1
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Liu Y, Li C, Cui X, Li M, Liu S, Wang Z. Potentially diagnostic and prognostic roles of piRNAs/PIWIs in pancreatic cancer: A review. Biochim Biophys Acta Rev Cancer 2025; 1880:189286. [PMID: 39952623 DOI: 10.1016/j.bbcan.2025.189286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/17/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited early diagnostic methods and therapeutic options, contributing to its poor prognosis. Recent advances in high-throughput sequencing have highlighted the critical roles of noncoding RNAs (ncRNAs), particularly PIWI-interacting RNAs (piRNAs), in cancer biology. In this review, we systematically summarize the emerging roles of piRNAs and their associated PIWI proteins in PDAC pathogenesis, progression, and prognosis. We provide a comprehensive analysis of the molecular mechanisms by which piRNAs/PIWIs regulate gene expression and cellular signaling pathways in PDAC. Furthermore, we discuss their potential as novel biomarkers for early diagnosis and therapeutic targets. Importantly, this review identifies key piRNAs/PIWIs involved in PDAC and proposes innovative strategies for improving diagnosis and treatment outcomes. Our work not only consolidates current knowledge but also offers new perspectives for future research and clinical applications in PDAC management.
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Affiliation(s)
- Yukun Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Changlei Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaotong Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Miaomiao Li
- Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Shiguo Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Zusen Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
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2
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Pindiprolu SKSS, Singh MT, Magham SV, Kumar CSP, Dasari N, Gummadi R, Krishnamurthy PT. Nanocarrier-mediated modulation of cGAS-STING signaling pathway to disrupt tumor microenvironment. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03835-3. [PMID: 39907784 DOI: 10.1007/s00210-025-03835-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 01/18/2025] [Indexed: 02/06/2025]
Abstract
The cGAS-STING signaling plays an important role in the immune response in a tumor microenvironment (TME) of triple-negative breast cancer (TNBC). The acute and controlled activation of cGAS-STING signaling results in tumor suppression, while chronic activation of cGAS-STING signaling results in immune-suppressive TME that could result in tumor survival. There is a need, therefore, to develop therapeutic strategies for harnessing tumor suppressive effects of cGAS-STING signaling while minimizing the risks associated with chronic activation. Combination therapies and nanocarriers-based delivery of cGAS-STING agonists have emerged as promising strategies in immunotherapy for controlled modulation of cGAS-STING signaling in cancer. These approaches aim to optimize the tumor suppressive effects of the cGAS-STING pathway while minimizing the challenges associated with modulators of cGAS-STING signaling. In the present review, we discuss recent advancements and strategies in combination therapies and nanocarrier-based delivery systems for effectively controlling cGAS-STING signaling in cancer immunotherapy. Further, we emphasized the significance of nanocarrier-based approaches for effective targeting of the cGAS-STING signaling, tackling resistance mechanisms, and overcoming key challenges like immune suppression, tumor heterogeneity, and off-target effects.
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Affiliation(s)
| | - Madhu Tanya Singh
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, 20, Rocklands, Ooty, 643001, The Nilgiris, Tamil Nadu, India
| | - Sai Varshini Magham
- Department of Pharmacology, Vignan Pharmacy College, Vadlamudi, Guntur, India
| | | | - Nagasen Dasari
- School of Pharmacy, Aditya University, Surampalem, Andhra Pradesh, India
| | | | - Praveen Thaggikuppe Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, 20, Rocklands, Ooty, 643001, The Nilgiris, Tamil Nadu, India.
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3
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Zhand S, Goss DM, Cheng YY, Warkiani ME. Recent Advances in Microfluidics for Nucleic Acid Analysis of Small Extracellular Vesicles in Cancer. Adv Healthc Mater 2025; 14:e2401295. [PMID: 39707658 DOI: 10.1002/adhm.202401295] [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: 04/08/2024] [Revised: 11/28/2024] [Indexed: 12/23/2024]
Abstract
Small extracellular vesicles (sEVs) are membranous vesicles released from cellular structures through plasma membrane budding. These vesicles contain cellular components such as proteins, lipids, mRNAs, microRNAs, long-noncoding RNA, circular RNA, and double-stranded DNA, originating from the cells they are shed from. Ranging in size from ≈25 to 300 nm and play critical roles in facilitating cell-to-cell communication by transporting signaling molecules. The discovery of sEVs in bodily fluids and their involvement in intercellular communication has revolutionized the fields of diagnosis, prognosis, and treatment, particularly in diseases like cancer. Conventional methods for isolating and analyzing sEVs, particularly their nucleic acid content face challenges including high costs, low purity, time-consuming processes, limited standardization, and inconsistent yield. The development of microfluidic devices, enables improved precision in sorting, isolating, and molecular-level separation using small sample volumes, and offers significant potential for the enhanced detection and monitoring of sEVs associated with cancer. These advanced techniques hold great promise for creating next-generation diagnostic and prognostic tools given their possibility of being cost-effective, simple to operate, etc. This comprehensive review explores the current state of research on microfluidic devices for the detection of sEV-derived nucleic acids as biomarkers and their translation into practical point-of-care and clinical applications.
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Affiliation(s)
- Sareh Zhand
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Dale Mark Goss
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Yuen Yee Cheng
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia
- Institute of Molecular Theranostics, Sechenov First Moscow State University, Moscow, 119991, Russia
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4
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Li R, Wang H, Wang X, Yang Y, Zhong K, Zhang X, Li H. MSC-EVs and UCB-EVs promote skin wound healing and spatial transcriptome analysis. Sci Rep 2025; 15:4006. [PMID: 39893214 PMCID: PMC11787299 DOI: 10.1038/s41598-025-87592-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025] Open
Abstract
Extracellular vesicles (EVs) are important paracrine mediators derived from various cells and biological fluids, including plasma, that are capable of inducing regenerative effects by transferring bioactive molecules such as microRNAs (miRNAs). This study investigated the effect of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) isolated from umbilical cord blood and human umbilical cord plasma-derived extracellular vesicles (UCB-EVs) on wound healing and scar formation reduction. Spatial transcriptomics (ST) was used to study the effects of MSC-EVs and UCB-EVs on the heterogeneity of major cell types and wound healing pathways in mouse skin tissue. MSC-EVs and UCB-EVs were isolated using ultracentrifugation and identified using transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of MSC-EVs and UCB-EVs on human dermal fibroblast-adult cell (HDF-a) migration and proliferation were evaluated using cell scratch assays, cell migration assays, and cell proliferation assays. In vivo, MSC-EVs and UCB-EVs were injected around full-cut wounds to evaluate their efficacy of wound healing by measuring wound closure rates and scar width and performing histological analysis. ST was performed on skin tissue samples from mice in each group after wound healing to analyze the heterogeneity of major cell types compared with the control group and investigate potential mechanisms affecting wound healing and scar formation. In vitro experiments demonstrated that MSC-EVs and UCB-EVs promoted the proliferation and migration of HDF-a cells. Local injection of MSC-EVs and UCB-EVs into the periphery of a mouse skin wound accelerated re-epithelialization, promoted wound healing, and reduced scar width. ST analysis of skin tissue from each group after wound healing revealed that MSC-EVs and UCB-EVs reduced the relative expression of marker genes in myofibroblasts, regulated wound healing, and decreased scar formation by reducing the expression of the TGF-β signaling pathway and increasing the expression of the Wnt signaling pathway. The results suggest that MSC-EVs and UCB-EVs play a significant role in the activity of cord blood plasma-derived mesenchymal stem cells and cord blood plasma. They can be considered promising new agents for promoting skin wound healing.
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Affiliation(s)
- Ruonan Li
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Haotian Wang
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Xiaolong Wang
- HenanYinfeng Biological Engineering Technology Co., LTD, No. 11 Changchun Road, Zhengzhou High tech Industrial Development Zone, Zhengzhou, 450000, China
| | - Yanbin Yang
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Kai Zhong
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China.
| | - Xuemei Zhang
- HenanYinfeng Biological Engineering Technology Co., LTD, No. 11 Changchun Road, Zhengzhou High tech Industrial Development Zone, Zhengzhou, 450000, China.
| | - Heping Li
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China.
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Lapato DM, Frye R, Yakovlev V, Roberson-Nay R. Oral Contraceptive Use Is Associated with Significant Differences in MicroRNA Cargo of L1CAM-Associated Extracellular Vesicles. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.15.25320605. [PMID: 39867402 PMCID: PMC11759612 DOI: 10.1101/2025.01.15.25320605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Oral contraceptives (OCs) are approved for use after onset of menarche, which is well before brain maturation is complete. OC use may induce biochemical changes in the brain, especially during the neurobiologically dynamic adolescent/young adult years. MicroRNA cargo in L1CAM-associated extracellular vesicles was measured from serum samples collected from young women using the miRCURY LNA miRNA Focus PCR Panel (Qiagen) and validated using quantitative PCR. Linear regression and F-tests were applied to identify differentially expressed microRNAs by OC use (never versus current), and PANTHER pathway analysis was conducted on the gene targets of significantly differentially expressed microRNAs. Twelve microRNAs had significant differential expression variability by OC use (Bonferroni adjusted p < 0.002). Pathway analysis revealed that the 1254 unique genes targeted by the significant microRNAs were most enriched for the Gonadotropin-releasing hormone receptor pathway (FDR q = 5 × 10-7), which is associated with the release of gonadotropins, pubertal development, and reproduction. The results are consistent with the hypothesis that microRNA cargo in circulating extracellular vesicles may reflect brain-related biological activity and that OC use may influence extracellular vesicle cargo composition. The significant difference in expression variability may have implications for designing future studies, including power calculations.
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Affiliation(s)
- Dana M Lapato
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Rebekah Frye
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22902, USA
| | - Vasily Yakovlev
- Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Roxann Roberson-Nay
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22902, USA
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6
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Yang C, Song Y, Luo M, Wang Q, Zhang Y, Cen J, Du G, Shi J. Exosomes-encapsulated biomimetic polydopamine carbon dots with dual-targeting effect alleviate motor and non-motor symptoms of Parkinson's disease via anti-neuroinflammation. Int J Biol Macromol 2025; 296:139724. [PMID: 39809402 DOI: 10.1016/j.ijbiomac.2025.139724] [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: 08/16/2024] [Revised: 12/22/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025]
Abstract
Currently, the clinical drugs for Parkinson's disease (PD) only focus on motor symptoms, while non-motor symptoms like depression are usually neglected. Even though, the efficacy of existing neurotherapeutic drugs is extremely poor which is due to the blood brain barrier (BBB). Therefore, a biomimetic polydopamine carbon dots (PDA C-dots) at 2-4 nm was synthesized, while exosomes from macrophages were applied to encapsulate PDA C-dots for improving their BBB-crossing ability and inflammation-targeting effect. Importantly, the prepared PDA C-dots@Exosomes (PEs) significantly alleviated both motor and non-motor symptoms of PD mice. Further mechanism research revealed that PEs eliminated oxidant stress and alleviated neuroinflammation to restore the injured neurons. The content of α-syn was markedly reduced, and the neural viability was dramatically improved on the areas of substantia nigra, striata, and prefrontal cortex. In summary, this work reported a mild synthetic approach to produce a kind of PDA C-dots, which had a fantastic neuroprotective effect. After being encapsulated with exosomes of macrophages, the obtained PEs could be utilized as a neuroprotective drug with great penetration ability of BBB and targeting ability into inflammatory zone. The great therapeutic effect on both motor and non-motor symptoms of PD indicates that PEs could become a promising drug for PD treatment.
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Affiliation(s)
- Chen Yang
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China
| | - Yanhao Song
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China
| | - Mingkai Luo
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China
| | - Qiuli Wang
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China
| | - Yumei Zhang
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China
| | - Juan Cen
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China.
| | - Guanhua Du
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China.
| | - Jiahua Shi
- Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan 475004, China; State Key Laboratory of Antiviral Drugs Henan University, Henan University, Kaifeng, Henan 475004, China.
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7
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Rana R, Devi SN, Bhardwaj AK, Yashavarddhan MH, Bohra D, Ganguly NK. Exosomes as nature's nano carriers: Promising drug delivery tools and targeted therapy for glioma. Biomed Pharmacother 2025; 182:117754. [PMID: 39731936 DOI: 10.1016/j.biopha.2024.117754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
Exosomes, minute vesicles originating from diverse cell types, exhibit considerable potential as carriers for drug delivery in glioma therapy. These naturally occurring nanocarriers facilitate the transfer of proteins, RNAs, and lipids between cells, offering advantages such as biocompatibility, efficient cellular absorption, and the capability to traverse the blood-brain barrier (BBB). In the realm of cancer, particularly gliomas, exosomes play pivotal roles in modulating tumor growth, regulating immunity, and combating drug resistance. Moreover, exosomes serve as valuable biomarkers for diagnosing diseases and assessing prognosis. This review aims to elucidate the therapeutic and diagnostic promise of exosomes in glioma treatment, highlighting the innovative advances in exosome engineering that enable precise drug loading and targeting. By circumventing challenges associated with current glioma treatments, exosome-mediated drug delivery strategies can enhance the efficacy of chemotherapy drugs like temozolomide and overcome drug resistance mechanisms. This review underscores the multifaceted roles of exosomes in glioma pathogenesis and therapy, underscoring their potential as natural nanocarriers for targeted therapy and heralding a new era of hope for glioma treatment.
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Affiliation(s)
- Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
| | | | - Amit Kumar Bhardwaj
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - M H Yashavarddhan
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Deepika Bohra
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
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8
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Maynard DM, Gochuico BR, Pri Chen H, Bleck CKE, Zerfas PM, Introne WJ, Gahl WA, Malicdan MCV. Insights into the renal pathophysiology in Hermansky-Pudlak syndrome-1 from urinary extracellular vesicle proteomics and a new mouse model. FEBS Lett 2024. [PMID: 39739361 DOI: 10.1002/1873-3468.15088] [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: 09/05/2024] [Revised: 11/07/2024] [Accepted: 12/01/2024] [Indexed: 01/02/2025]
Abstract
Hermansky-Pudlak syndrome type 1 (HPS-1) is a rare, autosomal recessive disorder caused by defects in the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Impaired kidney function is among its clinical manifestations. To investigate HPS-1 renal involvement, we employed 1D-gel-LC-MS/MS and compared the protein composition of urinary extracellular vesicles (uEVs) from HPS-1 patients to normal control individuals. We identified 1029 proteins, 149 of which were altered in HPS-1 uEVs. Ingenuity Pathway Analysis revealed disruptions in mitochondrial function and the LXR/RXR pathway that regulates lipid metabolism, which is supported by our novel Hps1 knockout mouse. Serum concentration of the LXR/RXR pathway protein ApoA1 in our patient cohort was positively correlated with kidney function (with the estimated glomerular filtration rate or eGFR). uEVs can be used to study epithelial cell protein trafficking in HPS-1 and may provide outcome measures for HPS-1 therapeutic interventions.
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Affiliation(s)
- Dawn M Maynard
- Section on Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD, USA
| | - Bernadette R Gochuico
- Section on Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD, USA
| | - Hadass Pri Chen
- Section on Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD, USA
| | - Christopher K E Bleck
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Patricia M Zerfas
- Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD, USA
| | - Wendy J Introne
- Section on Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD, USA
| | - William A Gahl
- Section on Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD, USA
| | - May C V Malicdan
- Section on Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD, USA
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9
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Di SJ, Cui XW, Liu TJ, Shi YY. Therapeutic potential of human breast milk-derived exosomes in necrotizing enterocolitis. Mol Med 2024; 30:243. [PMID: 39701931 DOI: 10.1186/s10020-024-01010-7] [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: 05/18/2024] [Accepted: 11/23/2024] [Indexed: 12/21/2024] Open
Abstract
Necrotizing enterocolitis (NEC) is a severe inflammatory and necrotizing disease of the intestine that primarily affects the neonates, particularly premature infants. It has a high incidence of approximately 8.9% in extremely preterm infants, with a mortality rate ranging from 20 to 30%. In recent years, exosomes, particularly those derived from breast milk, have emerged as potential candidates for NEC therapy. Human breast milk-derived exosomes (BME) have been shown to enhance intestinal barrier function, protect intestinal epithelial cells from oxidative stress, promote the proliferation and migration of intestinal epithelial cells, and reduce the severity of experimental NEC models. As a subset of extracellular vesicles, BME possess the membrane structure, low immunogenicity, and high permeability, making them ideal vehicles for the treatment of NEC. Additionally, exosomes derived from various sources, including stem cells, intestinal epithelial cells, plants, and bacteria, have been implicated in the development and protection of intestinal diseases. This article summarizes the mechanisms through which exosomes, particularly BME, exert their effects on NEC and discusses the feasibility and obstacles associated with this novel therapeutic strategy.
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Affiliation(s)
- Si-Jia Di
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xue-Wei Cui
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Tian-Jing Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Yong-Yan Shi
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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10
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Raghav PK, Mann Z. Nano-Delivery Revolution: Harnessing Mesenchymal Stem Cell-Derived Exosomes' Potential for Wound Healing. Biomedicines 2024; 12:2791. [PMID: 39767697 PMCID: PMC11673788 DOI: 10.3390/biomedicines12122791] [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: 12/27/2023] [Revised: 03/04/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025] Open
Abstract
Stem cell transplantation has proven effective in treating acute and chronic wounds, but its limitations, such as low cellular viability and the need for specialized transportation, highlight the necessity for alternative approaches. This review explores the potential of engineered exosomes, containing identified miRNAs/peptides, as a more stable and efficient cell-free therapy for regenerative medicine, particularly in wound healing. The discussion emphasizes the benefits of exosomes, including their stability, reduced damage, and consistent biological activity, paving the way for innovative applications like lyophilized exosomes, mist spray delivery, and exosome-based scaffolds. The exploration of cell-free therapy in this review holds promising implications for advancing wound-healing strategies.
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Affiliation(s)
- Pawan Kumar Raghav
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco (UCSF), San Francisco, CA 94118, USA
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11
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Wang L, Zhang Y, Mao C, Li X. Enhancing Exosomal Delivery to Abdominal Aortic Aneurysms using Magnetically Responsive Chemotactic Nanomotors for Elastic Matrix Regenerative Repair. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405085. [PMID: 39429209 PMCID: PMC11633499 DOI: 10.1002/advs.202405085] [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: 05/11/2024] [Revised: 09/13/2024] [Indexed: 10/22/2024]
Abstract
Abdominal aortic aneurysms (AAAs) involve localized dilation of the abdominal aorta, with the reversal of this condition being significantly limited by the inherently poor and abnormal regenerative repair of the aortic elastic matrix. Mesenchymal stem cell exosomes (MSCEs) are promising regenerative tools; however, achieving precise targeting of AAA with MSCEs is challenging owing to the high blood flow in the arterial system. In this study, an engineered exosomal nanomotor is developed for magnetic and chemical propulsion. The results demonstrate that this nanomotor effectively enhances the delivery of MSCEs to the AAA through magnetic field navigation and catalase-induced chemotaxis. The nanomotor significantly enhances the elastic matrix repair, reduces oxidative stress, and activates the PI3K/Akt pathway, leading to aneurysm shrinkage and reversal. In addition, the nanomotor possesses magnetic resonance imaging capabilities. The use of this nanomotor offers a novel, targeted drug delivery system in a rat model of AAA and holds promise as a potential therapeutic option for this condition.
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Affiliation(s)
- Lulu Wang
- Department of Vascular SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu210008China
| | - Yao Zhang
- National and Local Joint Engineering Research Center of Biomedical Functional MaterialsSchool of Chemistry and Materials ScienceNanjing Normal UniversityNanjingJiangsu210023China
| | - Chun Mao
- Department of Vascular SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu210008China
- National and Local Joint Engineering Research Center of Biomedical Functional MaterialsSchool of Chemistry and Materials ScienceNanjing Normal UniversityNanjingJiangsu210023China
| | - Xiaoqiang Li
- Department of Vascular SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu210008China
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12
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Cong F, Huang J, Wu C, Zhong H, Qiu G, Luo T, Tang W. Integrin α6 and integrin β4 in exosomes promote lung metastasis of colorectal cancer. J Cancer Res Ther 2024; 20:2082-2093. [PMID: 39792419 DOI: 10.4103/jcrt.jcrt_230_24] [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: 01/30/2024] [Accepted: 10/23/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common cancers worldwide. The mechanisms underlying metastasis, which contributes to poor outcomes, remain elusive. METHODS We used the Cancer Genome Atlas dataset to compare mRNA expression patterns of integrin α6 (ITGA6) and integrin β4 (ITGB4) in patients with CRC. We measured ITGA6 and ITGB4 expression levels in highly metastatic (i.e., HCT116 and SW620) and lowly metastatic (i.e., SW480 and Caco2) CRC cell lines. Exosomes were isolated from cell culture media and characterized using western blotting and nanoparticle analyses. The role of exosomes in lung metastasis was investigated using xenograft experiments in mice models, which received CRC cell injection and were treated with exosomes. RESULTS ITGA6 and ITGB4 were significantly overexpressed in CRC tissues, and ITGA6 was associated with the American Joint Committee on Cancer (AJCC) stage and outcome. ITGA6 and ITGB4, as well as exosomal ITGA6 and ITGB4, were significantly more highly expressed in HCT116 and SW620 cells than in SW480 and Caco2 cells. The proliferation and tubulogenesis of vascular endothelial cells were markedly decreased by disruption of ITGA6 and ITGB4 but were markedly increased by ectopic expression of ITGA6 and ITGB4. Exosomal ITGA6 and ITGB4 promoted CRC metastasis to the lung in vivo. CONCLUSIONS Taken together, our findings suggested that exosomal ITGA6 and ITGB4 displayed organotropism to the lung and upregulated proliferation and tubulogenic capacities, which might help reduce lung metastasis from CRC. These findings provided new insights into the mechanisms of CRC metastasis and provided novel potential therapeutic targets.
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Affiliation(s)
- Fengyun Cong
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiahao Huang
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Changtao Wu
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Huage Zhong
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, China
| | - Guanhua Qiu
- Department of Ultrasound, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Tao Luo
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, China
| | - Weizhong Tang
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, China
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13
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Kumrah R, Jindal AK, Rawat A, Singh S. Proteomics approach for biomarker discovery in Kawasaki disease. Expert Rev Clin Immunol 2024; 20:1449-1460. [PMID: 39041312 DOI: 10.1080/1744666x.2024.2383236] [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: 04/15/2024] [Revised: 06/07/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Kawasaki disease (KD) is a medium vessel vasculitis mainly affecting children below the age of 5. KD is the leading cause of acquired heart disease in developed countries. Diagnosis of KD is clinical, and there are no pathognomonic laboratory tests to confirm the diagnosis. There is a paucity of studies that have utilized proteomic approach for biomarker discovery in KD. Identification of these biomarkers may be helpful for early and more effective diagnosis and may aid in the treatment of KD. AREA COVERED The present review focuses on studies that have utilized the proteomic approach in the identification of biomarkers in patients with KD. We have divided these biomarkers into three different categories: the biomarkers used for (a) assessment of risk of KD; (b) assessment of risk of coronary artery aneurysms; and (c) assessment of treatment resistance. EXPERT OPINION Efforts to improve the clinical and diagnostic evaluation of KD have focused on general markers of inflammation that are not specific for KD. Identification of a proteomic-based biomarker can reliably and specifically differentiate KD from other diseases and could help in the prompt diagnosis. Comprehensive analysis of the serum proteome of patients with KD may be helpful in identifying candidate protein biomarkers.
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Affiliation(s)
- Rajni Kumrah
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ankur Kumar Jindal
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Surjit Singh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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14
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Zong R, Zheng Y, Yan Y, Sun W, Kong L, Huang Y, Liu Y, Jiang C, Ping J, Li C. Mesenchymal stem cells-derived exosomes alleviate liver fibrosis by targeting Hedgehog/SMO signaling. Hepatol Int 2024; 18:1781-1791. [PMID: 39138757 DOI: 10.1007/s12072-024-10717-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/28/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND & AIMS Despite increasing knowledge regarding the cellular and molecular mechanisms of liver fibrogenesis, there is currently no approved drug for the treatment of liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation. This study was designed to determine the protective effect and underlying mechanism of human umbilical cord-derived MSCs (UC-MSCs) on thioacetamide-induced liver fibrosis. METHODS Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide (TAA). Some mice were then given injection of UC-MSCs or UC-MSCs-derived exosomes (UC-MSCs-Exo) via the tail vein. Liver tissues were collected for histologic analysis. RESULTS We found that administration of UC-MSCs significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels, and attenuated hepatic inflammation and fibrosis. Moreover, the therapeutic effect of UC-MSCs-derived exosomes was similar to that of UC-MSCs. Intriguingly, UC-MSCs-Exo treatment downregulated the expression of smoothened (SMO), a fundamental component of Hedgehog signaling which plays a critical role in fibrogenesis, and subsequently inhibited the activation of hepatic stellate cells, a central driver of fibrosis in experimental and human liver injury. Furthermore, the anti-inflammatory and anti-fibrotic effects of UCMSCs- Exo was reversed by the SMO agonist SAG treatment in mice. CONCLUSION Our findings suggest that UC-MSCs-Exo exert therapeutic effects on liver fibrosis, at least in part, through inhibiting the Hedgehog/SMO signaling pathway.
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Affiliation(s)
- Ruobin Zong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yan Zheng
- Department of Pharmacy, Hubei Aerospace Hospital, Xiaogan, Hubei, China
| | - Yufei Yan
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Wenao Sun
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Liangyi Kong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yating Huang
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yujie Liu
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Chaochen Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jie Ping
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Changyong Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China.
- Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China.
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15
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Liu L, Yang M, Chen Z. Surface functionalized nanomaterial systems for targeted therapy of endocrine related tumors: a review of recent advancements. Drug Deliv 2024; 31:2390022. [PMID: 39138394 PMCID: PMC11328606 DOI: 10.1080/10717544.2024.2390022] [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: 03/19/2024] [Revised: 06/03/2024] [Accepted: 07/23/2024] [Indexed: 08/15/2024] Open
Abstract
The application of multidisciplinary techniques in the management of endocrine-related cancers is crucial for harnessing the advantages of multiple disciplines and their coordinated efforts in eliminating tumors. Due to the malignant characteristics of cancer cells, they possess the capacity to develop resistance to traditional treatments such as chemotherapy and radiotherapy. Nevertheless, despite diligent endeavors to enhance the prediction of outcomes, the overall survival rate for individuals afflicted with endocrine-related malignancy remains quite miserable. Hence, it is imperative to investigate innovative therapy strategies. The latest advancements in therapeutic tactics have offered novel approaches for the therapy of various endocrine tumors. This paper examines the advancements in nano-drug delivery techniques and the utilization of nanomaterials for precise cancer cures through targeted therapy. This review provides a thorough analysis of the potential of combined drug delivery strategies in the treatment of thyroid cancer, adrenal gland tumors, and pancreatic cancer. The objective of this study is to gain a deeper understanding of current therapeutic approaches, stimulate the development of new drug DDS, and improve the effectiveness of treatment for patients with these diseases. The intracellular uptake of pharmaceuticals into cancer cells can be significantly improved through the implantation of synthetic or natural substances into nanoparticles, resulting in a substantial reduction in the development of endocrine malignancies.
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Affiliation(s)
- Limei Liu
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Miao Yang
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ziyang Chen
- Department of Gastroenterology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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16
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Zhu Y, Huang Z, Li C, Li C, Wei M, Deng L, Deng W, Zhou X, Wu K, Yang B, Qu Y, Liu Q, Chen X, Li D, Wang C. Blood mir-331-3p is a potential diagnostic marker for giant panda (Ailuropoda melanoleuca) testicular tumor. BMC Vet Res 2024; 20:515. [PMID: 39548579 PMCID: PMC11566409 DOI: 10.1186/s12917-024-04326-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/10/2024] [Indexed: 11/18/2024] Open
Abstract
BACKGROUND In recent years, several giant pandas have suffered from testicular tumor, which has seriously affected giant panda health. However, the pathogenesis of testicular tumor in giant panda is still unclear. Studies have shown that miRNAs are involved in the occurrence and development of a variety of cancers. However, the effect of miRNAs on giant panda testicular tumor has been little studied. Therefore, this study explored the pathogenesis of giant panda testicular tumor through miRNA and mRNA sequencing, and screened out diagnostic markers of testicular tumor. RESULTS Combined with phenotypic symptoms and pathological section results, three giant pandas were diagnosed with testicular tumor and divided into tumor group, and three other giant pandas were divided into normal group. A total of 29 differentially expressed miRNAs (DEmiRNAs) were screened by blood miRNA-seq, and 3149 target gene candidates were predicted. Functional enrichment analysis showed that the target genes were mainly involved in intermembrane lipid transfer and ATP-dependent chromatin remodeling. However, only 5 DEmiRNAs were screened by miRNA-seq of blood-derived exosomes and 364 target genes were predicted, which were mainly involved in antigen processing and presentation. In addition, 216 differentially expressed genes (DEGs) were screened by RNA-seq, and functional enrichment analysis showed that tumor-specific DEGs significantly enriched to protein phosphorylation. Spearman correlation analysis of miRNA-mRNA showed that the expressions of miR-331-3p and PKIG were significantly positively correlated (spearman = 0.943, p < 0.01), while the expressions of miR-331-3p and ENSAMEG00000013628 were significantly negatively correlated (spearman= -0.829, p < 0.05). RT-PCR showed that the expression of miR-331-3p was significantly decreased in giant panda with tumor (p < 0.01). CONCLUSIONS blood miRNAs and exosomal miRNAs exhibit distinct regulatory patterns concerning giant panda testicular tumor, potentially reflecting divergent biological processes in the disease's etiology. Meanwhile, miR-331-3p could be used as a potential diagnostic marker for giant panda testicular tumor. Our findings are conducive to the rapid clinical diagnosis of testicular tumor in giant pandas, and are also expected to provide scientific reference for further research on the pathogenesis of testicular tumor.
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Affiliation(s)
- Yan Zhu
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Zhi Huang
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Caiwu Li
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Chengyao Li
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Ming Wei
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Linhua Deng
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Wenwen Deng
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Xiao Zhou
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Kai Wu
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Bo Yang
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Yuanyuan Qu
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Qin Liu
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Xuemei Chen
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China
| | - Desheng Li
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China.
| | - Chengdong Wang
- State Forestry and Grassland Administration Key Laboratory of Conservation Biology for Rare Animals of the Giant Panda State Park, China Conservation and Research Center for the Giant Panda, Chengdu, 610081, China.
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Zhang S, Chen J, Cao Y, Cui Y, Zhang M, Yue C, Yang B. Divergent Proteomic Profiles and Uptake Mechanisms of Exosomes Derived from Human Dental Pulp Stem Cells, Endothelial Cells, and Fibroblasts. Mol Pharm 2024. [PMID: 39535266 DOI: 10.1021/acs.molpharmaceut.4c00911] [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: 11/16/2024]
Abstract
Effective intercellular communication is crucial for tissue repair and regeneration, with exosomes playing a key role in mediating these processes by transferring proteins, lipids, and nucleic acids between cells. This study explored the mechanisms underlying the uptake of exosomes derived from human dental pulp stem cells (hDPSCs), human umbilical vein endothelial cells (HUVECs), and human fibroblasts (HFBs). Our findings revealed that hDPSCs exhibited the greatest capacity for exosome uptake across all three cell types. Moreover, exosomes originating from hDPSCs were also taken up in the highest amounts by all three cell types. Proteomic analysis uncovered significant differences in protein expression among exosomes from these different cell types, particularly in proteins related to endocytosis. Clathrin-dependent endocytosis emerged as the primary pathway for exosome uptake in hDPSCs and HUVECs, while HFBs appeared to use a different mechanism. Additionally, proteins such as fibronectin and tetraspanins were found to be highly expressed in hDPSC-derived exosomes, suggesting their potential involvement in exosome-cell interactions. This study offers new insights into exosome uptake mechanisms and highlights the potential of exosomes in advancing tissue engineering and regenerative medicine.
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Affiliation(s)
- Siqi Zhang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China
- National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Jun Chen
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China
- National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Yipu Cao
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China
- National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Yifan Cui
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China
- National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Mei Zhang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China
- National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Chongxia Yue
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China
- National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterial and Institute of Regulatory Science for Medical Devices and NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu 610064, People's Republic of China
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Bangcheng Yang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China
- National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
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18
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Fukutomi K, Fujimoto E, Shimokawatoko M, Takano E, Sunayama H, Takeuchi T, Tawa K. Single-Extracellular-Vesicle Detection with a Plasmonic Chip and Enhanced Fluorescence Microscopy. ACS OMEGA 2024; 9:44396-44406. [PMID: 39524643 PMCID: PMC11541535 DOI: 10.1021/acsomega.4c05678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/14/2024] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
Endocytosis-derived extracellular vesicles (EVs), which can be as small as 100 nm, are useful for disease prediction. However, very small EVs are below the optical diffraction limit and are difficult to visualize with conventional fluorescence microscopy. In this study, single EVs captured on a plasmonic chip, where fluorescently labeled antibodies were bound over the EV surface, were detected as bright spots using plasmon-field enhanced fluorescence without any pretreatment of isolating labeled EVs, followed by analyzing the full width at half-maximum and the fluorescence peak value for each enhanced fluorescence bright spot. Bright spots smaller than the threshold determined by the observation of the fluorescent nanospheres were attributed to single EVs. The number of single EVs was quantitatively evaluated against the concentration of EV solution injected in the 1.4 pM-95 fM range. Furthermore, single EVs were detected by labeling two different membrane proteins. A molecularly imprinted polymer was applied to a capture interface on a plasmonic chip, and it is found that nonspecific adsorption of aggregates was suppressed. To accurately distinguish single EVs from aggregates of labeled antibodies, the fluorescence microscopy with transmitted light was superior to the epifluorescence method. Finally, single EVs were successfully detected with multiple targets at multiple wavelengths by using different fluorescently labeled antibodies.
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Affiliation(s)
- Kazuma Fukutomi
- Graduate
School of Science and Technology, Kwansei
Gakuin University, 1
GakuenUegahara, Sanda, Hyogo 669-1330, Japan
| | - Eri Fujimoto
- Graduate
School of Science and Technology, Kwansei
Gakuin University, 1
GakuenUegahara, Sanda, Hyogo 669-1330, Japan
| | - Masaya Shimokawatoko
- Graduate
School of Science and Technology, Kwansei
Gakuin University, 1
GakuenUegahara, Sanda, Hyogo 669-1330, Japan
| | - Eri Takano
- Graduate
School of Engineering, Kobe University, 1-1, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Hirobumi Sunayama
- Graduate
School of Engineering, Kobe University, 1-1, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Toshifumi Takeuchi
- Innovation
Commercialization Division, Kobe University, 1-1, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Keiko Tawa
- Graduate
School of Science and Technology, Kwansei
Gakuin University, 1
GakuenUegahara, Sanda, Hyogo 669-1330, Japan
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19
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Liu X, Chen R, Cui G, Feng R, Liu K. Exosomes derived from platelet-rich plasma present a novel potential in repairing knee articular cartilage defect combined with cyclic peptide-modified β-TCP scaffold. J Orthop Surg Res 2024; 19:718. [PMID: 39497084 PMCID: PMC11533314 DOI: 10.1186/s13018-024-05202-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 10/23/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND The aim of this study was to investigate the therapeutic effects and mechanisms of PRP-exos combined with cyclic peptide-modified β-TCP scaffold in the treatment of rabbit knee cartilage defect. METHODS PRP-exos were extracted and characterized by TEM, NTA and WB. The therapeutic effects were evaluated by ICRS score, HE staining, Immunohistochemistry, qRT-PCR and ELISA. The repair mechanism of PRP-exos was estimated and predicted by miRNA sequencing analysis and protein-protein interaction network analysis. RESULTS The results showed that PRP-exos had a reasonable size distribution and exhibited typical exosome morphology. The combination of PRP-exos and cyclic peptide-modified β-TCP scaffold improved ICRS score and the expression level of COL-2, RUNX2, and SOX9. Moreover, this combination therapy reduced the level of MMP-3, TNF-α, IL-1β, and IL-6, while increasing the level of TIMP-1. In PRP-exos miRNA sequencing analysis, the total number of known miRNAs aligned across all samples was 252, and a total of 91 differentially expressed miRNAs were detected. The results of KEGG enrichment analysis and the protein-protein interaction network analysis indicated that the PI3K/AKT signaling pathway could impact the function of chondrocytes by regulating key transcription factors to repair cartilage defect. CONCLUSION PRP-exos combined with cyclic peptide-modified β-TCP scaffold effectively promoted cartilage repair and improved chondrocyte function in rabbit knee cartilage defect. Based on the analysis and prediction of PRP-exos miRNAs sequencing, PI3K/AKT signaling pathway may contribute to the therapeutic effect. These findings provide experimental evidence for the application of PRP-exos in the treatment of cartilage defect.
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Affiliation(s)
- Xuchang Liu
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwuweiqi Road, Jinan, 250021, Shandong, China
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan, 250103, Shandong, China
- Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, 28789 East Jingshi Road, Jinan, 250103, Shandong, China
| | - Rudong Chen
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwuweiqi Road, Jinan, 250021, Shandong, China
| | - Guanzheng Cui
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwuweiqi Road, Jinan, 250021, Shandong, China
| | - Rongjie Feng
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwuweiqi Road, Jinan, 250021, Shandong, China.
| | - Kechun Liu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan, 250103, Shandong, China.
- Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, 28789 East Jingshi Road, Jinan, 250103, Shandong, China.
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20
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Kim M, Kim TH, Salas ESS, Jeon S, Shin JH, Choi D. The efficacy of exosomes from human chemically derived hepatic progenitors in liver damage alleviation: a preclinical experimental study. Ann Surg Treat Res 2024; 107:252-263. [PMID: 39524547 PMCID: PMC11543897 DOI: 10.4174/astr.2024.107.5.252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/22/2024] [Accepted: 08/18/2024] [Indexed: 11/16/2024] Open
Abstract
Purpose Over the past decade, interest in exosomes as therapeutics has surged. In particular, stem-cell-derived exosomes may be more effective as a treatment for liver disease than the stem cells themselves. We have previously developed human chemically derived hepatic progenitors (hCdHs) from human hepatocytes. hCdHs can differentiate into hepatocytes and cholangiocytes, regenerating the liver in mouse models. In this study, we evaluated the mitigating effects of hCdHs-derived exosomes (hCdHs-exo) on liver damage and compared them with those of exosomes from bone marrow mesenchymal stem cells (BMMSCs-exo). Methods Exosomes were isolated from hCdHs and BMMSCs by culturing cells in large quantities and separating the exosomes from the culture medium using ultracentrifugation. Isolated exosomes were characterized by various methods before experimental use. In vitro, the ability of exosomes to inhibit activation of hepatic stellate cells (HSCs) by transforming growth factor beta 1 was evaluated. In vivo, exosomes were injected into mice with carbon tetrachloride (CCl4)-induced liver damage, and their effectiveness in mitigating liver damage was assessed by histological staining and biochemical analysis. Results The analyses confirmed the successful isolation of exosomes from both cell types. In vitro, hCdHs-exo significantly reduced the levels of transcription factors and activation markers in induced HSCs. In vivo, hCdHs-exo effectively alleviated liver damage caused by CCl4. Furthermore, both in vitro and in vivo studies confirmed that hCdHs-exo had a greater effect in alleviating liver damage than did BMMSCs-exo. Conclusion These results demonstrate that hCdHs-exo, similarly to hCdHs, have superior efficacy in alleviating liver damage compared with BMMSCs-exo.
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Affiliation(s)
- Min Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
| | - Tae Hun Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
| | - Elsy Soraya Silva Salas
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
| | - Soyoung Jeon
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
| | - Ji Hyun Shin
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
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21
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Palakurthi SS, Shah B, Kapre S, Charbe N, Immanuel S, Pasham S, Thalla M, Jain A, Palakurthi S. A comprehensive review of challenges and advances in exosome-based drug delivery systems. NANOSCALE ADVANCES 2024:d4na00501e. [PMID: 39484149 PMCID: PMC11523810 DOI: 10.1039/d4na00501e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 09/22/2024] [Indexed: 11/03/2024]
Abstract
Exosomes or so-called natural nanoparticles have recently shown enormous potential for targeted drug delivery systems. Several studies have reported that exosomes as advanced drug delivery platforms offer efficient targeting of chemotherapeutics compared to individual polymeric nanoparticles or liposomes. Taking structural constituents of exosomes, viz., proteins, nucleic acids, and lipids, into consideration, exosomes are the most promising carriers as genetic messengers and for treating genetic deficiencies or tumor progression. Unfortunately, very little attention has been paid to the factors like source, scalability, stability, and validation that contribute to the quality attributes of exosome-based drug products. Some studies suggested that exosomes were stable at around -80 °C, which is impractical for storing pharmaceutical products. Currently, no reports on the shelf-life and in vivo stability of exosome formulations are available. Exosomes are quickly cleared from blood circulation, and their in vivo distribution depends on the source. Considering these challenges, further studies are necessary to address major limitations such as poor drug loading, reduced in vivo stability, a need for robust, economical, and scalable production methods, etc., which may unlock the potential of exosomes in clinical applications. A few reports based on hybrid exosomes involving hybridization between different cell/tumor/macrophage-derived exosomes with synthetic liposomes through membrane fusion have shown to overcome some limitations associated with natural or synthetic exosomes. Yet, sufficient evidence is indispensable to prove their stability and clinical efficacy.
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Affiliation(s)
- Sushesh Srivatsa Palakurthi
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Brijesh Shah
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Sumedha Kapre
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Nitin Charbe
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Susan Immanuel
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Sindhura Pasham
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Maharshi Thalla
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Ankit Jain
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
| | - Srinath Palakurthi
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Kingsville TX 78363 USA +1-361-221-0748
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22
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Gaurav I, Thakur A, Zhang K, Thakur S, Hu X, Xu Z, Kumar G, Jaganathan R, Iyaswamy A, Li M, Zhang G, Yang Z. Peptide-Conjugated Vascular Endothelial Extracellular Vesicles Encapsulating Vinorelbine for Lung Cancer Targeted Therapeutics. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:1669. [PMID: 39453005 PMCID: PMC11510406 DOI: 10.3390/nano14201669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/24/2024] [Accepted: 10/14/2024] [Indexed: 10/26/2024]
Abstract
Lung cancer is one of the major cancer types and poses challenges in its treatment, including lack of specificity and harm to healthy cells. Nanoparticle-based drug delivery systems (NDDSs) show promise in overcoming these challenges. While conventional NDDSs have drawbacks, such as immune response and capture by the reticuloendothelial system (RES), extracellular vesicles (EVs) present a potential solution. EVs, which are naturally released from cells, can evade the RES without surface modification and with minimal toxicity to healthy cells. This makes them a promising candidate for developing a lung-cancer-targeting drug delivery system. EVs isolated from vascular endothelial cells, such as human umbilical endothelial-cell-derived EVs (HUVEC-EVs), have shown anti-angiogenic activity in a lung cancer mouse model; therefore, in this study, HUVEC-EVs were chosen as a carrier for drug delivery. To achieve lung-cancer-specific targeting, HUVEC-EVs were engineered to be decorated with GE11 peptides (GE11-HUVEC-EVs) via a postinsertional technique to target the epidermal growth factor receptor (EGFR) that is overexpressed on the surface of lung cancer cells. The GE11-HUVEC-EVs were loaded with vinorelbine (GE11-HUVEC-EVs-Vin), and then characterized and evaluated in in vitro and in vivo lung cancer models. Further, we examined the binding affinity of ABCB1, encoding P-glycoprotein, which plays a crucial role in chemoresistance via the efflux of the drug. Our results indicate that GE11-HUVEC-EVs-Vin effectively showed tumoricidal effects against cell and mouse models of lung cancer.
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Affiliation(s)
- Isha Gaurav
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China; (I.G.)
| | - Abhimanyu Thakur
- Department of Pharmacology, Delhi Pharmaceutical Sciences & Research University (DPSRU), New Delhi 110017, India
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Kui Zhang
- Ben May Department for Cancer Research, Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Sudha Thakur
- National Institute for Locomotor Disabilities (Divyangjan), Kolkata 700090, India
| | - Xin Hu
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410017, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410017, China
| | - Gaurav Kumar
- Clinical Research Division, Department of Biosciences, School of Basic and Applied Sciences, Galgotias University, Greater Noida 203201, India
| | - Ravindran Jaganathan
- Preclinical Department, Universiti Kuala Lumpur, Royal College of Medicine Perak (UniKL-RCMP), Ipoh 30450, Malaysia
| | - Ashok Iyaswamy
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China; (I.G.)
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, India
| | - Min Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China; (I.G.)
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen 518000, China
| | - Zhijun Yang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China; (I.G.)
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23
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Manzoor T, Farooq N, Sharma A, Shiekh PA, Hassan A, Dar LA, Nazir J, Godha M, Sheikh FA, Gugjoo MB, Saleem S, Ahmad SM. Exosomes in nanomedicine: a promising cell-free therapeutic intervention in burn wounds. Stem Cell Res Ther 2024; 15:355. [PMID: 39385310 PMCID: PMC11462792 DOI: 10.1186/s13287-024-03970-3] [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: 08/29/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
Burn injuries are serious injuries that have a big impact on a person's health and can even cause death. Incurring severe burns can incite an immune response and inflammation within the body, alongside metabolic changes. It is of utmost importance to grasp the fact that the effects of the burn injury extend beyond the body, affecting the mind and overall well-being. Burn injuries cause long-lasting changes that need to be taken care of in order to improve their quality of life. The intricate process of skin regeneration at the site of a burn wound involves a complex and dynamic interplay among diverse cells, growth factors, nerves, and blood vessels. Exciting opportunities have arisen in the field of stem cells and regenerative medicine, allowing us to explore the development of cell-free-based alternatives that can aid in the treatment of burn injuries. These cell-free-based therapies have emerged as a promising facet within regenerative medicine. Exosomes, also referred to as naturally occurring nanoparticles, are small endosome-derived vesicles that facilitate the delivery of molecular cargo between the cells, thus allowing intercellular communication. The knowledge gained in this field has continued to support their therapeutic potential, particularly in the domains of wound healing and tissue regeneration. Notably, exosomes derived from mesenchymal stem cells (MSCs) can be safely administered in the system, which is then adeptly uptaken and internalized by fibroblasts/epithelial cells, subsequently accelerating essential processes such as migration, proliferation, and collagen synthesis. Furthermore, exosomes released by immune cells, specifically macrophages, possess the capability to modulate inflammation and effectively diminish it in adjacent cells. Exosomes also act as carriers when integrated with a scaffold, leading to scarless healing of cutaneous wounds. This comprehensive review examines the role of exosomes in burn wound healing and their potential utility in regeneration and repair.
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Affiliation(s)
- Tasaduq Manzoor
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
- School of Life and Basic Sciences, Jaipur National University, Jagatpura, Jaipur, India
| | - Nida Farooq
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Arushi Sharma
- Centre for Biomedical Engineering, Indian Institute of Technology-Delhi, New Delhi, India
| | - Parvaiz A Shiekh
- Centre for Biomedical Engineering, Indian Institute of Technology-Delhi, New Delhi, India
| | - Amreena Hassan
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Lateef Ahmad Dar
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Junaid Nazir
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Meena Godha
- School of Life and Basic Sciences, Jaipur National University, Jagatpura, Jaipur, India
| | - Faheem A Sheikh
- Department of Nanotechnology, University of Kashmir, Srinagar, Kashmir, India
| | - Mudasir Bashir Gugjoo
- Veterinary Clinical Services Complex, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST- Srinagar, Kashmir, India
| | - Sahar Saleem
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India.
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24
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Wei Y, Hu X, Yuan S, Zhao Y, Zhu C, Guo M, Cui H. Identification of plasma exosomal lncRNA as a biomarker for early diagnosis of gastric cancer. Front Genet 2024; 15:1425591. [PMID: 39440243 PMCID: PMC11493672 DOI: 10.3389/fgene.2024.1425591] [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: 04/30/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
Background There were about 1,090,000 gastric cancer (GC) cases in 2020 in China. The incidence and mortality rates ranked the fifth and third among all kinds of cancers in China. Early diagnosis plays an important role in the treatment and prognosis of gastric cancer. In recent years, noninvasive diagnosis, especially plasma exosome lncRNAs, has become a promissing biomarkers with high specificity and sensitivity for early diagnosis of cancers. Methods In this study, plasma exosomes of patients with early gastric cancer were extracted efficiently by affinity membrane separation technology, including affinity adsorption, elution, affinity membrane regeneration and other steps. After identified by electron microscopy observation, particle size analysis and Western blot verification, the lncRNAs in the exosomes were extracted and were analysized by high-throughput RNA sequencing (RNA-Seq). The differentially expressed lncRNAs were verified by RT-qPCR in 93 patients with early gastric cancer and 49 normal controls. Results Electron microscopy, particle size analysis and Western blot showed that exosomes were successfully isolated from plasma. RNA-Seq results show that 76 lncRNAs were upregulated and 260 lncRNAs were downregulated in plasma exosomes of early gastric cancer patients compared with normal controls. RT-qPCR analysis indicated that a total of 6 lncRNAs were significantly and differentially expressed in gastric cancer patients compared to normal controls, with 2 (lncmstrg. 1319590, Lncmstrg. 2312697) highly expressed and 4 lowly expressed (lncmstr-g.1004024.1, lncmstrg. 2441832.8, lncmstrg. 315376.1, lncmstrg.907985.2,) (p < 0.05). The survival curve analysis indicated that lncmstrg.2441832.8 and lncmstrg.2312697 had higher sensitivity and specificity for the diagnosis of gastric cancer, respectively and AUC curve areas were 0.6211 and 0.631, p < 0.05, respectively, which were greater than the traditional clinical detection indexes CEA (0.61) and AFP (0.57). When combined lncmstrg.2441832.8 and lncmstrg.2312697 in gastric cancer diagnosis, AUC curve area reached 0.73, which was greater than CA199 (0.71). Conclusion Lncmstrg.2441832.8 and lncmstrg.2312697 may be a potential and promissing biomarkers for early diagnosis of gastric cancer.
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Affiliation(s)
- Ye Wei
- College of Medicine, Yangzhou University, Yangzhou, China
| | - Xuming Hu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Shuai Yuan
- Yangzhou center for disease control and prevention, Yangzhou, China
| | - Yue Zhao
- Department of Medical Affaires, Yangzhou Maternity and Child Health Hospital, Yangzhou, China
| | - Chunhui Zhu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - Hengmi Cui
- College of Medicine, Yangzhou University, Yangzhou, China
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, China
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25
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Carciero L, Di Giuseppe G, Di Piazza E, Parand E, Soldovieri L, Ciccarelli G, Brunetti M, Gasbarrini A, Nista EC, Pani G, Pontecorvi A, Giaccari A, Mezza T. The interplay of extracellular vesicles in the pathogenesis of metabolic impairment and type 2 diabetes. Diabetes Res Clin Pract 2024; 216:111837. [PMID: 39173679 DOI: 10.1016/j.diabres.2024.111837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/15/2024] [Accepted: 08/20/2024] [Indexed: 08/24/2024]
Abstract
The pathogenesis of type 2 diabetes (T2D) involves dysfunction in multiple organs, including the liver, muscle, adipose tissue, and pancreas, leading to insulin resistance and β cell failure. Recent studies highlight the significant role of extracellular vesicles (EVs) in mediating inter-organ communication in T2D. This review investigates the role of EVs, focusing on their presence and biological significance in human plasma and tissues affected by T2D. We explore specific EV cargo, such as miRNAs and proteins, which affect insulin signaling and glucose metabolism, emphasizing their potential as biomarkers. By highlighting the diagnostic and therapeutic potential of EVs, we aim to provide new insights into their role in early detection, disease monitoring, and innovative treatment strategies for T2D.
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Affiliation(s)
- Lorenzo Carciero
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Gianfranco Di Giuseppe
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Eleonora Di Piazza
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Erfan Parand
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Soldovieri
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gea Ciccarelli
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Michela Brunetti
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Pancreas Unit, CEMAD Digestive Diseases Center, Internal Medicine and Gastroenterology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Enrico C Nista
- Pancreas Unit, CEMAD Digestive Diseases Center, Internal Medicine and Gastroenterology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Giovambattista Pani
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Teresa Mezza
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Pancreas Unit, CEMAD Digestive Diseases Center, Internal Medicine and Gastroenterology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy.
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26
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Chow SKH, Gao Q, Pius A, Morita M, Ergul Y, Murayama M, Shinohara I, Cekuc MS, Ma C, Susuki Y, Goodman SB. The Advantages and Shortcomings of Stem Cell Therapy for Enhanced Bone Healing. Tissue Eng Part C Methods 2024; 30:415-430. [PMID: 39311464 DOI: 10.1089/ten.tec.2024.0252] [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: 10/05/2024] Open
Abstract
This review explores the regenerative potential of key progenitor cell types and therapeutic strategies to improve healing of complex fractures and bone defects. We define, summarize, and discuss the differentiation potential of totipotent, pluripotent, and multipotent stem cells, emphasizing the advantages and shortcomings of cell therapy for bone repair and regeneration. The fundamental role of mesenchymal stem cells is highlighted due to their multipotency to differentiate into the key lineage cells including osteoblasts, osteocytes, and chondrocytes, which are crucial for bone formation and remodeling. Hematopoietic stem cells (HSCs) also play a significant role; immune cells such as macrophages and T-cells modulate inflammation and tissue repair. Osteoclasts are multinucleated cells that are important to bone remodeling. Vascular progenitor (VP) cells are critical to oxygen and nutrient supply. The dynamic interplay among these lineages and their microenvironment is essential for effective bone restoration. Therapies involving cells that are more than "minimally manipulated" are controversial and include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). ESCs, derived from early-stage embryos, possess pluripotent capabilities and have shown promise in preclinical studies for bone healing. iPSCs, reprogrammed from somatic cells, offer personalized medicine applications and can differentiate into various tissue-specific cell lines. Minimally manipulative cell therapy approaches such as the use of bone marrow aspirate concentrate (BMAC), exosomes, and various biomaterials for local delivery are explored for their effectiveness in bone regeneration. BMAC, which contains mostly immune cells but few mesenchymal and VPs, probably improves bone healing by facilitating paracrine-mediated intercellular communication. Exosome isolation harnesses the biological signals and cellular by-products that are a primary source for cell crosstalk and activation. Safe, efficacious, and cost-effective strategies to enhance bone healing using novel cellular therapies are part of a changing paradigm to modulate the inflammatory, repair, and regenerative pathways to achieve earlier more robust tissue healing and improved physical function. Impact Statement Stem cell therapy holds immense potential for bone healing due to its ability to regenerate damaged tissue. Nonmanipulated bone marrow aspirate contains mesenchymal stem cells that promote bone repair and reduce healing time. Induced pluripotent stem cells offer the advantage of creating patient-specific cells that can differentiate into osteoblasts, aiding in bone regeneration. Other delivery methods, such as scaffold-based techniques, enhance stem cell integration and function. Collectively, these approaches can improve treatment outcomes, reduce recovery periods, and advance our understanding of bone healing mechanisms, making them pivotal in orthopedic research and regenerative medicine.
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Affiliation(s)
- Simon Kwoon-Ho Chow
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Qi Gao
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Alexa Pius
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Mayu Morita
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Yasemin Ergul
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Masatoshi Murayama
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Issei Shinohara
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Mehmet Sertac Cekuc
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Chao Ma
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Yosuke Susuki
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
- Department of Bioengineering, Stanford University, Stanford, California, USA
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27
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Yahyavi Y, Kheradi N, Karimi A, Ebrahimi-Kalan A, Ramezani F, Yousefi S, Teymouri Nobari S, Sadrekarimi H, Nouri M, Edalati M. Novel Advances in Cell-Free Therapy for Premature Ovarian Failure (POF): A Comprehensive Review. Adv Pharm Bull 2024; 14:543-557. [PMID: 39494249 PMCID: PMC11530876 DOI: 10.34172/apb.2024.059] [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: 02/19/2024] [Revised: 06/23/2024] [Accepted: 07/30/2024] [Indexed: 11/05/2024] Open
Abstract
Premature ovarian failure (POF), is a condition characterized by the early decline of ovulation function. POF is a complex disorder that can be caused by various factors, and the idiopathic form represents a significant proportion of POF patients. Hormone replacement therapy (HRT) is currently considered the first-line treatment for POF. This review aims to provide a comprehensive overview of recent advancements in platelet-rich plasma (PRP), in vitro activation (IVA), stem cell therapy, exosome therapy, microRNAs, and mitochondrial targeting therapies as a promising cell-free therapeutic approach in reproductive medicine. PLT-Exos, a new generation of cells, has been used to treat POF for more than a decade and has been shown to attenuate oocyte morphology and promote the differentiation of theca cells through the upregulation of PI3K/Akt and Bcl2, as well as the downregulation of the Smad and Bax signaling pathways. This review summarizes the current state of the art in the field of PLT-Exos and discusses the advantages and limitations of their potential clinical applications.
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Affiliation(s)
- Yahya Yahyavi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Kheradi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Karimi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Ebrahimi-Kalan
- Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Ramezani
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soudabe Yousefi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Teymouri Nobari
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Hourieh Sadrekarimi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Nouri
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Edalati
- Department of Laboratory Science, Faculty of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran
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28
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Deng H, Zhao J, Li J, Chen C, Hu Z, Wu X, Ge L. Therapeutic Efficacy of Extracellular Vesicles Derived from Stem Cell for Alzheimer's Disease: A Meta-Analysis Study. FRONT BIOSCI-LANDMRK 2024; 29:340. [PMID: 39344329 DOI: 10.31083/j.fbl2909340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/29/2024] [Accepted: 08/06/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) poses a significant public health challenge, increasingly affecting patients' finances, mental health, and functional abilities as the global population ages. Stem cell-derived extracellular vesicles (SC-EVs) have emerged as a promising cell-free therapeutic approach for AD, although their precise mechanisms remain unclear. This meta-analysis aims to evaluate the effectiveness of SC-EVs in treating AD. METHODS We systematically searched PubMed, EMBASE, and Web of Science databases up to December 31, 2023, identifying studies investigating SC-EVs therapy in AD rodent models. Outcome measures included Morris water maze and Y maze tests, β-amyloid pathology, and inflammatory markers. Statistical analyses utilized Stata 15.1 and R software. RESULTS This meta-analysis of 16 studies (2017-2023, 314 animals) demonstrates significant efficacy of SC-EVs therapy in AD models. Pooled analyses demonstrated that SC-EVs therapy significantly increased the learning function as measured by Morris water maze tests (MWM) by -1.83 (95% CI = -2.51 to -1.15, p < 0.0001), Y maze test by 1.66 (95% CI = 1.03 to 2.28, p < 0.0001), decreased Aβ plaques in the hippocampal by -2.10 (95% CI = -2.96 to -1.23, p < 0.0001), and proinflammatory cytokines Tumor necrosis factor alpha (TNFα) by -2.61 (95% CI = -4.87 to -0.35, p < 0.05), Interleukin-1 beta (IL-1β) by -2.37 (95% CI = -3.68 to -1.05, p < 0.001). CONCLUSIONS SC-EVs therapy shows promise in enhancing cognitive function and mitigating AD progression in preclinical models. Future research should focus on standardizing methodologies and comparing SC-EVs isolation techniques and dosing strategies to facilitate clinical translation.
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Affiliation(s)
- Huiyin Deng
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Jing Zhao
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Jiuyi Li
- Department of Anesthesiology, the Fouth People's Hospital of Changsha, 410006 Changsha, Hunan, China
| | - Chunli Chen
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Xiaomei Wu
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Lite Ge
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, 410003 Changsha, Hunan, China
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Kim SY, Lee S, Park JT, Lee SJ, Kim HS. Postmortem-Derived Exosomal MicroRNA 486-5p as Potential Biomarkers for Ischemic Heart Disease Diagnosis. Int J Mol Sci 2024; 25:9619. [PMID: 39273565 PMCID: PMC11395318 DOI: 10.3390/ijms25179619] [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: 07/30/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Exosomes are nanovesicles 30-150 nm in diameter released extracellularly. Those isolated from human body fluids reflect the characteristics of their cells or tissues of origin. Exosomes carry extensive biological information from their parent cells and have significant potential as biomarkers for disease diagnosis and prognosis. However, there are limited studies utilizing exosomes in postmortem diagnostics. In this study, we extended our initial research which identified the presence and established detection methodologies for exosomes in postmortem fluids. We analyzed exosomal miRNA extracted from plasma and pericardial fluid samples of a control group (n = 13) and subjects with acute myocardial infarction (AMI; n = 24). We employed next-generation sequencing (NGS) to investigate whether this miRNA could serve as biomarkers for coronary atherosclerosis leading to acute myocardial infarction. Our analysis revealed 29 miRNAs that were differentially expressed in the AMI group compared to the control group. Among these, five miRNAs exhibited more than a twofold increase in expression across all samples from the AMI group. Specifically, miR-486-5p levels were significantly elevated in patients with high-grade (type VI or above) atherosclerotic plaques, as per the American Heart Association criteria, highlighting its potential as a predictive biomarker for coronary atherosclerosis progression. Our results indicate that postmortem-derived exosomal microRNAs can serve as potential biomarkers for various human diseases, including cardiovascular disorders. This finding has profound implications for forensic diagnostics, a field critically lacking diagnostic markers.
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Affiliation(s)
- So-Yeon Kim
- Department of Forensic Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; (S.-Y.K.); (J.-T.P.)
| | - Sookyoung Lee
- Department of Forensic Medicine, National Forensic Service, 10, Ipchun-ro, Wonju-si 61469, Republic of Korea;
| | - Jong-Tae Park
- Department of Forensic Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; (S.-Y.K.); (J.-T.P.)
| | - Su-Jin Lee
- Department of Forensic Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; (S.-Y.K.); (J.-T.P.)
| | - Hyung-Seok Kim
- Department of Forensic Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; (S.-Y.K.); (J.-T.P.)
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30
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Liu YG, Jiang ST, Zhang JW, Zheng H, Zhang L, Zhao HT, Sang XT, Xu YY, Lu X. Role of extracellular vesicle-associated proteins in the progression, diagnosis, and treatment of hepatocellular carcinoma. Cell Biosci 2024; 14:113. [PMID: 39227992 PMCID: PMC11373138 DOI: 10.1186/s13578-024-01294-6] [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: 05/17/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, characterized by difficulties in early diagnosis, prone to distant metastasis, and high recurrence rates following surgery. Extracellular vesicles (EVs) are a class of cell-derived particles, including exosomes, characterized by a phospholipid bilayer. They serve as effective carriers for intercellular communication cargo, including proteins and nucleic acids, and are widely involved in tumor progression. They are being explored as potential tumor biomarkers and novel therapeutic avenues. We provide a brief overview of the biogenesis and characteristics of EVs to better understand their classification standards. The focus of this review is on the research progress of EV-associated proteins in the field of HCC. EV-associated proteins are involved in tumor growth and regulation in HCC, participate in intercellular communication within the tumor microenvironment (TME), and are implicated in events including angiogenesis and epithelial-mesenchymal transition (EMT) during tumor metastasis. In addition, EV-associated proteins show promising diagnostic efficacy for HCC. For the treatment of HCC, they also demonstrate significant potential including enhancing the efficacy of tumor vaccines, and as targeting cargo anchors. Facing current challenges, we propose the future directions of research in this field. Above all, research on EV-associated proteins offers the potential to enhance our comprehension of HCC and offer novel insights for developing new treatment strategies.
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Affiliation(s)
- Yao-Ge Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Shi-Tao Jiang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Jun-Wei Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Han Zheng
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Lei Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Hai-Tao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Xin-Ting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Yi-Yao Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China.
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China.
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Lu R, Yang L, Jia S, Zhang Y, Xu X, Cao X, Sun J. Proteomic analysis of exosomes derived from fatty hepatocytes of grass carp. JOURNAL OF FISH BIOLOGY 2024; 105:886-893. [PMID: 38897922 DOI: 10.1111/jfb.15840] [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: 04/07/2024] [Revised: 05/12/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024]
Abstract
Exosomes participate in intercellular communication by carrying proteins, messenger RNA, microRNAs, and non-coding RNA. Fatty liver is a common phenomenon in farmed fish, but there has been little study of fatty hepatocytes-derived exosomes. Here, we successfully isolated exosomes from hepatocytes of grass carp, named Exos (hepatocytes-derived exosomes) and OA-Exos (fatty hepatocytes-derived exosomes), from which 617 differentially expressed proteins were identified using liquid chromatography tandem mass spectrometry. Of these, 320 proteins were promoted and 297 proteins were restrained, which were gathered in biological processes and cellular components (cellular processes, cells, and intracellular structures). The results of kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the differential expression proteins were gathered in "carbohydrate transport and metabolism", "translation, ribosomal structure and biogenesis", "posttranslational modification, protein turnover, chaperones", and "intracellular trafficking, secretion, and vesicular transport". In addition, five differentially expressed exosomal proteins were further confirmed by parallel reaction monitoring, including 2-phospho-D-glycerate hydrolyase, cytochrome b5, fatty acid-binding protein domain-containing protein, metallothionein, and malate dehydrogenas, which were downregulated. These findings provided evidence that exosomes derived from fatty hepatocytes of grass carp may be biomarkers for the early diagnosis, treatment, and prevention of fatty liver in fishery development.
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Affiliation(s)
- Ronghua Lu
- College of Fisheries, Henan Normal University, Xinxiang, People's Republic of China
| | - Lulu Yang
- College of Fisheries, Henan Normal University, Xinxiang, People's Republic of China
| | - Shenzong Jia
- College of Fisheries, Henan Normal University, Xinxiang, People's Republic of China
| | - Yuru Zhang
- College of Fisheries, Henan Normal University, Xinxiang, People's Republic of China
| | - Xinxin Xu
- College of Fisheries, Henan Normal University, Xinxiang, People's Republic of China
| | - Xianglin Cao
- College of Fisheries, Henan Normal University, Xinxiang, People's Republic of China
| | - Jian Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, People's Republic of China
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Arslan Bozdag L, Açik L, Ersoy HE, Bayir Ö, Korkmaz MH, Mollaoglu N, Gultekin SE. PDCD4 and MIR-21 are promising biomarkers in the follow-up of OED in liquid biopsies. Oral Dis 2024; 30:3873-3883. [PMID: 38098243 DOI: 10.1111/odi.14817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/08/2023] [Indexed: 09/03/2024]
Abstract
This research aims to examine the impact of programmed cell death 4 (PDCD4), microRNA-21 (miR-21) and microRNA-208a (miR-208a) transcripts, and protein levels on oral epithelial dysplasia (OED) development in oral squamous cell carcinoma (OSCC). METHODS The research investigation involved the collection of saliva, blood, and tissue samples from a total of 20 patients diagnosed with OSCC, 15 patients diagnosed with OED, and 15 healthy individuals. PDCD4, miR-21, and miR-208a expression was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). PDCD4 protein levels were assessed using enzyme-linked immunosorbent assay (ELISA) in both saliva and blood samples. For statistical analysis, the Kruskal-Wallis test and the Spearmen rank test were utilised. RESULTS PDCD4 expression levels were considerably lower in patients with OSCC and OED (p < 0.05) in three biological samples. In contrast, miR-21 expression was higher in OED and OSCC patients. Patients with low PDCD4 mRNA levels and strong miR-21 expression had a significant connection (p < 0.05) with tumor size and depth. CONCLUSIONS Examining PDCD4 and miR-21 transcript levels may help detect the transition from OED to OSCC. This work suggests that PDCD4 and miR-21 expression levels in liquid biopsies may be biomarkers for OED monitoring in the future.
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Affiliation(s)
| | - Leyla Açik
- Department of Biology, Faculty of Science, Gazi University, Ankara, Turkey
| | - H Erhan Ersoy
- Department of Oral, Dental, and Maxillofacial Surgery, Gazi University, Ankara, Turkey
| | - Ömer Bayir
- Department of Otorhinolaryngology, T.R. Ministry of Health Ankara Etlik City Hospital, Ankara, Turkey
| | | | - Nur Mollaoglu
- Department of Oral, Dental, and Maxillofacial Surgery, Gazi University, Ankara, Turkey
| | - S Elif Gultekin
- Department of Oral Pathology, Faculty of Dentistry, Gazi University, Ankara, Turkey
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Yu M, Jin Y, Yuan K, Liu B, Zhu N, Zhang K, Li S, Tai Z. Effects of exosomes and inflammatory response on tumor: a bibliometrics study and visualization analysis via CiteSpace and VOSviewer. J Cancer Res Clin Oncol 2024; 150:405. [PMID: 39210153 PMCID: PMC11362500 DOI: 10.1007/s00432-024-05915-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Tumor is a new organism formed by abnormal hyperplasia of local tissue cells under the action of various tumorigenic factors. Inflammation plays a decisive role in inducing tumorigenesis, promoting tumor development, invasion and migration. More and more evidence indicate that exosomes are involved in regulating the formation of tumor microenvironment in the process of proinflammatory carcinogenesis, leading to the stimulation of anti-tumor immune response or systemic immunosuppression, and exosomes play a crucial role in the development of tumor. METHODS The articles on tumor-derived exosomes and inflammatory responses from January 2005 to January 2024 were collected through Web of Science (WOS), and the inclusion criteria were "Article", "Review Article" and "Early Access". Articles obtained after excluding "Book Chapters", "Editorial Material", "Proceeding Paper", "Meeting Abstract" and "Retracted Publication". Bibliometrics and visualization analysis were carried out on the obtained articles using CiteSpace6.2.R6 and VOSviewer1.6.20. RESULTS Total of 703 articles were included. The number of published documents showed a fluctuating growth trend year by year. A total of 61 countries have participated in the research on the effects of exosomes and inflammatory responses on tumors, among which China and the United States have the largest influence in this field. The obtained articles have been published in 60 journals around the world, among which PLOS ONE and NAT REV IMMUNOL are the journals with the most published articles and the highest co-citations respectively. The article from French author THERY C was cited the most (202 times). As a major researcher on the basic function of exosomes, THERY C established the gold standard for extraction, separation and identification of exosomes, and found that exosomes promote tumor metastasis through direct regulation of miRNA. Her research has had a huge impact on the field. Keyword co-occurrence analysis indicate that extracellular vesicles, inflammation, cancer, miRNAs, mesenchymal stem cells, drug delivery, gastric cancer and circulating endothelial microparticles are the research hotspot at present stage. The main keywords of the cluster analysis show that extracellular vesicles, human papilloma virus, myeloid cells, tumor macro-environment are the current research hotspots and frontier. The research hotspots have developed over time from the time chart of keywords and clustering, especially after 2016, exosomes have established extensive links with drug delivery, cancer treatment, inflammatory response and other fields. Tumor-derived exosomes stimulate receptor cells to secrete pro-inflammatory cytokines and growth factors, enabling immune and inflammatory cells to perceive the intracellular environment of cancer cells even when cancer cells do not express any tumor-specific antigens. For example, in anoxic environment, cancer cells can secrete exosomes containing pro-inflammatory factors to promote the invasion and metastasis of cancer cells. In the complex tumor microenvironment, both tumor cells and various stromal cells will secrete specific exosomes, and promote the development of tumors through various ways, so that tumor cells have drug resistance, and bring adverse effects on the clinical treatment of tumor patients. MicroRNAs and long noncoding RNA as hot keywords play important roles in regulating and mediating tumor development, and their specificity makes them important biomarkers for cancer prediction and diagnosis. Highlighting word analysis shows that microRNAs secreted by leukemia patients can effectively promote the proliferation of malignant cells and the development of cardiovascular diseases. At the same time, exosomes can induce the secretion of some microRNAs in patients, leading to cardiac repair and regeneration. Therefore, the detection and screening of microRNAs plays a crucial role in predicting the incidence of cardiovascular diseases in patients. CONCLUSION Exosomes have attracted increasing attention due to their significant heterogeneity and ability to regulate the tumor immune microenvironment. However, tumor cell-derived exosomes accelerate tumor progression by enhancing immunosuppression and inflammation, increasing oxidative stress, and promoting angiogenesis, which may lead to poor prognosis.
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Affiliation(s)
- Miao Yu
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Yaxuan Jin
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Kaize Yuan
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Bohao Liu
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Na Zhu
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Ke Zhang
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Shuying Li
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China.
| | - Zhihui Tai
- North China University of Science and Technology Affiliated Hospital, Tangshan, China.
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Zhao Q, Li B, Zhang X, Zhao H, Xue W, Yuan Z, Xu S, Duan G. M2 macrophage-derived lncRNA NORAD in EVs promotes NSCLC progression via miR-520g-3p/SMIM22/GALE axis. NPJ Precis Oncol 2024; 8:185. [PMID: 39215037 PMCID: PMC11364787 DOI: 10.1038/s41698-024-00675-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 08/19/2024] [Indexed: 09/04/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) constitutes the majority of lung cancer cases, accounting for over 80%. RNAs in EVs play a pivotal role in various biological and pathological processes mediated by extracellular vesicle (EV). Long non-coding RNAs (lncRNAs) are widely associated with cancer-related functions, including cell proliferation, migration, invasion, and drug resistance. Tumor-associated macrophages are recognized as pivotal contributors to tumorigenesis. Given these insights, this study aims to uncover the impact of lncRNA NORAD in EVs derived from M2 macrophages in NSCLC cell lines and xenograft mouse models of NSCLC. EVs were meticulously isolated and verified based on their morphology and specific biomarkers. The interaction between lncRNA NORAD and SMIM22 was investigated using immunoprecipitation. The influence of SMIM22/GALE or lncRNA NORAD in EVs on glycolysis was assessed in NSCLC cell lines. Additionally, we evaluated the effects of M2 macrophage-derived lncRNA NORAD in EVs on cell proliferation and apoptosis through colony formation and flow cytometry assays. Furthermore, the impact of M2 macrophage-derived lncRNA NORAD in EVs on tumor growth was confirmed using xenograft tumor animal models. The results underscored the potential role of M2 macrophage-derived lncRNA NORAD in EVs in NSCLC. SMIM22/GALE promoted glycolysis and the proliferation of NSCLC cells. Furthermore, lncRNA NORAD in EVs targeted SMIM22 and miR-520g-3p in NSCLC cells. Notably, lncRNA NORAD in EVs promoted the proliferation of NSCLC cells and facilitated NSCLC tumor growth through the miR-520g-3p axis. In conclusion, M2 macrophage-derived lncRNA NORAD in EVs promotes NSCLC progression through the miR-520g-3p/SMIM22/GALE axis.
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Affiliation(s)
- Qingtao Zhao
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei Province, China
| | - Bin Li
- Hebei Bio-High Technology Development Co.Ltd, Shijiazhuang, Hebei Province, China
| | - Xiaopeng Zhang
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei Province, China
| | - Huanfen Zhao
- Department of Pathology, Hebei General Hospital, Shijiazhuang, Hebei Province, China
| | - Wenfei Xue
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei Province, China
| | - Zheng Yuan
- Department of Nursing, Hebei General Hospital, Shijiazhuang, Hebei Province, China
| | - Shun Xu
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Guochen Duan
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei Province, China.
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Vadhan A, Gupta T, Hsu WL. Mesenchymal Stem Cell-Derived Exosomes as a Treatment Option for Osteoarthritis. Int J Mol Sci 2024; 25:9149. [PMID: 39273098 PMCID: PMC11395657 DOI: 10.3390/ijms25179149] [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: 07/30/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Osteoarthritis (OA) is a leading cause of pain and disability worldwide in elderly people. There is a critical need to develop novel therapeutic strategies that can effectively manage pain and disability to improve the quality of life for older people. Mesenchymal stem cells (MSCs) have emerged as a promising cell-based therapy for age-related disorders due to their multilineage differentiation and strong paracrine effects. Notably, MSC-derived exosomes (MSC-Exos) have gained significant attention because they can recapitulate MSCs into therapeutic benefits without causing any associated risks compared with direct cell transplantation. These exosomes help in the transport of bioactive molecules such as proteins, lipids, and nucleic acids, which can influence various cellular processes related to tissue repair, regeneration, and immune regulation. In this review, we have provided an overview of MSC-Exos as a considerable treatment option for osteoarthritis. This review will go over the underlying mechanisms by which MSC-Exos may alleviate the pathological hallmarks of OA, such as cartilage degradation, synovial inflammation, and subchondral bone changes. Furthermore, we have summarized the current preclinical evidence and highlighted promising results from in vitro and in vivo studies, as well as progress in clinical trials using MSC-Exos to treat OA.
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Affiliation(s)
- Anupama Vadhan
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin 632007, Taiwan
| | - Tanvi Gupta
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Wen-Li Hsu
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin 632007, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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Ning X, Liu R, Huang Y, Huang Z, Li H, Li Q, Sheng Z, Wu J. Dental Stem Cell-Derived Exosomes: A Review of Their Isolation, Classification, Functions, and Mechanisms. Stem Cells Int 2024; 2024:2187392. [PMID: 39184549 PMCID: PMC11343633 DOI: 10.1155/2024/2187392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 07/12/2024] [Accepted: 07/25/2024] [Indexed: 08/27/2024] Open
Abstract
The scientific field concerned with the study of regeneration has developed rapidly in recent years. Stem cell therapy is a highly promising therapeutic modality for repairing tissue defects; however, several limitations exist, such as cytotoxicity, potential immune rejection, and ethical issues. Exosomes secreted by stem cells are cell-specific secreted vesicles that play a regulatory role in many biological functions in the human body; they not only have a series of functional roles of stem cells and exert the expected therapeutic effects, but they can also overcome the mass limitations of stem cells and are thus considered in the research as an alternative treatment strategy for stem cells. Since dental stem cell-derived exosomes (DSC-Exos) are easy to acquire and present modulating effects in several fields, including neurovascular regeneration and craniofacial soft and hard tissue regeneration processes, they are served as an emerging cell-free therapeutic strategy in various systematic diseases. There is a growing body of research on various types of DSC-Exos; however, they lack systematic elaboration and tabular summarization. Therefore, this review presents the isolation, characterization, and phenotypes of DSC-Exos and focuses on their current status of functions and mechanisms, as well as the multiple challenges prior to clinical applications.
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Affiliation(s)
- Xiner Ning
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Rui Liu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and RegenerationNational Clinical Research Center for Oral DiseasesShaanxi Key Laboratory of StomatologyNursing DepartmentSchool of StomatologyThe Fourth Military Medical University, Xi'an 710032, China
| | - Yingying Huang
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Zhilong Huang
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Haodi Li
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Qiqi Li
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Zengyan Sheng
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Junjie Wu
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
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Wisdom EC, Lamont A, Martinez H, Rockovich M, Lee W, Gilchrist KH, Ho VB, Klarmann GJ. An Exosome-Laden Hydrogel Wound Dressing That Can Be Point-of-Need Manufactured in Austere and Operational Environments. Bioengineering (Basel) 2024; 11:804. [PMID: 39199762 PMCID: PMC11351238 DOI: 10.3390/bioengineering11080804] [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: 07/22/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Skin wounds often form scar tissue during healing. Early intervention with tissue-engineered materials and cell therapies may promote scar-free healing. Exosomes and extracellular vesicles (EV) secreted by mesenchymal stromal cells (MSC) are believed to have high regenerative capacity. EV bioactivity is preserved after lyophilization and storage to enable use in remote and typically resource-constrained environments. We developed a bioprinted bandage containing reconstituted EVs that can be fabricated at the point-of-need. An alginate/carboxymethyl cellulose (CMC) biomaterial ink was prepared, and printability and mechanical properties were assessed with rheology and compression testing. Three-dimensional printed constructs were evaluated for Young's modulus relative to infill density and crosslinking to yield material with stiffness suitable for use as a wound dressing. We purified EVs from human MSC-conditioned media and characterized them with nanoparticle tracking analysis and mass spectroscopy, which gave a peak size of 118 nm and identification of known EV proteins. Fluorescently labeled EVs were mixed to form bio-ink and bioprinted to characterize EV release. EV bandages were bioprinted on both a commercial laboratory bioprinter and a custom ruggedized 3D printer with bioprinting capabilities, and lyophilized EVs, biomaterial ink, and thermoplastic filament were deployed to an austere Arctic environment and bioprinted. This work demonstrates that EVs can be bioprinted with an alginate/CMC hydrogel and released over time when in contact with a skin-like substitute. The technology is suitable for operational medical applications, notably in resource-limited locations, including large-scale natural disasters, humanitarian crises, and combat zones.
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Affiliation(s)
- E. Cate Wisdom
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
| | - Andrew Lamont
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
| | - Hannah Martinez
- The United States Air Force Academy, 2304 Cadet Drive, USAF Academy, CO 80840, USA
- School of Medicine, Uniformed Service University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Michael Rockovich
- The United States Naval Academy, 121 Blake Rd., Annapolis, MD 21402, USA
| | - Woojin Lee
- The United States Military Academy, 606 Thayer Rd., West Point, NY 10996, USA
| | - Kristin H. Gilchrist
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
| | - Vincent B. Ho
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
| | - George J. Klarmann
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
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Luan W, Lu X, Peng H, Shen X, Rao M, Ruan H. Exosomal miR-19a derived from melanoma cell promotes the vemurafenib resistance of malignant melanoma through directly targeting LRIG1 to reactivate AKT and MAPK pathway. Pathol Res Pract 2024; 260:155410. [PMID: 38955119 DOI: 10.1016/j.prp.2024.155410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 04/04/2024] [Accepted: 06/13/2024] [Indexed: 07/04/2024]
Abstract
Exosomes derived from neighboring v-raf murine sarcoma viral oncogene homolog B1 inhibitor (BRAFi)-resistant melanoma cells mediate the formation of resistance in melanoma cells sensitive to BRAFi. The function and molecular mechanisms of exosomal miRNA in BRAFi resistance of melanoma have not been studied. We found that the expression of miR-19a in BRAFi resistant melanoma cells was significantly higher than that in sensitive cells, and miR-19a contributes to the resistance of melanoma cells to BRAFi by targeting immunoglobulin-like domains protein 1 (LRIG1). miR-19a was highly enriched in exosomes secreted from BRAFi resistant melanoma cells, and these exosomal miR-19a promote the spread of BRAFi resistant. The reactivation of Protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways is the main reason for the BRAFi resistant of melanoma cells. We demonstrated that exosomal miR-19a derived from melanoma cell promotes the formation and spread of BRAFi resistant in melanoma through targeting LRIG1 to reactivate AKT and MAPK pathway. Therefore, miR-19a may serve as a potential therapeutic target in melanoma patients with acquired drug resistance.
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Affiliation(s)
- Wenkang Luan
- Department of Plastic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xu Lu
- Department of Plastic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Huiyong Peng
- Department of Laboratory Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang Medical School of Nanjing Medical University, Zhenjiang, Jiangsu, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuanlin Shen
- Department of Rehabilitation, Changshu No. 2 People's Hospital (Changshu Hospital affiliated the NanTong University), Changshu, Jiangsu 215500, China
| | - Min Rao
- Hepatobiliary surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Hongru Ruan
- Department of Plastic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
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Gabr MM, El-Halawani SM, Refaie AF, Khater SM, Ismail AM, Karras MS, Magar RW, Sayed SE, Kloc M, Uosef A, Sabek OM, Ghoneim MA. Modulation of naïve mesenchymal stromal cells by extracellular vesicles derived from insulin-producing cells: an in vitro study. Sci Rep 2024; 14:17844. [PMID: 39090166 PMCID: PMC11294623 DOI: 10.1038/s41598-024-68104-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024] Open
Abstract
This study was to determine whether extracellular vesicles (EVs) derived from insulin-producing cells (IPCs) can modulate naïve mesenchymal stromal cells (MSCs) to become insulin-secreting. MSCs were isolated from human adipose tissue. The cells were then differentiated to generate IPCs by achemical-based induction protocol. EVs were retrieved from the conditioned media of undifferentiated (naïve) MSCs (uneducated EVs) and from that of MSC-derived IPCs (educated EVs) by sequential ultracentrifugation. The obtained EVs were co-cultured with naïve MSCs.The cocultured cells were evaluated by immunofluorescence, flow cytometry, C-peptide nanogold silver-enhanced immunostaining, relative gene expression and their response to a glucose challenge.Immunostaining for naïve MSCs cocultured with educated EVs was positive for insulin, C-peptide, and GAD65. By flow cytometry, the median percentages of insulin-andC-peptide-positive cells were 16.1% and 14.2% respectively. C-peptide nanogoldimmunostaining providedevidence for the intrinsic synthesis of C-peptide. These cells released increasing amounts of insulin and C-peptide in response to increasing glucose concentrations. Gene expression of relevant pancreatic endocrine genes, except for insulin, was modest. In contrast, the results of naïve MSCs co-cultured with uneducated exosomes were negative for insulin, C-peptide, and GAD65. These findings suggest that this approach may overcome the limitations of cell therapy.
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Affiliation(s)
- Mahmoud M Gabr
- Biotechnology Department, Urology and Nephrology Center, Mansoura, Egypt
| | | | - Ayman F Refaie
- Nephrology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Sherry M Khater
- Pathology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Amani M Ismail
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Mary S Karras
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Raghda W Magar
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Shorouk El Sayed
- Microbiology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Malgorzata Kloc
- The Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
- Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Ahmed Uosef
- The Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Omaima M Sabek
- The Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
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40
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Xu F, Luo S, Lu P, Cai C, Li W, Li C. Composition, functions, and applications of exosomal membrane proteins. Front Immunol 2024; 15:1408415. [PMID: 39148736 PMCID: PMC11324478 DOI: 10.3389/fimmu.2024.1408415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/15/2024] [Indexed: 08/17/2024] Open
Abstract
Exosomes play a crucial role in various biological processes, such as human development, immune responses, and disease occurrence. The membrane proteins on exosomes are pivotal factors for their biological functionality. Currently, numerous membrane proteins have been identified on exosome membranes, participating in intercellular communication, mediating target cell recognition, and regulating immune processes. Furthermore, membrane proteins from exosomes derived from cancer cells can serve as relevant biomarkers for early cancer diagnosis. This article provides a comprehensive review of the composition of exosome membrane proteins and their diverse functions in the organism's biological processes. Through in-depth exploration of exosome membrane proteins, it is expected to offer essential foundations for the future development of novel biomedical diagnostics and therapies.
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Affiliation(s)
- Fang Xu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Shumin Luo
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Pengpeng Lu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Chao Cai
- Integrated Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Weihua Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Integrated Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Chuanyun Li
- Beijing Youan Hospital, Capital Medical University, Beijing, China
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41
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Kim J, Xu S, Jung S, Nguyen A, Cheng Y, Zhao M, Fujimoto BS, Nelson W, Schiro P, Franklin JL, Higginbotham JN, Coffey RJ, Shi M, Vojtech LN, Hladik F, Tewari M, Tigges J, Ghiran I, Jovanovic‐Talisman T, Laurent LC, Das S, Gololobova O, Witwer KW, Xu T, Charest A, Jensen KVK, Raffai RL, Jones JC, Welsh JA, Nolan JP, Chiu DT. Comparison of EV characterization by commercial high-sensitivity flow cytometers and a custom single-molecule flow cytometer. J Extracell Vesicles 2024; 13:e12498. [PMID: 39140467 PMCID: PMC11322860 DOI: 10.1002/jev2.12498] [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: 03/11/2024] [Accepted: 07/25/2024] [Indexed: 08/15/2024] Open
Abstract
High-sensitivity flow cytometers have been developed for multi-parameter characterization of single extracellular vesicles (EVs), but performance varies among instruments and calibration methods. Here we compare the characterization of identical (split) EV samples derived from human colorectal cancer (DiFi) cells by three high-sensitivity flow cytometers, two commercial instruments, CytoFLEX/CellStream, and a custom single-molecule flow cytometer (SMFC). DiFi EVs were stained with the membrane dye di-8-ANEPPS and with PE-conjugated anti-EGFR or anti-tetraspanin (CD9/CD63/CD81) antibodies for estimation of EV size and surface protein copy numbers. The limits of detection (LODs) for immunofluorescence and vesicle size based on calibration using cross-calibrated, hard-dyed beads were ∼10 PE/∼80 nm EV diameter for CytoFLEX and ∼10 PEs/∼67 nm for CellStream. For the SMFC, the LOD for immunofluorescence was 1 PE and ≤ 35 nm for size. The population of EVs detected by each system (di-8-ANEPPS+/PE+ particles) differed widely depending on the LOD of the system; for example, CellStream/CytoFLEX detected only 5.7% and 1.5% of the tetraspanin-labelled EVs detected by SMFC, respectively, and median EV diameter and antibody copy numbers were much larger for CellStream/CytoFLEX than for SMFC as measured and validated using super-resolution/single-molecule TIRF microscopy. To obtain a dataset representing a common EV population analysed by all three platforms, we filtered out SMFC and CellStream measurements for EVs below the CytoFLEX LODs as determined by bead calibration (10 PE/80 nm). The inter-platform agreement using this filtered dataset was significantly better than for the unfiltered dataset, but even better concordance between results was obtained by applying higher cutoffs (21 PE/120 nm) determined by threshold analysis using the SMFC data. The results demonstrate the impact of specifying LODs to define the EV population analysed on inter-instrument reproducibility in EV flow cytometry studies, and the utility of threshold analysis of SMFC data for providing semi-quantitative LOD values for other flow cytometers.
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Affiliation(s)
- James Kim
- Department of ChemistryUniversity of WashingtonSeattleWashingtonUSA
| | - Shihan Xu
- Department of ChemistryUniversity of WashingtonSeattleWashingtonUSA
| | | | - Alya Nguyen
- Department of ChemistryUniversity of WashingtonSeattleWashingtonUSA
| | - Yuanhua Cheng
- Department of ChemistryUniversity of WashingtonSeattleWashingtonUSA
| | - Mengxia Zhao
- Department of ChemistryUniversity of WashingtonSeattleWashingtonUSA
| | | | - Wyatt Nelson
- Department of ChemistryUniversity of WashingtonSeattleWashingtonUSA
| | | | - Jeffrey L. Franklin
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | | | - Robert J. Coffey
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Department of Cell BiologyVanderbilt UniversityNashvilleTennesseeUSA
| | - Min Shi
- Department of PathologyUniversity of WashingtonSeattleWashingtonUSA
| | - Lucia N. Vojtech
- Department of Obstetrics and GynecologyUniversity of WashingtonSeattleWashingtonUSA
| | - Florian Hladik
- Department of Obstetrics and GynecologyUniversity of WashingtonSeattleWashingtonUSA
- Division of Allergy and Infectious Diseases, Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
- Vaccine and Infectious Disease DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Muneesh Tewari
- Division of Hematology/OncologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
- Rogel Comprehensive Cancer CenterUniversity of MichiganAnn ArborMichiganUSA
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMichiganUSA
- Center for Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMichiganUSA
- VA Ann Arbor Healthcare SystemAnn ArborMichiganUSA
| | - John Tigges
- Department of MedicineBeth Israel Deaconess Medical CenterBoston and CambridgeMassachusettsUSA
| | - Ionita Ghiran
- Department of MedicineBeth Israel Deaconess Medical CenterBoston and CambridgeMassachusettsUSA
| | - Tijana Jovanovic‐Talisman
- Department of Molecular MedicineBeckman Research Institute of the City of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Louise C. Laurent
- Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative MedicineUniversity of California San DiegoSan DiegoCaliforniaUSA
| | - Saumya Das
- Cardiovascular Research Center, Massachusetts General HospitalHarvard Medical schoolBostonMassachusettsUSA
| | - Olesia Gololobova
- Department of Molecular and Comparative PathologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Kenneth W. Witwer
- Department of Molecular and Comparative PathologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Tuoye Xu
- Cancer Research InstituteBeth Israel Deaconess Medical CenterBostonMassachusettsUSA
- Department of MedicineHarvard Medical SchoolBostonMassachusettsUSA
| | - Al Charest
- Cancer Research InstituteBeth Israel Deaconess Medical CenterBostonMassachusettsUSA
- Department of MedicineHarvard Medical SchoolBostonMassachusettsUSA
| | | | - Robert L. Raffai
- Department of Veterans AffairsSurgical Service (112G), San Francisco VA Medical CenterSan FranciscoCaliforniaUSA
| | - Jennifer C. Jones
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Joshua A. Welsh
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | | | - Daniel T. Chiu
- Department of ChemistryUniversity of WashingtonSeattleWashingtonUSA
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Li D, Zhang T, Guo Y, Bi C, Liu M, Wang G. Biological impact and therapeutic implication of tumor-associated macrophages in hepatocellular carcinoma. Cell Death Dis 2024; 15:498. [PMID: 38997297 PMCID: PMC11245522 DOI: 10.1038/s41419-024-06888-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: 03/11/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024]
Abstract
The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell-cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.
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Affiliation(s)
- Deming Li
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Ting Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, 110001, PR China
| | - Ye Guo
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Cong Bi
- Department of Radiology, The First Hospital of China Medical University, Shenyang, 110001, PR China.
| | - Ming Liu
- Department of Oral Radiology, School of Stomatology, China Medical University, Shenyang, Liaoning, 110002, PR China.
| | - Gang Wang
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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43
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Chen YF, Luh F, Ho YS, Yen Y. Exosomes: a review of biologic function, diagnostic and targeted therapy applications, and clinical trials. J Biomed Sci 2024; 31:67. [PMID: 38992695 PMCID: PMC11238361 DOI: 10.1186/s12929-024-01055-0] [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: 04/30/2024] [Accepted: 06/16/2024] [Indexed: 07/13/2024] Open
Abstract
Exosomes are extracellular vesicles generated by all cells and they carry nucleic acids, proteins, lipids, and metabolites. They mediate the exchange of substances between cells,thereby affecting biological properties and activities of recipient cells. In this review, we briefly discuss the composition of exocomes and exosome isolation. We also review the clinical applications of exosomes in cancer biology as well as strategies in exosome-mediated targeted drug delivery systems. Finally, the application of exosomes in the context of cancer therapeutics both in practice and literature are discussed.
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Affiliation(s)
- Yi-Fan Chen
- International Master Program in Translation Science, College of Medical Science and Technology, Taipei Medical University, New Taipei City, 23564, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, New Taipei City, 23564, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, New Taipei City, 23564, Taiwan
- Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan
| | - Frank Luh
- Sino-American Cancer Foundation, Covina, CA, 91722, USA
| | - Yuan-Soon Ho
- Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, 406040, Taiwan.
| | - Yun Yen
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, 406040, Taiwan.
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 110301, Taiwan.
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 110301, Taiwan.
- Cancer Center, Taipei Municipal WanFang Hospital, Taipei, 11696, Taiwan.
- Center for Cancer Translational Research, Tzu Chi University, Hualien City, 970374, Taiwan.
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44
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Choudhery MS, Arif T, Mahmood R, Harris DT. Stem Cell-Based Acellular Therapy: Insight into Biogenesis, Bioengineering and Therapeutic Applications of Exosomes. Biomolecules 2024; 14:792. [PMID: 39062506 PMCID: PMC11275160 DOI: 10.3390/biom14070792] [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: 06/06/2024] [Revised: 06/25/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
The vast regenerative potential of stem cells has laid the foundation for stem cell-based therapies. However, certain challenges limit the application of cell-based therapies. The therapeutic use of cell-free therapy can avoid limitations associated with cell-based therapies. Acellular stem cell-based therapies rely on the use of biological factors released by stem cells, including growth factors and extracellular vesicles such as exosomes. Due to their comparable regenerative potential, acellular therapies may provide a feasible and scalable alternative to stem cell-based therapies. Exosomes are small vesicles secreted by various types of cells, including stem cells. Exosomes contain parent cell-derived nucleic acids, proteins, lipids, and other bioactive molecules. They play an important role in intra-cellular communication and influence the biological characteristics of cells. Exosomes inherit the properties of their parent cells; therefore, stem cell-derived exosomes are of particular interest for applications of regenerative medicine. In comparison to stem cell-based therapy, exosome therapy offers several benefits, such as easy transport and storage, no risk of immunological rejection, and few ethical dilemmas. Unlike stem cells, exosomes can be lyophilized and stored off-the-shelf, making acellular therapies standardized and more accessible while reducing overall treatment costs. Exosome-based acellular treatments are therefore readily available for applications in patients at the time of care. The current review discusses the use of exosomes as an acellular therapy. The review explores the molecular mechanism of exosome biogenesis, various methods for exosome isolation, and characterization. In addition, the latest advancements in bioengineering techniques to enhance exosome potential for acellular therapies have been discussed. The challenges in the use of exosomes as well as their diverse applications for the diagnosis and treatment of diseases have been reviewed in detail.
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Affiliation(s)
- Mahmood S. Choudhery
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 54600, Pakistan; (M.S.C.); (T.A.)
| | - Taqdees Arif
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 54600, Pakistan; (M.S.C.); (T.A.)
| | - Ruhma Mahmood
- Allama Iqbal Medical College, Jinnah Hospital, Lahore 54700, Pakistan;
| | - David T. Harris
- Department of Immunobiology, College of Medicine, University of Arizona Health Sciences Biorepository, University of Arizona, Tucson, AZ 85721, USA
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Ansari FJ, Tafti HA, Amanzadeh A, Rabbani S, Shokrgozar MA, Heidari R, Behroozi J, Eyni H, Uversky VN, Ghanbari H. Comparison of the efficiency of ultrafiltration, precipitation, and ultracentrifugation methods for exosome isolation. Biochem Biophys Rep 2024; 38:101668. [PMID: 38405663 PMCID: PMC10885727 DOI: 10.1016/j.bbrep.2024.101668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/27/2024] Open
Abstract
Extracellular vesicles (EVs) are enclosed by a lipid-bilayer membrane and secreted by all types of cells. They are classified into three groups: apoptotic bodies, microvesicles, and exosomes. Exosomes play a number of important roles in the intercellular communication and crosstalk between tissues in the body. In this study, we use three common methods based on different principles for exosome isolation, namely ultrafiltration, precipitation, and ultracentrifugation. We use field emission scanning electron microscopy (FESEM) and dynamic light scattering (DLS) analyses for characterization of exosomes. The functionality and effect of isolated exosomes on the viability of hypoxic cells was investigated by alamarBlue and Flow-cytometry. The results of the FESEM study show that the ultrafiltration method isolates vesicles with higher variability of shapes and sizes when compared to the precipitation and ultracentrifugation methods. DLS results show that mean size of exosomes isolated by ultrafiltration, precipitation, and ultracentrifugation methods are 122, 89, and 60 nm respectively. AlamarBlue analysis show that isolated exosomes increase the viability of damaged cells by 11%, 15%, and 22%, respectively. Flow-cytometry analysis of damaged cells also show that these vesicles increase the content of live cells by 9%, 15%, and 20%, respectively. This study shows that exosomes isolated by the ultracentrifugation method are characterized by smaller size and narrow size distribution. Furthermore, more homogenous particles isolated by this method show increased efficiency of the protection of hypoxic cells in comparison with the exosomes isolated by the two other methods.
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Affiliation(s)
- Farshid Jaberi Ansari
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Ahmadi Tafti
- Research Center for Advanced Technologies in Cardiovascular Medicine, Cardiovascular Disease Research Institute, Tehran Heart Center Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Amanzadeh
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | - Shahram Rabbani
- Research Center for Advanced Technologies in Cardiovascular Medicine, Cardiovascular Disease Research Institute, Tehran Heart Center Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Reza Heidari
- Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, 1411718541, Iran
| | - Javad Behroozi
- Research Center for Cancer Screening and Epidemiology, AJA University of Medical Sciences, Tehran, Iran
| | - Hossein Eyni
- Stem Cell and Regenerative Medicine Research Center, Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vladimir N. Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Hossein Ghanbari
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Advanced Technologies in Cardiovascular Medicine, Cardiovascular Disease Research Institute, Tehran Heart Center Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Institute for Biomaterials, University of Tehran & Tehran University of Medical Sciences, Tehran, Iran
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46
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Li W, Wang C, Zhang Y, Lu Y. Lipid Nanocarrier-Based mRNA Therapy: Challenges and Promise for Clinical Transformation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2310531. [PMID: 38287729 DOI: 10.1002/smll.202310531] [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: 11/16/2023] [Revised: 01/19/2024] [Indexed: 01/31/2024]
Abstract
Due to the outbreak of novel coronavirus pneumonia, messenger RNA (mRNA) technology has attracted heated attention. A specific, safe, and efficient mRNA delivery system is needed. Lipid nanocarriers have become attractive carriers for mRNA delivery due to their high delivery efficiency, few side effects, and easy modification to change their structures and functions. To achieve the desired biological effect, lipid nanocarriers must reach the designated location for effective drug delivery. Therefore, the effects of the composition of lipid nanocarriers on their key properties are briefly reviewed. In addition, the progress of smart drug delivery by changing the composition of lipid nanocarriers is summarized, and the importance of component design and structure is emphasized. Subsequently, this review summarizes the latest progress in lipid nanocarrier-based mRNA technology and provides corresponding strategies for its current challenges, putting forward valuable information for the future design of lipid nanocarriers and mRNA.
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Affiliation(s)
- Wenchao Li
- Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China
- Key Laboratory of Industrial Biocatalysis, Ministry of Education, Tsinghua University, Beijing, 100084, China
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Chen Wang
- Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China
- Key Laboratory of Industrial Biocatalysis, Ministry of Education, Tsinghua University, Beijing, 100084, China
| | - Yifei Zhang
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yuan Lu
- Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China
- Key Laboratory of Industrial Biocatalysis, Ministry of Education, Tsinghua University, Beijing, 100084, China
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47
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Rahmani A, Soleymani A, Almukhtar M, Behzad Moghadam K, Vaziri Z, Hosein Tabar Kashi A, Adabi Firoozjah R, Jafari Tadi M, Zolfaghari Dehkharghani M, Valadi H, Moghadamnia AA, Gasser RB, Rostami A. Exosomes, and the potential for exosome-based interventions against COVID-19. Rev Med Virol 2024; 34:e2562. [PMID: 38924213 DOI: 10.1002/rmv.2562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 05/17/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024]
Abstract
Since late 2019, the world has been devastated by the coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with more than 760 million people affected and ∼seven million deaths reported. Although effective treatments for COVID-19 are currently limited, there has been a strong focus on developing new therapeutic approaches to address the morbidity and mortality linked to this disease. An approach that is currently being investigated is the use of exosome-based therapies. Exosomes are small, extracellular vesicles that play a role in many clinical diseases, including viral infections, infected cells release exosomes that can transmit viral components, such as miRNAs and proteins, and can also include receptors for viruses that facilitate viral entry into recipient cells. SARS-CoV-2 has the ability to impact the formation, secretion, and release of exosomes, thereby potentially facilitating or intensifying the transmission of the virus among cells, tissues and individuals. Therefore, designing synthetic exosomes that carry immunomodulatory cargo and antiviral compounds are proposed to be a promising strategy for the treatment of COVID-19 and other viral diseases. Moreover, exosomes generated from mesenchymal stem cells (MSC) might be employed as cell-free therapeutic agents, as MSC-derived exosomes can diminish the cytokine storm and reverse the suppression of host anti-viral defences associated with COVID-19, and boost the repair of lung damage linked to mitochondrial activity. The present article discusses the significance and roles of exosomes in COVID-19, and explores potential future applications of exosomes in combating this disease. Despite the challenges posed by COVID-19, exosome-based therapies could represent a promising avenue for improving patient outcomes and reducing the impact of this disease.
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Affiliation(s)
- Abolfazl Rahmani
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Soleymani
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | | | - Kimia Behzad Moghadam
- Independent Researcher, Former University of California, San Francisco (UCSF), San Francisco, California, USA
| | - Zahra Vaziri
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Hosein Tabar Kashi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Reza Adabi Firoozjah
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mehrdad Jafari Tadi
- Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Maryam Zolfaghari Dehkharghani
- Department of Healthcare Administration and Policy, School of Public Health, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA
| | - Hadi Valadi
- Department of Rheumatology and Inflammation Research Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ali Akbar Moghadamnia
- Department of Pharmacology and Toxicology, Babol University of Medical Sciences, Babol, Iran
- Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Robin B Gasser
- Department of Veterinary Biosciences, Faculty of Science, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia
| | - Ali Rostami
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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48
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Bobo TA, Robinson M, Tofade C, Sokolski‐Papkov M, Nichols P, Vorobiov S, Fu H. AAV gene replacement therapy for treating MPS IIIC: Facilitating bystander effects via EV-mRNA cargo. J Extracell Vesicles 2024; 13:e12464. [PMID: 38961538 PMCID: PMC11222166 DOI: 10.1002/jev2.12464] [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: 01/10/2024] [Accepted: 05/22/2024] [Indexed: 07/05/2024] Open
Abstract
MPS IIIC is a lysosomal storage disease caused by mutations in heparan-α-glucosaminide N-acetyltransferase (HGSNAT), for which no treatment is available. Because HGSNAT is a trans-lysosomal-membrane protein, gene therapy for MPS IIIC needs to transduce as many cells as possible for maximal benefits. All cells continuously release extracellular vesicles (EVs) and communicate by exchanging biomolecules via EV trafficking. To address the unmet need, we developed a rAAV-hHGSNATEV vector with an EV-mRNA-packaging signal in the 3'UTR to facilitate bystander effects, and tested it in an in vitro MPS IIIC model. In human MPS IIIC cells, rAAV-hHGSNATEV enhanced HGSNAT mRNA and protein expression, EV-hHGSNAT-mRNA packaging, and cleared GAG storage. Importantly, incubation with EVs led to hHGSNAT protein expression and GAG contents clearance in recipient MPS IIIC cells. Further, rAAV-hHGSNATEV transduction led to the reduction of pathological EVs in MPS IIIC cells to normal levels, suggesting broader therapeutic benefits. These data demonstrate that incorporating the EV-mRNA-packaging signal into a rAAV-hHGSNAT vector enhances EV packaging of hHGSNAT-mRNA, which can be transported to non-transduced cells and translated into functional rHGSNAT protein, facilitating cross-correction of disease pathology. This study supports the therapeutic potential of rAAVEV for MPS IIIC, and broad diseases, without having to transduce every cell.
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Affiliation(s)
- Tierra A. Bobo
- Gene Therapy CenterChapel HillUSA
- Division of Genetics and Metabolism, Department of PediatricsSchool of MedicineChapel HillUSA
| | | | | | - Marina Sokolski‐Papkov
- Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
| | | | | | - Haiyan Fu
- Gene Therapy CenterChapel HillUSA
- Division of Genetics and Metabolism, Department of PediatricsSchool of MedicineChapel HillUSA
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49
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Hushmandi K, Saadat SH, Raei M, Aref AR, Reiter RJ, Nabavi N, Taheriazam A, Hashemi M. The science of exosomes: Understanding their formation, capture, and role in cellular communication. Pathol Res Pract 2024; 259:155388. [PMID: 38850846 DOI: 10.1016/j.prp.2024.155388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/06/2024] [Accepted: 06/01/2024] [Indexed: 06/10/2024]
Abstract
Extracellular vesicles (EVs) serve as a crucial method for transferring information among cells, which is vital in multicellular organisms. Among these vesicles, exosomes are notable for their small size, ranging from 20 to 150 nm, and their role in cell-to-cell communication. They carry lipids, proteins, and nucleic acids between cells. The creation of exosomes begins with the inward budding of the cell membrane, which then encapsulates various macromolecules as cargo. Once filled, exosomes are released into the extracellular space and taken up by target cells via endocytosis and similar processes. The composition of exosomal cargo varies, encompassing diverse macromolecules with specific functions. Because of their significant roles, exosomes have been isolated from various cell types, including cancer cells, endothelial cells, macrophages, and mesenchymal cells, with the aim of harnessing them for therapeutic applications. Exosomes influence cellular metabolism, and regulate lipid, glucose, and glutamine pathways. Their role in pathogenesis is determined by their cargo, which can manipulate processes such as apoptosis, proliferation, inflammation, migration, and other molecular pathways in recipient cells. Non-coding RNA transcripts, a common type of cargo, play a pivotal role in regulating disease progression. Exosomes are implicated in numerous biological and pathological processes, including inflammation, cancer, cardiovascular diseases, diabetes, wound healing, and ischemic-reperfusion injury. As a result, they hold significant potential in the treatment of both cancerous and non-cancerous conditions.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Seyed Hassan Saadat
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehdi Raei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Department of Translational Sciences, Xsphera Biosciences Inc. Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio, TX, USA
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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50
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Liu X, Meng Q, Shi S, Geng X, Wang E, Li Y, Lin F, Liang X, Xi X, Han W, Fan H, Zhou X. Cardiac-derived extracellular vesicles improve mitochondrial function to protect the heart against ischemia/reperfusion injury by delivering ATP5a1. J Nanobiotechnology 2024; 22:385. [PMID: 38951822 PMCID: PMC11218245 DOI: 10.1186/s12951-024-02618-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 02/28/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear. RESULTS Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs. CONCLUSIONS These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.
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Affiliation(s)
- Xuan Liu
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Cardiothoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Qingshu Meng
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Shanshan Shi
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xuedi Geng
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Enhao Wang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yinzhen Li
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Fang Lin
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xiaoting Liang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xiaoling Xi
- Department of Heart Failure, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Wei Han
- Department of Heart Failure, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Huimin Fan
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
- Department of Cardiothoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
| | - Xiaohui Zhou
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Rd, Pudong, Shanghai, 200092, China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
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