistan Region Iraq
| | - Firoozeh Niazvand
- School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Raheleh Hazrati
- Department of Medicinal Chemistry, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Meysam Mohammadi Khah
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Sima Marzban
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Armin Sohrabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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29
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Park HS, Chugh RM, Pergande MR, Cetin E, Siblini H, Esfandyari S, Cologna SM, Al-Hendy A. Non-Cytokine Protein Profile of the Mesenchymal Stem Cell Secretome That Regulates the Androgen Production Pathway. Int J Mol Sci 2022; 23:ijms23094633. [PMID: 35563028 PMCID: PMC9101816 DOI: 10.3390/ijms23094633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/15/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-aged women, and it typically involves elevated androgen levels. Recently, it has been reported that human bone marrow mesenchymal stem cells (hBM-MSCs) can regulate androgen synthesis pathways. However, the details of the mechanism are still unclear. hBM-MSC-derived secreted factors (the secretome) are promising sources of cell-based therapy as they consist of various types of proteins. It is thus important to know which proteins interact with disease-implicated biomolecules. This work aimed to investigate which secretome components contain the key factor that inhibits testosterone synthesis. In this study, we fractionated hBM-MSC-conditioned media into three fractions based on their molecular weights and found that, of the three fractions, one had the ability to inhibit the androgen-producing genes efficiently. We also analyzed the components of this fraction and established a protein profile of the hBM-MSC secretome, which was shown to inhibit androgen synthesis. Our study describes a set of protein components present in the hBM-MSC secretome that can be used therapeutically to treat PCOS by regulating androgen production for the first time.
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Affiliation(s)
- Hang-Soo Park
- Department of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA; (H.-S.P.); (E.C.); (H.S.)
| | - Rishi Man Chugh
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (R.M.C.); (S.E.)
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Melissa R. Pergande
- Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA; (M.R.P.); (S.M.C.)
| | - Esra Cetin
- Department of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA; (H.-S.P.); (E.C.); (H.S.)
| | - Hiba Siblini
- Department of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA; (H.-S.P.); (E.C.); (H.S.)
| | - Sahar Esfandyari
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (R.M.C.); (S.E.)
| | - Stephanie M. Cologna
- Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA; (M.R.P.); (S.M.C.)
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA; (H.-S.P.); (E.C.); (H.S.)
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (R.M.C.); (S.E.)
- Correspondence:
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30
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Shin MJ, Park JY, Lee DH, Khang D. Stem Cell Mimicking Nanoencapsulation for Targeting Arthritis. Int J Nanomedicine 2022; 16:8485-8507. [PMID: 35002240 PMCID: PMC8725870 DOI: 10.2147/ijn.s334298] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 12/05/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are considered a promising regenerative therapy due to their ability to migrate toward damaged tissues. The homing ability of MSCs is unique compared with that of non-migrating cells and MSCs are considered promising therapeutic vectors for targeting major cells in many pathophysiological sites. MSCs have many advantages in the treatment of malignant diseases, particularly rheumatoid arthritis (RA). RA is a representative autoimmune disease that primarily affects joints, and secreted chemokines in the joints are well recognized by MSCs following their migration to the joints. Furthermore, MSCs can regulate the inflammatory process and repair damaged cells in the joints. However, the functionality and migration ability of MSCs injected in vivo still show insufficient. The targeting ability and migration efficiency of MSCs can be enhanced by genetic engineering or modification, eg, overexpressing chemokine receptors or migration-related genes, thus maximizing their therapeutic effect. However, there are concerns about genetic changes due to the increased probability of oncogenesis resulting from genome integration of the viral vector, and thus, clinical application is limited. Furthermore, it is suspected that administering MSCs can promote tumor growth and metastasis in xenograft and orthotopic models. For this reason, MSC mimicking nanoencapsulations are an alternative strategy that does not involve using MSCs or bioengineered MSCs. MSC mimicking nanoencapsulations consist of MSC membrane-coated nanoparticles, MSC-derived exosomes and artificial ectosomes, and MSC membrane-fused liposomes with natural or genetically engineered MSC membranes. MSC mimicking nanoencapsulations not only retain the targeting ability of MSCs but also have many advantages in terms of targeted drug delivery. Specifically, MSC mimicking nanoencapsulations are capable of encapsulating drugs with various components, including chemotherapeutic agents, nucleic acids, and proteins. Furthermore, there are fewer concerns over safety issues on MSC mimicking nanoencapsulations associated with mutagenesis even when using genetically engineered MSCs, because MSC mimicking nanoencapsulations use only the membrane fraction of MSCs. Genetic engineering is a promising route in clinical settings, where nano-encapsulated technology strategies are combined. In this review, the mechanism underlying MSC homing and the advantages of MSC mimicking nanoencapsulations are discussed. In addition, genetic engineering of MSCs and MSC mimicking nanoencapsulation is described as a promising strategy for the treatment of immune-related diseases.
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Affiliation(s)
- Min Jun Shin
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea.,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea
| | - Jun Young Park
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea.,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea
| | - Dae Ho Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, 21999, South Korea.,Department of Internal Medicine, Gachon University College of Medicine, Incheon, 21999, South Korea
| | - Dongwoo Khang
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea.,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea.,Department of Physiology, School of Medicine, Gachon University, Incheon, 21999, South Korea
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31
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Chang WL, Lee WR, Kuo YC, Huang YH. Vitiligo: An Autoimmune Skin Disease and its Immunomodulatory Therapeutic Intervention. Front Cell Dev Biol 2022; 9:797026. [PMID: 34970551 PMCID: PMC8712646 DOI: 10.3389/fcell.2021.797026] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
Vitiligo is a chronic autoimmune depigmenting skin disorder characterized by patches of the skin losing functional melanocytes. Multiple combinatorial factors are involved in disease development, among which immune T cells play a prominent role. The immune cells implicated in melanocyte destruction through adaptive immunity include CD8+ cytotoxic T cells and regulatory T cells, and aberrantly activated skin-resident memory T cells also play a role in melanocyte destruction. Over the past several years, major progress in understanding vitiligo pathogenesis has led to the development of targeted therapies. Janus kinase (JAK) inhibitors, which share the similar mechanism that autoactivates CD8+ T cells in chronic inflammatory diseases, have been reported to have therapeutic significance in vitiligo. Recently, immunomodulatory therapeutic interventions in vitiligo have been emerging. Mesenchymal stem cells (MSCs) regulate cytokine secretion and the balance of T-cell subsets, which makes them a promising cell-based treatment option for autoimmune diseases. The induction of MSC-mediated immunomodulation is complicated and occurs by contact-dependent mechanisms and soluble extracellular vesicle (EV) mediators. EVs released from MSCs contain various growth factors and cytokines with anti-inflammatory effects in the skin immune response. Here, we summarize and discuss the progress to date in targeted therapies that immunomodulate the niche environment of vitiligo, from the clinical trial of JAK inhibitors to the potential of MSCs and MSC-EVs. The available information was collected to highlight the need for further research into the treatment of vitiligo.
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Affiliation(s)
- Wei-Ling Chang
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.,International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Woan-Ruoh Lee
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.,Department of Dermatology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan
| | - Yung-Che Kuo
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yen-Hua Huang
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.,International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan.,PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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32
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Zheng Z, Wang J. Bone marrow mesenchymal stem cells combined with Atractylodes macrocephala polysaccharide attenuate ulcerative colitis. Bioengineered 2022; 13:824-833. [PMID: 34898358 PMCID: PMC8805825 DOI: 10.1080/21655979.2021.2012954] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/27/2021] [Indexed: 11/01/2022] Open
Abstract
The aim of the present study was to explore the effects of bone marrow mesenchymal stem cells (BMSCs), combined with Atractylodes macrocephala polysaccharide (AMP), in an experimental model of ulcerative colitis. BMSCs were first isolated, cultured, and identified by flow cytometry. A rat model of colitis was established by trinitrobenzene sulfonic acid (TNBS) injection. Rats were treated with BMSCs with or without AMP for 1 or 2 weeks. H&E staining was performed to assess the extent of histological injury. IEC-6 and BMSCs were co-cultured and treated with AMP. Cell migration was measured using the Transwell assay, whilst the levels of cytokines in the rat blood samples were detected using ELISA. In addition, cytokine levels in the cell supernatant were measured by microarray. The results showed that BMSCs were successfully isolated. BMSCs treatment could markedly alleviate injury according to histological analysis and regulate inflammatory cytokine production in this rat model of TNBS-induced colitis, where a higher number of BMSCs was found in the intestinal tract, compared to the model. AMP not only potentiated the effects of BMSCs on preventing TNBS-induced colitis but also promoted BMSC homing to the injured tissue and regulated cytokines. Furthermore, BMSCs and AMP promoted the migration of IEC in vitro and influenced multiple genes. In conclusion, AMP treatment improved the therapeutic effects of BMSCs on ulcerative colitis, potentially providing a novel clinical treatment strategy for colitis.
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Affiliation(s)
- Zhijuan Zheng
- Experimental Center, Key Laboratory of Traditional Chinese Medicine Classical Theory, Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Junqing Wang
- College of Health Science, Shandong University of Traditional Chinese Medicine, Jinan, China
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Belkozhayev AM, Al-Yozbaki M, George A, Niyazova RY, Sharipov KO, Byrne LJ, Wilson CM. Extracellular Vesicles, Stem Cells and the Role of miRNAs in Neurodegeneration. Curr Neuropharmacol 2022; 20:1450-1478. [PMID: 34414870 PMCID: PMC9881087 DOI: 10.2174/1570159x19666210817150141] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/16/2021] [Accepted: 06/14/2021] [Indexed: 11/22/2022] Open
Abstract
There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington's disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases.
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Affiliation(s)
- Ayaz M. Belkozhayev
- Al-Farabi Kazakh National University, Faculty of Biology and Biotechnology, Almaty, Republic of Kazakhstan
- Structural and Functional Genomics Laboratory of M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, Almaty, Republic of Kazakhstan
| | - Minnatallah Al-Yozbaki
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
| | - Alex George
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
- Jubilee Centre for Medical Research, Jubilee Mission Medical College & Research Institute, Thrissur, Kerala, India
| | - Raigul Ye Niyazova
- Al-Farabi Kazakh National University, Faculty of Biology and Biotechnology, Almaty, Republic of Kazakhstan
| | - Kamalidin O. Sharipov
- Structural and Functional Genomics Laboratory of M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, Almaty, Republic of Kazakhstan
| | - Lee J. Byrne
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
| | - Cornelia M. Wilson
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
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Pavlova LN, Zhavoronkov LP, Pavlov VV, Panfilova VV, Izmest'eva OS, Chibisova OF, Ivanov VL, Shegai PV, Kaprin AD. Experimental Study of the Efficacy of Sodium Deoxyribonucleate Used in Combination with Co-Transplantation of Mesenchymal and Hematopoietic Stem Cells after Exposure to γ-Radiation. Bull Exp Biol Med 2021; 172:236-244. [PMID: 34855080 DOI: 10.1007/s10517-021-05369-z] [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: 02/16/2021] [Indexed: 11/26/2022]
Abstract
We studied the possibility of using sodium deoxyribonucleate (Derinat) for improving the efficiency of co-transplantation of mesenchymal (MSC) and hematopoietic stem cells (HSC) to female F1(CBA×C57BL/6) mice with bone marrow aplasia caused by exposure to γ-radiation. It was found that immunomodulator Derinat enhanced the effect of co-transplantation, in particular, triple post-irradiation administration of Derinat accelerated hematopoiesis recovery judging from the parameters of peripheral blood, total cellularity of the bone marrow and spleen, and animal survival. Single or double administration of Derinat prior to irradiation was ineffective. The optimal result was obtained when the following scheme was applied: MSC→HSC with an interval of 48 h starting during the first hours after irradiation and triple administration of Derinat (in 10-15 min, 3 and 7 days after irradiation) in a dose of 3 mg/mouse.
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Affiliation(s)
- L N Pavlova
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia.
| | - L P Zhavoronkov
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - V V Pavlov
- Clinical Hospital No. 8, Federal Medical-Biological Agency of Russia, Obninsk, Russia
| | - V V Panfilova
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - O S Izmest'eva
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - O F Chibisova
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - V L Ivanov
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - P V Shegai
- National Medical Research Centre of Radiology, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - A D Kaprin
- National Medical Research Centre of Radiology, Ministry of Health of the Russian Federation, Obninsk, Russia
- Peoples' Friendship University of Russia, Moscow, Russia
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MacVittie TJ, Farese AM. Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule. JOURNAL OF RADIOLOGICAL PROTECTION : OFFICIAL JOURNAL OF THE SOCIETY FOR RADIOLOGICAL PROTECTION 2021; 41:S438-S453. [PMID: 34433144 DOI: 10.1088/1361-6498/ac20e0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/25/2021] [Indexed: 06/13/2023]
Abstract
Recent advances in medical countermeasures (MCMs) has been dependent on the Food and Drug Administration (FDA) animal rule (AR) and the final guidance document provided for industry on product development. The criteria outlined therein establish the path for approval under the AR. The guidance document, along with the funding and requirements from the federal agencies provided the basic considerations for animal model development in assessing radiation effects and efficacy against the potential lethal effects of acute radiation injury and the delayed effects of acute exposure. Animal models, essential for determining MCM efficacy, were developed and validated to assess organ-specific, potentially lethal, radiation effects against the gastrointestinal (GI) and hematopoietic acute radiation syndrome (H-ARS), and radiation-induced delayed effects to lung and associated comorbidities of prolonged immune suppression, GI, kidney and heart injury. Partial-body irradiation models where marginal bone marrow was spared resulted in the ability to evaluate the concomitant evolution of multiple organ injury in the acute and delayed effects in survivors of acute radiation exposure. There are no MCMs for prophylaxis against the major sequelae of the ARS or the delayed effects of acute exposure. Also lacking are MCMs that will mitigate the GI ARS consequent to potentially lethal exposure from a terrorist event or major radiation accident. Additionally, the gap in countermeasures for prophylaxis may extend to mixed neutron/gamma radiation if current modelling predicts prompt exposure from an improvised nuclear device. However, progress in the field of MCM development has been made due to federal and corporate funding, clarification of the critical criteria for efficacy within the FDA AR and the concomitant development and validation of additional animal models. These models provided for a strategic and tactical approach to determine radiation effects and MCM efficacy.
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Affiliation(s)
- Thomas J MacVittie
- Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD, 21201, United States of America
| | - Ann M Farese
- Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD, 21201, United States of America
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36
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Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment. Int J Mol Sci 2021; 22:ijms222011187. [PMID: 34681842 PMCID: PMC8538190 DOI: 10.3390/ijms222011187] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 12/15/2022] Open
Abstract
Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem cells (MSCs) can cross biological barriers, migrate to sites of injuries to exert many healing effects, and be engineered to incorporate different types of cargo, making them an ideal vehicle to transport anti-tumor agents to the central nervous system. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) have valuable innate properties from parent cells, and are being exploited as cell-free treatments for many neurological diseases. Compared to using MSCs, targeted delivery via MSC-EVs has a better pharmacokinetic profile, yet avoids many critical issues of cell-based systems. As the field of MSC therapeutic applications is quickly expanding, this article aims to give an overall picture for one direction of EV-based targeting of brain tumors, with updates on available techniques, outcomes of experimental models, and critical challenges of this concept.
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Cell-Based Transplantation versus Cell Homing Approaches for Pulp-Dentin Complex Regeneration. Stem Cells Int 2021; 2021:8483668. [PMID: 34646323 PMCID: PMC8505125 DOI: 10.1155/2021/8483668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/01/2021] [Accepted: 08/19/2021] [Indexed: 12/19/2022] Open
Abstract
Regenerative dentistry has paved the way for a new era for the replacement of damaged dental tissues. Whether the causative factor is dental caries, trauma, or chemical insult, the loss of the pulp vitality constitutes one of the major health problems worldwide. Two regenerative therapies were introduced for a fully functional pulp-dentin complex regeneration, namely, cell-based (cell transplantation) and cell homing (through revascularization or homing by injection of stem cells in situ or intravenously) therapies, with each demonstrating advantages as well as drawbacks, especially in clinical application. The present review is aimed at elaborating on these two techniques in the treatment of irreversibly inflamed or necrotic pulp, which is aimed at regenerating a fully functional pulp-dentin complex.
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Farese AM, Drouet M, Herodin F, Bertho JM, Thrall KD, Authier S, Doyle-Eisele M, MacVittie TJ. Acute Radiation Effects, the H-ARS in the Non-human Primate: A Review and New Data for the Cynomolgus Macaque with Reference to the Rhesus Macaque. HEALTH PHYSICS 2021; 121:304-330. [PMID: 34546214 DOI: 10.1097/hp.0000000000001442] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
ABSTRACT Medical countermeasure development under the US Food and Drug Administration animal rule requires validated animal models of acute radiation effects. The key large animal model is the non-human primate, rhesus macaque. To date, only the rhesus macaque has been used for both critical supportive data and pivotal efficacy trials seeking US Food and Drug Administration approval. The potential for use of the rhesus for other high priority studies such as vaccine development underscores the need to identify another non-human primate model to account for the current lack of rhesus for medical countermeasure development. The cynomolgus macaque, Macaca fascicularis, has an existing database of medical countermeasure development against the hematopoietic acute radiation syndrome, as well as the use of radiation exposure protocols that mimic the likely nonuniform and heterogenous exposure consequent to a nuclear terrorist event. The review herein describes published studies of adult male cynomolgus macaques that used two exposure protocols-unilateral, nonuniform total-body irradiation and partial-body irradiation with bone marrow sparing-with the administration of subject-based medical management to assess mitigation against the hematopoietic acute radiation syndrome. These studies assessed the efficacy of cytokine combinations and cell-based therapy to mitigate acute radiation-induced myelosuppression. Both therapeutics were shown to mitigate the myelosuppression of the hematopoietic acute radiation syndrome. Additional studies being presented herein further defined the dose-dependent hematopoietic acute radiation syndrome of cynomolgus and rhesus macaques and a differential dose-dependent effect with young male and female cynomolgus macaques. The database supports the investigation of the cynomolgus macaque as a comparable non-human primate for efficacy testing under the US Food and Drug Administration animal rule. Critical gaps in knowledge required to validate the models and exposure protocols are also identified.
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Affiliation(s)
- Ann M Farese
- University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore
| | - Michel Drouet
- Armed Forces Biomedical Research Institute, France, Department of Radiobiology, Brétigny-sur-Orge, France
| | | | - Jean-Marc Bertho
- Institute of Radiation Protection and Nuclear Safety (IRSN), 31 avenue de la division Leclerc, 92260, Fontenay-aux-Roses, France; Present address: French Nuclear Safety Authority (ASN), 15 rue Louis Lejeune 92540 Montrouge, France
| | | | - Simon Authier
- Charles River, 445 Armand Frappier, Laval, QC, Canada, H7V 4B3
| | - Melanie Doyle-Eisele
- Lovelace Biomedical Research Institute, Laboratory Animal Sciences (Life Sciences), Albuquerque, NM
| | - Thomas J MacVittie
- University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore
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Fish BL, MacVittie TJ, Gao F, Narayanan J, Gasperetti T, Scholler D, Sheinin Y, Himburg HA, Hart B, Medhora M. Rat Models of Partial-body Irradiation with Bone Marrow-sparing (Leg-out PBI) Designed for FDA Approval of Countermeasures for Mitigation of Acute and Delayed Injuries by Radiation. HEALTH PHYSICS 2021; 121:419-433. [PMID: 34546222 PMCID: PMC8577554 DOI: 10.1097/hp.0000000000001444] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
ABSTRACT The goal of this study was to develop rat models of partial body irradiation with bone-marrow sparing (leg-out PBI) to test medical countermeasures (MCM) of both acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE) under the FDA animal rule. The leg-out PBI models were developed in female and male WAG/RijCmcr rats at doses of 12.5-14.5 Gy. Rats received supportive care consisting of fluids and antibiotics. Gastrointestinal ARS (GI-ARS) was assessed by lethality to d 7 and diarrhea scoring to d 10. Differential blood counts were analyzed between d 1-42 for the natural history of hematopoietic ARS (H-ARS). Lethality and breathing intervals (BI) were measured between d 28-110 to assess delayed injury to the lung (L-DEARE). Kidney injury (K-DEARE) was evaluated by measuring elevation of blood urea nitrogen (BUN) between d 90-180. The LD50/30, including both lethality from GI-ARS and H-ARS, for female and male rats are 14.0 Gy and 13.5 Gy, respectively, while the LD50/7 for only GI-ARS are 14.3 Gy and 13.6 Gy, respectively. The all-cause mortalities, including ARS and L-DEARE, through 120 d (LD50/120) are 13.5 Gy and 12.9 Gy, respectively. Secondary end points confirmed occurrence of four distinct sequelae representing GI, hematopoietic, lung, and kidney toxicities after leg-out PBI. Adult rat models of leg-out PBI showed the acute and long-term sequelae of radiation damage that has been reported in human radiation exposure case studies. Sex-specific differences were observed in the DRR between females and males. These rat models are among the most useful for the development and approval of countermeasures for mitigation of radiation injuries under the FDA animal rule.
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Affiliation(s)
- Brian L. Fish
- Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Thomas J. MacVittie
- Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD 21201
| | - Feng Gao
- Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Jayashree Narayanan
- Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Tracy Gasperetti
- Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Dana Scholler
- Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Yuri Sheinin
- Department of Pathology, Medical College of Wisconsin, 9200 Watertown Plank Road, Milwaukee, WI 53226
| | - Heather A. Himburg
- Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Barry Hart
- Innovation Pathways, Palo Alto, CA. 94301
| | - Meetha Medhora
- Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
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Farese AM, Booth C, Tudor GL, Cui W, Cohen EP, Parker GA, Hankey KG, MacVittie TJ. The Natural History of Acute Radiation-induced H-ARS and Concomitant Multi-organ Injury in the Non-human Primate: The MCART Experience. HEALTH PHYSICS 2021; 121:282-303. [PMID: 34546213 PMCID: PMC8462029 DOI: 10.1097/hp.0000000000001451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
ABSTRACT The dose response relationship and corresponding values for mid-lethal dose and slope are used to define the dose- and time-dependent parameters of the hematopoietic acute radiation syndrome. The characteristic time course of mortality, morbidity, and secondary endpoints are well defined. The concomitant comorbidities, potential mortality, and other multi-organ injuries that are similarly dose- and time-dependent are less defined. Determination of the natural history or pathophysiology associated with the lethal hematopoietic acute radiation syndrome is a significant gap in knowledge, especially when considered in the context of a nuclear weapon scenario. In this regard, the exposure is likely ill-defined, heterogenous, and nonuniform. These conditions forecast sparing of bone marrow and increased survival from the acute radiation syndrome consequent to threshold doses for the delayed effects of acute radiation exposure due to marrow sparing, medical management, and use of approved medical countermeasures. The intent herein is to provide a composite natural history of the pathophysiology concomitant with the evolution of the potentially lethal hematopoietic acute radiation syndrome derived from studies that focused on total body irradiation and partial body irradiation with bone marrow sparing. The marked differential in estimated LD50/60 from 7.5 Gy to 10.88 Gy for the total body irradiation and partial body irradiation with 5% bone marrow sparing models, respectively, provided a clear distinction between the attendant multiple organ injury and natural history of the two models that included medical management. Total body irradiation was focused on equivalent LD50/60 exposures. The 10 Gy and 11 Gy partial body with 5% bone marrow sparing exposures bracketed the LD50/60 (10.88 Gy). The incidence, progression, and duration of multiple organ injury was described for each exposure protocol within the hematopoietic acute radiation syndrome. The higher threshold doses for the partial body irradiation with bone marrow sparing protocol induced a marked degree of multiple organ injury to include lethal gastrointestinal acute radiation syndrome, prolonged crypt loss and mucosal damage, immune suppression, acute kidney injury, body weight loss, and added clinical comorbidities that defined a complex timeline of organ injury through the acute hematopoietic acute radiation syndrome. The natural history of the acute radiation syndrome presents a 60-d time segment of multi-organ sequelae that is concomitant with the latent period or time to onset of the evolving multi-organ injury of the delayed effects of acute radiation exposure.
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Affiliation(s)
- Ann M. Farese
- University of Maryland, School of Medicine, Baltimore, MD
| | | | | | - Wanchang Cui
- Armed Forces Radiobiology Research Institute, Bethesda, MD
| | - Eric P. Cohen
- University of Maryland, School of Medicine, Baltimore, MD
| | | | - Kim G. Hankey
- University of Maryland, School of Medicine, Baltimore, MD
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IFN- γ Licensing Does Not Enhance the Reduced Immunomodulatory Potential and Migratory Ability of Differentiation-Induced Porcine Bone Marrow-Derived Mesenchymal Stem Cells in an In Vitro Xenogeneic Application. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4604856. [PMID: 34527737 PMCID: PMC8437647 DOI: 10.1155/2021/4604856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 01/10/2023]
Abstract
IFN-γ licensing to mesenchymal stem cells (MSCs) is applied to enhance the therapeutic potential of MSCs. However, although the features of MSCs are affected by several stimuli, little information is available on changes to the therapeutic potential of IFN-γ-licensed differentiated MSCs during xenogeneic applications. Therefore, the present study is aimed at clarifying the effects of adipogenic/osteogenic differentiation and IFN-γ licensing on the in vitro immunomodulatory and migratory properties of porcine bone marrow-derived MSCs in xenogeneic applications using human peripheral blood mononuclear cells (PBMCs). IFN-γ licensing in differentiated MSCs lowered lineage-specific gene expression but did not affect MSC-specific cell surface molecules. Although indoleamine 2,3 deoxygenase (IDO) activity and expression were increased after IFN-γ licensing in undifferentiated MSCs, they were reduced after differentiation. IFN-γ licensing to differentiated MSCs elevated the reduced IDO expression in differentiated MSCs; however, the increase was not sufficient to reach to the level achieved by undifferentiated MSCs. During a mixed lymphocyte reaction with quantification of TNF-α concentration, proliferation and activation of xenogeneic PBMCs were suppressed by undifferentiated MSCs but inhibited to a lesser extent by differentiated MSCs. IFN-γ licensing increasingly suppressed proliferation of PBMCs in undifferentiated MSCs but it was incapable of elevating the reduced immunosuppressive ability of differentiated MSCs. Migratory ability through a scratch assay and gene expression study was reduced in differentiated MSCs than their undifferentiated counterparts; IFN-γ licensing was unable to enhance the reduced migratory ability in differentiated MSCs. Similar results were found in a Transwell system with differentiated MSCs in the upper chamber toward xenogeneic PBMCs in the lower chamber, despite IFN-γ licensing increased the migratory ability of undifferentiated MSCs. Overall, IFN-γ licensing did not enhance the reduced immunomodulatory and migratory properties of differentiated MSCs in a xenogeneic application. This study provides a better understanding of the ways in which MSC therapy can be applied.
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Mesenchymal Stem Cell-Conditioned Media Regulate Steroidogenesis and Inhibit Androgen Secretion in a PCOS Cell Model via BMP-2. Int J Mol Sci 2021; 22:ijms22179184. [PMID: 34502090 PMCID: PMC8431467 DOI: 10.3390/ijms22179184] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Previous studies have demonstrated the therapeutic efficacy of human bone marrow mesenchymal stem cells (BM-hMSCs) for PCOS; however, the regulatory mechanism remains unknown. Bone morphogenetic proteins (BMPs) secreted by BM-hMSCs may underlie the therapeutic effect of these cells on PCOS, based on the ability of BMPs to modulate androgen production and alter steroidogenesis pathway enzymes. In this study, we analyze the effect of BMP-2 on androgen production and steroidogenic pathway enzymes in H295R cells as a human PCOS in vitro cell model. In H295R cells, BMP-2 significantly suppressed cell proliferation, androgen production, and expression of androgen-synthesizing genes, as well as inflammatory gene expression. Furthermore, H295R cells treated with the BM-hMSCs secretome in the presence of neutralizing BMP-2 antibody or with BMP-2 gene knockdown showed augmented expression of androgen-producing genes. Taken together, these results indicate that BMP-2 is a key player mediating the favorable effects of the BM-hMSCs secretome in a human PCOS cell model. BMP-2 overexpression could increase the efficacy of BM-hMSC-based therapy, serving as a novel stem cell therapy for patients with intractable PCOS.
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da Silva KN, Gobatto ALN, Costa-Ferro ZSM, Cavalcante BRR, Caria ACI, de Aragão França LS, Nonaka CKV, de Macêdo Lima F, Lopes-Pacheco M, Rocco PRM, de Freitas Souza BS. Is there a place for mesenchymal stromal cell-based therapies in the therapeutic armamentarium against COVID-19? Stem Cell Res Ther 2021; 12:425. [PMID: 34315546 PMCID: PMC8314259 DOI: 10.1186/s13287-021-02502-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023] Open
Abstract
The COVID-19 pandemic, caused by the rapid global spread of the novel coronavirus (SARS-CoV-2), has caused healthcare systems to collapse and led to hundreds of thousands of deaths. The clinical spectrum of COVID-19 is not only limited to local pneumonia but also represents multiple organ involvement, with potential for systemic complications. One year after the pandemic, pathophysiological knowledge has evolved, and many therapeutic advances have occurred, but mortality rates are still elevated in severe/critical COVID-19 cases. Mesenchymal stromal cells (MSCs) can exert immunomodulatory, antiviral, and pro-regenerative paracrine/endocrine actions and are therefore promising candidates for MSC-based therapies. In this review, we discuss the rationale for MSC-based therapies based on currently available preclinical and clinical evidence of safety, potential efficacy, and mechanisms of action. Finally, we present a critical analysis of the risks, limitations, challenges, and opportunities that place MSC-based products as a therapeutic strategy that may complement the current arsenal against COVID-19 and reduce the pandemic's unmet medical needs.
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Affiliation(s)
- Kátia Nunes da Silva
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | | | - Zaquer Suzana Munhoz Costa-Ferro
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | - Bruno Raphael Ribeiro Cavalcante
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil
| | - Alex Cleber Improta Caria
- Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Salvador, Brazil
| | - Luciana Souza de Aragão França
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | - Carolina Kymie Vasques Nonaka
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | | | - Miquéias Lopes-Pacheco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patricia Rieken Macêdo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
- COVID-19 Virus Network, Ministry of Science and Technology, and Innovation, Rio de Janeiro, Brazil
| | - Bruno Solano de Freitas Souza
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil.
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil.
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil.
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Mercer-Smith AR, Findlay IA, Bomba HN, Hingtgen SD. Intravenously Infused Stem Cells for Cancer Treatment. Stem Cell Rev Rep 2021; 17:2025-2041. [PMID: 34138421 DOI: 10.1007/s12015-021-10192-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2021] [Indexed: 01/14/2023]
Abstract
Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be engineered to secrete cytotoxic products, loaded with oncolytic viruses or nanoparticles containing small molecule drugs, or conjugated with immunotherapies. Herein we describe these preclinical and clinical studies, discuss the distribution and migration of stem cells following intravenous infusion, and examine both the limitations of and the methods to improve the migration and therapeutic efficacy of tumoritropic, therapeutic stem cells.
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Affiliation(s)
- Alison R Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Ingrid A Findlay
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Hunter N Bomba
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA. .,Department of Neurosurgery, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA.
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Sandonà M, Di Pietro L, Esposito F, Ventura A, Silini AR, Parolini O, Saccone V. Mesenchymal Stromal Cells and Their Secretome: New Therapeutic Perspectives for Skeletal Muscle Regeneration. Front Bioeng Biotechnol 2021; 9:652970. [PMID: 34095095 PMCID: PMC8172230 DOI: 10.3389/fbioe.2021.652970] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells found in different tissues: bone marrow, peripheral blood, adipose tissues, skeletal muscle, perinatal tissues, and dental pulp. MSCs are able to self-renew and to differentiate into multiple lineages, and they have been extensively used for cell therapy mostly owing to their anti-fibrotic and immunoregulatory properties that have been suggested to be at the basis for their regenerative capability. MSCs exert their effects by releasing a variety of biologically active molecules such as growth factors, chemokines, and cytokines, either as soluble proteins or enclosed in extracellular vesicles (EVs). Analyses of MSC-derived secretome and in particular studies on EVs are attracting great attention from a medical point of view due to their ability to mimic all the therapeutic effects produced by the MSCs (i.e., endogenous tissue repair and regulation of the immune system). MSC-EVs could be advantageous compared with the parental cells because of their specific cargo containing mRNAs, miRNAs, and proteins that can be biologically transferred to recipient cells. MSC-EV storage, transfer, and production are easier; and their administration is also safer than MSC therapy. The skeletal muscle is a very adaptive tissue, but its regenerative potential is altered during acute and chronic conditions. Recent works demonstrate that both MSCs and their secretome are able to help myofiber regeneration enhancing myogenesis and, interestingly, can be manipulated as a novel strategy for therapeutic interventions in muscular diseases like muscular dystrophies or atrophy. In particular, MSC-EVs represent promising candidates for cell free-based muscle regeneration. In this review, we aim to give a complete picture of the therapeutic properties and advantages of MSCs and their products (MSC-derived EVs and secreted factors) relevant for skeletal muscle regeneration in main muscular diseases.
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Affiliation(s)
- Martina Sandonà
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Lorena Di Pietro
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Federica Esposito
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Alessia Ventura
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Antonietta Rosa Silini
- Centro di Ricerca "E. Menni", Fondazione Poliambulanza - Istituto Ospedaliero, Brescia, Italy
| | - Ornella Parolini
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy
| | - Valentina Saccone
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy.,Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
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Abstract
PURPOSE OF REVIEW Liver transplantation is the gold standard for the treatment of end-stage liver disease. However, a shortage of donor organs, high cost, and surgical complications limit the use of this treatment. Cellular therapies using hepatocytes, hematopoietic stem cells, bone marrow mononuclear cells, and mesenchymal stem cells (MSCs) are being investigated as alternative treatments to liver transplantation. The purpose of this review is to describe studies using MSC transplantation for liver diseases based on the reported literature and to discuss prospective research designed to improve the efficacy of MSC therapy. RECENT FINDINGS MSCs have several properties that show potential to regenerate injured tissues or organs, such as homing, transdifferentiation, immunosuppression, and cellular protective capacity. Additionally, MSCs can be noninvasively isolated from various tissues and expanded ex vivo in sufficient numbers for clinical evaluation. SUMMARY Currently, there is no approved MSC therapy for the treatment of liver disease. However, MSC therapy is considered a promising alternative treatment for end-stage liver diseases and is reported to improve liver function safely with no side effects. Further robust preclinical and clinical studies will be needed to improve the therapeutic efficacy of MSC transplantation.
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Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, Huang YH, Ling TY. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci 2021; 28:28. [PMID: 33849537 PMCID: PMC8043779 DOI: 10.1186/s12929-021-00725-7] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.
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Affiliation(s)
- Wei-Zhan Zhuang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Yi-Heng Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan
| | - Long-Jyun Su
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan
| | - Meng-Shiue Wu
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan
| | - Han-Yin Jeng
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Huan-Cheng Chang
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.,Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. .,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. .,Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. .,The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. .,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan.
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Ma Z, Zhou J, Yang T, Xie W, Song G, Song Z, Chen J. Mesenchymal stromal cell therapy for pancreatitis: Progress and challenges. Med Res Rev 2021; 41:2474-2488. [PMID: 33840113 DOI: 10.1002/med.21801] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/17/2020] [Accepted: 03/23/2021] [Indexed: 12/15/2022]
Abstract
Pancreatitis is a common gastrointestinal disease with no effective therapeutic options, particularly for cases of severe acute and chronic pancreatitis (CP). Mesenchymal stromal cells (MSCs) are multipotent cells with diverse biological properties, including directional migration, paracrine, immunosuppressive, and antiinflammatory effects, which are considered an ideal candidate cell type for repairing tissue damage caused by various pathogenies. Several researchers have reported significant therapeutic efficacy of MSCs in animal models of acute and CP. However, the specific underlying mechanisms are yet to be clarified and clinical application of MSCs as pancreatitis therapy has rarely been reported. This review mainly focuses on the potential and challenges in clinical application of MSCs for treatment of acute and CP, along with discussion of the underlying molecular mechanisms.
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Affiliation(s)
- Zhilong Ma
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jia Zhou
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tingsong Yang
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wangcheng Xie
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guodong Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhenshun Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ji Chen
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002944. [PMID: 33854883 PMCID: PMC8024997 DOI: 10.1002/advs.202002944] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/23/2020] [Indexed: 05/13/2023]
Abstract
Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell-based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell-based therapies.
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Affiliation(s)
- Anna Andrzejewska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Sylwia Dabrowska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Barbara Lukomska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Miroslaw Janowski
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
- Center for Advanced Imaging ResearchDepartment of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
- Tumor Immunology and Immunotherapy ProgramUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
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50
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Yigitbilek F, Conley SM, Tang H, Saadiq IM, Jordan KL, Lerman LO, Taner T. Comparable in vitro Function of Human Liver-Derived and Adipose Tissue-Derived Mesenchymal Stromal Cells: Implications for Cell-Based Therapy. Front Cell Dev Biol 2021; 9:641792. [PMID: 33842466 PMCID: PMC8033021 DOI: 10.3389/fcell.2021.641792] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have been investigated extensively for their immunotherapeutic and regenerative properties, which may differ by cell source. In MSCs harvested from donors matched for sex, age, and body mass index, we compared the proliferative and migration functions of liver-derived MSCs (L-MSCs) and adipose tissue-derived MSCs (A-MSCs) (n = 6 donors each). Cellular senescence was evaluated by senescence-associated beta-galactosidase enzyme activity and expression of senescence-associated secretory phenotype (SASP) factors using real-time quantitative polymerase chain and by western blot assay. The pro-angiogenic and reparative potency of MSCs was compared by co-culturing MSCs with injured human umbilical vein endothelial cells (HUVEC). The proliferation and migration properties were similar in L-MSCs and A-MSCs. Although cell cycle arrest and SASP genes were similarly expressed in both MSCs, tumor necrosis factor alpha gene and protein expression were significantly downregulated in L-MSCs. In co-cultured injured HUVEC, A-MSCs restored significantly more tubes and tube connections than L-MSCs. Therefore, despite many functional similarities between L-MSCs and A-MSCs, L-MSCs have enhanced immunomodulatory properties, while A-MSCs appear to have better pro-angiogenic and vascular reparative potency. Availability of a broad range of cellular options might enable selecting cell-based therapy appropriate for the specific underlying disease.
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Affiliation(s)
- Furkan Yigitbilek
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
| | - Sabena M. Conley
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Ishran M. Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Kyra L. Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Timucin Taner
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
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