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Aldali F, Deng C, Nie M, Chen H. Advances in therapies using mesenchymal stem cells and their exosomes for treatment of peripheral nerve injury: state of the art and future perspectives. Neural Regen Res 2025; 20:3151-3171. [PMID: 39435603 PMCID: PMC11881730 DOI: 10.4103/nrr.nrr-d-24-00235] [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: 02/26/2024] [Revised: 07/26/2024] [Accepted: 08/26/2024] [Indexed: 10/23/2024] Open
Abstract
"Peripheral nerve injury" refers to damage or trauma affecting nerves outside the brain and spinal cord. Peripheral nerve injury results in movements or sensation impairments, and represents a serious public health problem. Although severed peripheral nerves have been effectively joined and various therapies have been offered, recovery of sensory or motor functions remains limited, and efficacious therapies for complete repair of a nerve injury remain elusive. The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function. Mesenchymal stem cells, as large living cells responsive to the environment, secrete various factors and exosomes. The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins, microRNA, and messenger RNA derived from parent mesenchymal stem cells. Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function, offering solutions to changes associated with cell-based therapies. Despite ongoing investigations, mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage. A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation. This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury, exploring the underlying mechanisms. Subsequently, it provides an overview of the current status of mesenchymal stem cell and exosome-based therapies in clinical trials, followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes. Finally, the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes, offering potential solutions and guiding future directions.
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Affiliation(s)
- Fatima Aldali
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Chunchu Deng
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mingbo Nie
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hong Chen
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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2
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Ruan K, Zhang J, Chu Z, Wang X, Zhang X, Liu Q, Yang J. Exosomes in acute pancreatitis: Pathways to cellular death regulation and clinical application potential. Int Immunopharmacol 2025; 153:114491. [PMID: 40117803 DOI: 10.1016/j.intimp.2025.114491] [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: 01/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/23/2025]
Abstract
Acute pancreatitis (AP) is a severe inflammatory condition of the digestive system which, in severe cases, can lead to persistent organ failure (POF). Developing novel therapeutic interventions and diagnostic biomarkers is critical to improve the management and prognosis of this disease. Exosomes, small extracellular vesicles, can reflect the inflammatory state of the pancreas, providing valuable insights into disease progression. Moreover, these vesicles are essential mediators of intercellular communication, modulating inflammatory responses by affecting patterns of cell death and macrophage polarization-key factors in determining AP clinical outcomes. Their stability, bioavailability, and capacity to transport various bioactive molecules render exosomes promising tools for early diagnosis and precision therapy, potentially enhancing patient outcomes. This review highlights the innovative potential of exosomes in transforming the management of AP, providing a foundation for more accurate diagnostics and targeted treatments with clinical applicability.
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Affiliation(s)
- Kaiyi Ruan
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Jinglei Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhuohuan Chu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiang Wang
- Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Xiaofeng Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China; Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310006, China.
| | - Qiang Liu
- Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310006, China.
| | - Jianfeng Yang
- Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310006, China.
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Ashrafi F, Emami A, Sefidbakht S, Aghayan H, Soleimani F, Omidfar K. Accelerated healing of full-thickness skin wounds by multifunctional exosome-loaded scaffolds of alginate hydrogel/PCL nanofibers with hemostatic efficacy. Int J Biol Macromol 2025; 307:142271. [PMID: 40112978 DOI: 10.1016/j.ijbiomac.2025.142271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
Although employing exosomes (EXOs) for promoting tissue repair is already in the pipeline as a new cell-free wound treatment, the rapid clearance of EXOs is still a challenge. This study assesses the effectiveness of a hybrid design of nanofibers and hydrogel in the controlled delivery of EXOs to wounds for an enhanced healing process. EXOs are isolated from the human placenta-derived stem cells and characterized by a novel nano-fluorescent dot blot assay. They are incorporated into an alginate hydrogel composited with a nanofibrous layer of poly(ε-caprolactone) to mimic the bilayer structure of the dermis and epidermis. The scaffold characteristics, including morphology, mechanobiological properties, physical properties, anti-inflammatory activity, and cytocompatibility are comprehensively evaluated. The tailored hydrophilic/hydrophobic design of the scaffolds presents controlled degradability, controlled EXOs release, enhanced cell proliferation, hemostatic activity with insignificant hemolysis, and a balance of strength and conformability suitable for full-thickness wound milieu. The repair of full-thickness wounds is further investigated in a rat model. Animal study results indicate that the EXO-loaded scaffolds accelerate wound closure, inflammation reduction, re-epithelialization, and collagen synthesis. For the latter, a collagen content of 22 % and 33 % higher than that for the unloaded scaffold and the control was observed, respectively.
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Affiliation(s)
- Fatemeh Ashrafi
- Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Asrin Emami
- Iranian tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Salma Sefidbakht
- Department of Pathology, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Foad Soleimani
- Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Kobra Omidfar
- Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Borger A, Haertinger M, Millesi F, Semmler L, Supper P, Stadlmayr S, Rad A, Radtke C. Conditioning period impacts the morphology and proliferative effect of extracellular vesicles derived from rat adipose tissue derived stromal cell. J Nanobiotechnology 2025; 23:164. [PMID: 40033315 PMCID: PMC11877948 DOI: 10.1186/s12951-025-03273-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
A serum-free conditioning period is a crucial step during small extracellular vesicle (sEV) preparation ranging from 12 to 72h. There is a paucity of knowledge about downstream effects of serum-free conditioning on sEVs and the optimal duration of the conditioning period. The aim of this study was to investigate the influence of the serum-free conditioning period on the sEVs derived from primary adipose stromal cells (AdSCs) and their regenerative potential. Primary AdSCs were conditioned in serum-free medium for 72h. Conditioned medium was collected and refreshed every 24h obtaining three fractions, namely sEVs released after 24h (early), 24h to 48h (intermediate) and 48h to 72h (late). After sEV enrichment with ultracentrifugation, the sEV fractions were analyzed by their size, phenotypic expression, and morphology. Proliferation assays of primary Schwann cells after treatment with sEVs were performed. Particles meeting criteria to be classified as sEVs were detected in all fractions. However, sEVs differed by their size and phenotypic expression. A long conditioning period led to a heterogenous population of larger sEVs and increased protein per particle ratio. Moreover, the expression of tetraspanines was affected. Lastly, the proliferative effect of sEVs on Schwann cells decreased with increasing conditioning period. In conclusion, particles meeting the criteria of EVs are released by primary AdSCs over 72h under serum free conditioning. Nonetheless, they significantly differ in their proliferative effect on Schwann cells cultures.
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Affiliation(s)
- Anton Borger
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Maximilian Haertinger
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Flavia Millesi
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Lorenz Semmler
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Paul Supper
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Sarah Stadlmayr
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Anda Rad
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Christine Radtke
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Austrian Cluster for Tissue Regeneration, Vienna, Austria.
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Khanabdali R, Shojaee M, Johnson J, Law SQK, Lim MBL, James PF, Tester A, Kalionis B. Profiling the extracellular vesicles of two human placenta-derived mesenchymal stromal cell populations. Exp Cell Res 2025; 444:114387. [PMID: 39706285 DOI: 10.1016/j.yexcr.2024.114387] [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: 08/12/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Increasing evidence shows extracellular vesicles (EVs) are primarily responsible for the beneficial effects of cell-based therapies. EVs derived from mesenchymal stromal cells (MSCs) show promise as a source of EVs for cell-free therapies. The human placental fetal-maternal interface is a rich and abundant source of MSCs from which EVs can be isolated. This study focusses on chorionic MSCs (CMSC) located on the fetal aspect of the interface and decidual MSCs (DMSC) on the maternal aspect. This study used Ligand-based Exosome Affinity Purification (LEAP) chromatography to isolate EVs from well-characterized placental hTERT-transduced CMSC29 and DMSC23 cell lines, which retain many important stem cell-like properties of primary CMSC and DMSC, respectively. After initial biophysical characterization of the EVs isolated from each cell line, the biological activities and the protein, lipid and small RNA contents of CMSC29-EVs and DMSC23-EVs were compared and assessed. LEAP-purified EVs from both sources were validated at the biophysical level by Spectradyne, Cryo-Transmission Electron Microscopy (Cryo-TEM), and Western blot analysis. EVs from each type were labelled with the live cell stain PKH26 and their in vitro uptake and internalization by human dermal fibroblast cells was assessed, as well as their phosphorylation of the protein kinase B/AKT (AKT) pathway. The protein and lipid contents were analyzed by mass spectrometry and the nucleic acid content by RNA sequencing (RNA-seq). Lastly, the biological activities of the EVs were evaluated in a BioMAP® Diversity PLUS® screen system across a panel of 12 human primary cell-based systems and in vitro cell proliferation. EVs isolated from both DMSC23 and CMSC29 significantly increased proliferation of fibroblasts and showed phosphorylation of the AKT pathway. Protein mass spectrometry analysis identified a large number of proteins including cell surface receptors, cytokines, chemokines, matrix molecules and enzymes in both EV types. Lipidomic analysis identified species including phosphatidylcholine, triacylglycerides and diacylglycerides in both DMSC23 and CMSC29-derived EVs. There were some significant differences in identified microRNAs (miRNAs) between the two EV types. The top differentially expressed miRNAs between the two EV types show pathways association with matrix interaction, transcriptional regulation, proliferation, cellular protein modification processes, and vasculogenesis. Differences were also detected between DMSC23- and CMSC29-EVs in the biological activity they displayed in the BioMAP® Diversity PLUS® screen.
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Affiliation(s)
- Ramin Khanabdali
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Mozhgan Shojaee
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Jancy Johnson
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia; University of Melbourne Department of Biochemistry and Pharmacology, Parkville, VIC, 3052, Australia
| | - Sam Q K Law
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Melissa B L Lim
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Patrick F James
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Angus Tester
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Bill Kalionis
- Department of Maternal-Fetal Medicine Pregnancy Research Centre, Royal Women's Hospital, Parkville, VIC, 3052, Australia; University of Melbourne Department of Obstetrics and Gynaecology and Newborn Health, Royal Women's Hospital, Parkville, VIC, 3052, Australia.
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Arai K, Yoshida S, Furuichi E, Iwanaga S, Mir TA, Yoshida T. Transplanted artificial amnion membrane enhanced wound healing in third-degree burn injury diabetic mouse model. Regen Ther 2024; 27:170-180. [PMID: 38571890 PMCID: PMC10987674 DOI: 10.1016/j.reth.2024.03.016] [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: 12/07/2023] [Revised: 02/29/2024] [Accepted: 03/15/2024] [Indexed: 04/05/2024] Open
Abstract
Introduction Wound healing is severely compromised in patients with diabetes owing to factors such poor blood circulation, delayed immune response, elevated blood sugar levels, and neuropathy. Although the development of new wound healing products and prevention of serious complications such as infections in wounds have received substantial interest, wound healing remains a challenge in regenerative medicine. Burn wounds, especially third-degree burns, are difficult to treat because they are associated with immune and inflammatory reactions and distributive shock. Wound care and treatment that protects the burn site from infection and allows wound healing can be achieved with bioengineered wound dressings. However, few studies have reported effective dressings for third-degree burn wounds, making it important to develop new dressing materials. Methods In this study, we developed an artificial amniotic membrane (AM) using epithelial and mesenchymal cells derived from human amnion as a novel dressing material. The artificial AM was applied to the wound of a diabetic third-degree burn model and its wound healing ability was evaluated. Results This artificial amnion produced multiple growth factors associated with angiogenesis, fibroblast proliferation, and anti-inflammation. In addition, angiogenesis and granulation tissue formation were promoted in the artificial AM-treated mouse group compared with the control group. Furthermore, the inflammatory phase was prolonged in the control group. Conclusions Our preliminary results indicate that the artificial AM might be useful as a new dressing for refractory ulcers and third-degree burns. This artificial AM-based material represents great potential for downstream clinical research and treatment of diabetes patients with third-degree burns.
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Affiliation(s)
- Kenichi Arai
- Department of Clinical Biomaterial Applied Science, Faculty of Medicine, University of Toyama, Toyama, Japan
- Department of Biotechnology, Faculty of Bioresource Sciences, Akita Prefectural University, Akita, Japan
| | - Satoshi Yoshida
- Department of Medical Oncology, Toyama University Hospital, Toyama, Japan
| | - Etsuko Furuichi
- Department of Clinical Biomaterial Applied Science, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Shintaroh Iwanaga
- Division of Biomedical System Engineering, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan
| | - Tanveer Ahmad Mir
- Tissue/Organ Bioengineering and BioMEMS Lab, Organ Transplant Centre of Excellence (TR&I Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Toshiko Yoshida
- Department of Clinical Biomaterial Applied Science, Faculty of Medicine, University of Toyama, Toyama, Japan
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Li J, Song J, Jia L, Wang M, Ji X, Meng R, Zhou D. Exosomes in Central Nervous System Diseases: A Comprehensive Review of Emerging Research and Clinical Frontiers. Biomolecules 2024; 14:1519. [PMID: 39766226 PMCID: PMC11673277 DOI: 10.3390/biom14121519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/20/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Exosomes, nano-sized lipid bilayer vesicles, have garnered significant attention as mediators of cell communication, particularly within the central nervous system (CNS). Their unique properties, including high stability, low immunogenicity, and the ability to traverse the blood-brain barrier (BBB), position them as promising tools for understanding and addressing CNS diseases. This comprehensive review delves into the biogenesis, properties, composition, functions, and isolation of exosomes, with a particular focus on their roles in cerebrovascular diseases, neurodegenerative disorders, and CNS tumors. Exosomes are involved in key pathophysiological processes in the CNS, including angiogenesis, inflammation, apoptosis, and cellular microenvironment modification. They demonstrate promise in mitigating ischemic injury, regulating inflammatory responses, and providing neuroprotection across various CNS conditions. Furthermore, exosomes carry distinct biomolecules, offering a novel method for the early diagnosis and monitoring of CNS diseases. Despite their potential, challenges such as complex extraction processes, the heterogeneity of exosomal contents, and targeted delivery limitations hinder their clinical application. Nevertheless, exosomes hold significant promise for advancing our understanding of CNS diseases and developing novel therapeutic strategies. This manuscript significantly contributes to the field by highlighting exosomes' potential in advancing our understanding of CNS diseases, underscoring their unique value in developing novel therapeutic strategies and mediating cellular communication.
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Affiliation(s)
- Jingrun Li
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Jiahao Song
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Lina Jia
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Mengqi Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Xunming Ji
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Ran Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Da Zhou
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
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Liu X, Lyu Y, Yu Y, Wang Z, Sun Y, Li M, Liang C, Tian W, Liao L. ApoEVs Transfer Mitochondrial Component to Modulate Macrophages in Periodontal Regeneration. Oral Dis 2024. [PMID: 39530336 DOI: 10.1111/odi.15181] [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: 05/25/2024] [Revised: 09/12/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE Macrophages are key players in the host immune response to periodontal pathogens and tissue repair. The aim of this study was to explore the potential of apoptotic cell-derived extracellular vesicles (ApoEVs) in modulating the mitochondrial function of macrophages as a mean to enhance periodontal tissue regeneration. SUBJECTS AND METHODS ApoEVs were extracted from periodontal ligament stem cells (PDLSCs) and characterized to observe their effects on macrophage function. In vivo experiments, ApoEVs were mixed with hyaluronic acid and injected into the periodontal pockets of rats with periodontitis to observe their impact on periodontal tissue regeneration and the immune microenvironment. Functional assays were conducted to confirm whether ApoEVs contained mitochondrial components and which specific components were transferred to regulate macrophage function. RESULTS The experimental findings showed that treatment of ApoEVs efficiently restored the homeostasis of macrophage and improved tissue regeneration in a periodontitis rat model. Mechanism investigation demonstrated that the efferocytosis of ApoEVs resulted in the transfer of mitochondrial components from PDLSCs to macrophage. The increased mitochondrial components within macrophages improved mitochondrial function and polarization of macrophages towards the anti-inflammatory M2 phenotype, resulting in the improvement of inflammatory environment in periodontal tissues. CONCLUSION ApoEVs can transfer mtDNA to enhance mitochondrial function in macrophages, fostering their transition to an anti-inflammatory phenotype. Ultimately, this process improves the immune microenvironment in periodontitis and promotes periodontal tissue regeneration.
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Affiliation(s)
- Xiaodong Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yun Lyu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yejia Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zhuo Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yanping Sun
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Maojiao Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Chao Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Weidong Tian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Li Liao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Hegde M, Singh AK, Kannan S, Kolkundkar U, Seetharam RN. Therapeutic Applications of Engineered Mesenchymal Stromal Cells for Enhanced Angiogenesis in Cardiac and Cerebral Ischemia. Stem Cell Rev Rep 2024; 20:2138-2154. [PMID: 39305405 PMCID: PMC11554727 DOI: 10.1007/s12015-024-10787-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2024] [Indexed: 11/12/2024]
Abstract
Ischemic diseases are characterized by obstruction of blood flow to the respective organs, of which ischemia of the heart and brain are the most prominent manifestations with shared pathophysiological mechanisms and risk factors. While most revascularization therapies aim to restore blood flow, this can be challenging due to the limited therapeutic window available for treatment approaches. For a very long time, mesenchymal stromal cells have been used to treat cerebral and cardiac ischemia. However, their application is restricted either by inefficient mode of delivery or the low cell survival rates following implantation into the ischemic microenvironment. Nonetheless, several studies are currently focusing on using of mesenchymal stromal cells engineered to overexpress therapeutic genes as a cell-based gene therapy to restore angiogenesis. This review delves into the utilization of MSCs for angiogenesis and the applications of engineered MSCs for the treatment of cardiac and cerebral ischemia. Moreover, the safety issues related to the genetic modification of MSCs have also been discussed.
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Affiliation(s)
- Madhavi Hegde
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India
| | - Abhishek Kumar Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India
| | - Suresh Kannan
- Stempeutics Research Pvt. Ltd., 3rd Floor, Manipal Hospitals Whitefield #143, EPIP Industrial Area, ITPL Main Road, Bangalore, 560 048, India
| | - Udaykumar Kolkundkar
- Stempeutics Research Pvt. Ltd., 3rd Floor, Manipal Hospitals Whitefield #143, EPIP Industrial Area, ITPL Main Road, Bangalore, 560 048, India
| | - Raviraja N Seetharam
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India.
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10
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Peng C, Xu H, Zhuang Q, Liu J, Ding Y, Tang Q, Wang Z, Yao K. Placenta-derived mesenchymal stem cells promote diabetic wound healing via exosomal protein interaction networks. Wound Repair Regen 2024; 32:638-651. [PMID: 39022990 DOI: 10.1111/wrr.13199] [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: 09/05/2023] [Revised: 04/17/2024] [Accepted: 05/29/2024] [Indexed: 07/20/2024]
Abstract
There is a lack of effective treatment options for diabetic refractory wounds, which presents a critical clinical issue that needs to be addressed urgently. Our research has demonstrated that human placenta-derived mesenchymal stem cells (plaMSCs) facilitate the migration and proliferation of HaCat cells, thereby enhancing diabetic wound healing primarily via the exosomes derived from plaMSCs (plaMSCs-Ex). Using label-free proteomics, plaMSCs and their exosomes were analysed for proteome taxonomic content in order to explore the underlying effective components mechanism of plaMSCs-Ex in diabetic wound healing. Differentially expressed proteins enriched in plaMSCs-Ex were identified and underwent bioinformatics analysis including GO annotation, KEGG pathway enrichment, gene set enrichment analysis (GSEA) and protein-protein interaction analysis (PPI). Results showed that the proteins enriched in plaMSCs-Ex are significantly involved in extracellular matrix organisation, epithelium morphogenesis, cell growth, adhesion, proliferation and angiogenesis. PPI analysis filtered 2 wound healing-related clusters characterised by hub proteins such as POSTN, FN1, SPARC, TIMP1, SERPINE1, LRP1 and multiple collagens. In brief, the exosomal proteins derived from plaMSCs reveal diverse functions of regeneration and tissue remodelling based on proteomics analysis and potentially play a role in diabetic wound healing.
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Affiliation(s)
- Cheng Peng
- Department of Burns and Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Hongbo Xu
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Quan Zhuang
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jinya Liu
- Department of Burns and Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yinhe Ding
- Department of Spine Surgery, The Xiangya Hospital of Central South University, Changsha, China
| | - Qiyu Tang
- Department of Burns and Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zheng Wang
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Kai Yao
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
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11
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Goushki MA, Kharat Z, Kehtari M, Sohi AN, Ahvaz HH, Rad I, HosseinZadeh S, Kouhkan F, Kabiri M. Applications of extraembryonic tissue-derived cells in vascular tissue regeneration. Stem Cell Res Ther 2024; 15:205. [PMID: 38982541 PMCID: PMC11234723 DOI: 10.1186/s13287-024-03784-3] [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: 02/29/2024] [Accepted: 06/06/2024] [Indexed: 07/11/2024] Open
Abstract
Vascular tissue engineering is a promising approach for regenerating damaged blood vessels and developing new therapeutic approaches for heart disease treatment. To date, different sources of cells have been recognized that offer assistance within the recovery of heart supply routes and veins with distinctive capacities and are compelling for heart regeneration. However, some challenges still remain that need to be overcome to establish the full potential application of these cells. In this paper, we review the different cell sources used for vascular tissue engineering, focusing on extraembryonic tissue-derived cells (ESCs), and elucidate their roles in cardiovascular disease. In addition, we highlight the intricate interplay between mechanical and biochemical factors in regulating mesenchymal stem cell (MSC) differentiation, offering insights into optimizing their application in vascular tissues.
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Affiliation(s)
- Mehdi Amiri Goushki
- Department of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, 14395-1561, Iran
| | - Zahra Kharat
- Department of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, 14395-1561, Iran
| | - Mousa Kehtari
- School of Biology, College of Sciences, University of Tehran, Tehran, 1417614411, Iran
| | - Alireza Naderi Sohi
- National Institute of Genetic Engineering and Biotechnology, Tehran, 1497716316, Iran
| | | | - Iman Rad
- Stem Cell Technology Research Center, Tehran, 15856-36473, Iran
| | - Simzar HosseinZadeh
- Department of Tissue Engineering and Regenerative Medicine, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Kouhkan
- Stem Cell Technology Research Center, Tehran, 15856-36473, Iran
| | - Mahboubeh Kabiri
- Department of Biotechnology, College of Science, University of Tehran, Tehran, 14155-6455, Iran.
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12
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Li J, Liu Y, Zhang R, Yang Q, Xiong W, He Y, Ye Q. Insights into the role of mesenchymal stem cells in cutaneous medical aesthetics: from basics to clinics. Stem Cell Res Ther 2024; 15:169. [PMID: 38886773 PMCID: PMC11184751 DOI: 10.1186/s13287-024-03774-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/27/2024] [Indexed: 06/20/2024] Open
Abstract
With the development of the economy and the increasing prevalence of skin problems, cutaneous medical aesthetics are gaining more and more attention. Skin disorders like poor wound healing, aging, and pigmentation have an impact not only on appearance but also on patients with physical and psychological issues, and even impose a significant financial burden on families and society. However, due to the complexities of its occurrence, present treatment options cannot produce optimal outcomes, indicating a dire need for new and effective treatments. Mesenchymal stem cells (MSCs) and their secretomics treatment is a new regenerative medicine therapy that promotes and regulates endogenous stem cell populations and/or replenishes cell pools to achieve tissue homeostasis and regeneration. It has demonstrated remarkable advantages in several skin-related in vivo and in vitro investigations, aiding in the improvement of skin conditions and the promotion of skin aesthetics. As a result, this review gives a complete description of recent scientific breakthroughs in MSCs for skin aesthetics and the limitations of their clinical applications, aiming to provide new ideas for future research and clinical transformation.
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Affiliation(s)
- Junyi Li
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ye Liu
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Rui Zhang
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Qianyu Yang
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Wei Xiong
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, 430030, China.
| | - Qingsong Ye
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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13
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Egger D, Baier L, Moldaschl J, Taschner M, Lorber V, Kasper C. Development of a novel high-throughput culture system for hypoxic 3D hydrogel cell culture. Sci Rep 2024; 14:9904. [PMID: 38688981 PMCID: PMC11061291 DOI: 10.1038/s41598-024-60822-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] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 04/27/2024] [Indexed: 05/02/2024] Open
Abstract
Animal models lack physiologic relevance to the human system which results in low clinical translation of results derived from animal testing. Besides spheroids or organoids, hydrogel-based 3D in vitro models are used to mimic the in vivo situation increasing the relevance while reducing animal testing. However, to establish hydrogel-based 3D models in applications such as drug development or personalized medicine, high-throughput culture systems are required. Furthermore, the integration of oxygen-reduced (hypoxic) conditions has become increasingly important to establish more physiologic culture models. Therefore, we developed a platform technology for the high-throughput generation of miniaturized hydrogels for 3D cell culture. The Oli-Up system is based on the shape of a well-plate and allows for the parallel culture of 48 hydrogel samples, each with a volume of 15 µl. As a proof-of-concept, we established a 3D culture of gelatin-methacryloyl (GelMA)-encapsulated mesenchymal stem/stromal cells (MSCs). We used a hypoxia reporter cell line to establish a defined oxygen-reduced environment to precisely trigger cellular responses characteristic of hypoxia in MSCs. In detail, the expression of hypoxia response element (HRE) increased dependent on the oxygen concentration and cell density. Furthermore, MSCs displayed an altered glucose metabolism and increased VEGF secretion upon oxygen-reduction. In conclusion, the Oli-Up system is a platform technology for the high-throughput culture of hydrogel-based 3D models in a defined oxygen environment. As it is amenable for automation, it holds the potential for high-throughput screening applications such as drug development and testing in more physiologic 3D in vitro tissue models.
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Affiliation(s)
- Dominik Egger
- Institute of Cell Biology and Biophysics, Leibniz University Hannover, Hannover, Germany.
| | - Luisa Baier
- Institute of Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Vienna, Austria
| | - Julia Moldaschl
- Institute of Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Vienna, Austria
| | | | | | - Cornelia Kasper
- Institute of Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Vienna, Austria
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14
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Poomani MS, Regurajan R, Perumal R, Ramachandran A, Mariappan I, Muthan K, Subramanian V. Differentiation of placenta-derived MSCs cultured in human platelet lysate: a xenofree supplement. 3 Biotech 2024; 14:116. [PMID: 38524240 PMCID: PMC10959853 DOI: 10.1007/s13205-024-03966-z] [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: 03/16/2022] [Accepted: 02/22/2024] [Indexed: 03/26/2024] Open
Abstract
In the last few decades, mesenchymal stem cells (MSCs)-based regenerative therapies in clinical applications have gradually become a hot topic due to their long-term self-renewal and multilineage differentiation ability. In this scenario, placenta (p) has been considered as a good source of MSCs. As a tissue of fetal origin with abundant number of stem cells compared to other sources, their non-invasive acquisition, strong immunosuppression, and lack of ethical concerns make placenta an indispensable source of MSC in stem cell research and therapy. The mesenchymal stem cells were derived from human term placenta (p-MSCs) in xenofree condition using platelet lysate (PL) as a suitable alternative to fetal bovine serum (FBS). Upon isolation, p-MSCs showed plastic adherence with spindle-shaped, fibroblast-like morphology under microscope. p-MSCs flourished well in PL-containing media. Immunophenotyping showed classical MSC markers (> 90%) and lack expression of hematopoietic and HLA-DR (< 1%). Surprisingly, differentiation study showed differentiation of p-MSCs to mature adipocytes in both induced cells and control (spontaneous differentiation), as observed via oil red staining. This is in line with gene expression data where both control and induced cells were positive for visfatin and leptin. Thus, we propose that p-MSCs can be used for clinical applications in the treatment of various chronic and degenerative diseases.
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Affiliation(s)
- Merlin Sobia Poomani
- Genetic Engineering and Regenerative Biology Lab, Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012 India
| | - Rathika Regurajan
- Centre for Marine Science and Technology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012 India
| | | | | | - Iyyadurai Mariappan
- Genetic Engineering and Regenerative Biology Lab, Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012 India
| | - Krishnaveni Muthan
- Department of Animal Science, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012 India
| | - Venkatesh Subramanian
- Genetic Engineering and Regenerative Biology Lab, Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012 India
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15
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Wen S, Huang X, Ma J, Zhao G, Ma T, Chen K, Huang G, Chen J, Shi J, Wang S. Exosomes derived from MSC as drug system in osteoarthritis therapy. Front Bioeng Biotechnol 2024; 12:1331218. [PMID: 38576449 PMCID: PMC10993706 DOI: 10.3389/fbioe.2024.1331218] [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: 10/31/2023] [Accepted: 03/08/2024] [Indexed: 04/06/2024] Open
Abstract
Osteoarthritis (OA) is the most common degenerative disease of the joint with irreversible cartilage damage as the main pathological feature. With the development of regenerative medicine, mesenchymal stem cells (MSCs) have been found to have strong therapeutic potential. However, intraarticular MSCs injection therapy is limited by economic costs and ethics. Exosomes derived from MSC (MSC-Exos), as the important intercellular communication mode of MSCs, contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. With excellent editability and specificity, MSC-Exos function as a targeted delivery system for OA treatment, modulating immunity, inhibiting apoptosis, and promoting regeneration. This article reviews the mechanism of action of MSC-Exos in the treatment of osteoarthritis, the current research status of the preparation of MSC-Exos and its application of drug delivery in OA therapy.
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Affiliation(s)
- Shuzhan Wen
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Xin Huang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingchun Ma
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Guanglei Zhao
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Tiancong Ma
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Kangming Chen
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Gangyong Huang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Jie Chen
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingsheng Shi
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Siqun Wang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
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16
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Zhang S, Li J, Li C, Xie X, He J, Ling F, Li B, Wu H, Li Z, Zhen J, Liu G. CD73-positive pediatric urethral mesenchymal stem-like cell-derived small extracellular vesicles stimulate angiogenesis. Regen Ther 2024; 25:77-84. [PMID: 38111468 PMCID: PMC10727923 DOI: 10.1016/j.reth.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 11/24/2023] [Accepted: 12/07/2023] [Indexed: 12/20/2023] Open
Abstract
Introduction Angiogenesis plays an important role in the repair of urethral injury, and stem cells and their secretomes can promote angiogenesis. We obtained pediatric urethral mesenchymal stem-like cells (PU-MSLCs) in an earlier study. This project studied the pro-angiogenic effect of PU-MSLC-derived small extracellular vesicles (PUMSLC-sEVs) and the underlying mechanisms. Materials and methods PUMSLCs and PUMSLC-sEVs were cultivated and identified. Then, biological methods such as the ethynyl deoxyuridine (EdU) incorporation assay, Cell Counting Kit-8 (CCK-8) assay, scratch wound assay, Transwell assay, and tube formation assay were used to study the effect of PUMSLC-sEVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). We explored whether the proangiogenic effect of PUMSLC-sEVs is related to CD73 and whether adenosine (ADO, a CD73 metabolite) promoted angiogenesis. GraphPad Prism 8 software was used for data analysis. Results We observed that PUMSLC-sEVs significantly promoted the proliferation, migration, and tube-forming abilities of HUVECs. PUMSLC-sEVs delivered CD73 molecules to HUVECs to promote angiogenesis. The angiogenic ability of HUVECs was enhanced after treatment with extracellular ADO produced by CD73, and PUMSLC-sEVs further promoted angiogenesis by activating Adenosine Receptor A2A (A2AR). Conclusions These observations suggest that PUMSLC-sEVs promote angiogenesis, possibly through activation of the CD73/ADO/A2AR signaling axis.
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Affiliation(s)
- Shilin Zhang
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Jierong Li
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Chunjing Li
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Xumin Xie
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Jun He
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Fengsheng Ling
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Bowei Li
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Huayan Wu
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Zhilin Li
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Jianwei Zhen
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
| | - Guoqing Liu
- Department of Urology, Foshan Maternity & Child Healthcare Hospital, Foshan 528000, China
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17
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Shi H, Yang Z, Cui J, Tao H, Ma R, Zhao Y. Mesenchymal stem cell-derived exosomes: a promising alternative in the therapy of preeclampsia. Stem Cell Res Ther 2024; 15:30. [PMID: 38317195 PMCID: PMC10845755 DOI: 10.1186/s13287-024-03652-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 01/29/2024] [Indexed: 02/07/2024] Open
Abstract
Preeclampsia (PE) is a common morbid complication during pregnancy, affecting 2%-8% of pregnancies globally and posing serous risks to the health of both mother and fetus. Currently, the only effective treatment for PE is timely termination of pregnancy, which comes with increased perinatal risks. However, there is no effective way to delay pathological progress and improve maternal and fetal outcomes. In light of this, it is of great significance to seek effective therapeutic strategies for PE. Exosomes which are nanoparticles carrying bioactive substances such as proteins, lipids, and nucleic acids, have emerged as a novel vehicle for intercellular communication. Mesenchymal stem cell-derived exosomes (MSC-Exos) participate in various important physiological processes, including immune regulation, cell proliferation and migration, and angiogenesis, and have shown promising potential in tissue repair and disease treatment. Recently, MSC-Exos therapy has gained popularity in the treatment of ischaemic diseases, immune dysfunction, inflammatory diseases, and other fields due to their minimal immunogenicity, characteristics similar to donor cells, ease of storage, and low risk of tumor formation. This review elaborates on the potential therapeutic mechanism of MSC-Exos in treating preeclampsia, considering the main pathogenic factors of the condition, including placental vascular dysplasia, immunological disorders, and oxidative stress, based on the biological function of MSC-Exos. Additionally, we discuss in depth the advantages and challenges of MSC-Exos as a novel acellular therapeutic agent in preeclampsia treatment.
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Affiliation(s)
- Haoran Shi
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Zejun Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jianjian Cui
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Hui Tao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Ruilin Ma
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Yin Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China.
- Shenzhen Huazhong University of Science and Technology Research Institute, Shen Zhen, 518000, China.
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18
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Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 2-Emerging leaders in regenerative medicine. Periodontol 2000 2024; 94:257-414. [PMID: 38591622 DOI: 10.1111/prd.12561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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19
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Sun N, Sun Y, Xing Y, Xu L, Chen Z, Qing L, Wu P, Tang J. Knowledge mapping and research trends of stem cell in wound healing: A bibliometric analysis. Int Wound J 2024; 21:e14587. [PMCID: PMC10830390 DOI: 10.1111/iwj.14587] [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: 10/31/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 01/12/2025] Open
Abstract
Wound nonhealing is a common and difficult problem in clinic. Stem cells are pluripotent cells, and their undifferentiated and self‐replicating characteristics have attracted much attention in the regenerative medicine‐related researches. New treatment approaches might result from an understanding of the function of stem cells in wound healing. Using bibliometric techniques, this study proposed to analyse the research status, hotspots, and research trends in stem cell and wound healing. By using the Web of Science Core Collection (WoSCC), we conducted an in‐depth review of publications on stem cells in wound healing from 1999 to 2023. We used scientometric analysis methods to examine annual trends, institutions, countries, journals, authors, keywords, co‐occurrence references and their closed relationship, revealing present hotspots and potential future advancements in this field. We analysed 19 728 English studies and discovered a consistent rise in annual publications. The United States and China were the two countries with the most publications. The most three influential institutions in the field were Shanghai Jiao Tong University, Sun Yat‐sen University, and University of Pittsburgh. International Journal of Molecular Sciences and Biomaterials were considered the most influential journals in this field. International Journal of Molecular Sciences had the most publications, and the most quantity of citations and the highest H‐index were found in Biomaterials . The dual‐map overlay revealed that publications in Molecular/Biology/Genetics and Health/Nursing/Medicine co‐cited journals received the majority of the citations for studies from Molecular/Biology/Immunology and Medicine/Medical/Clinical. In terms of publication production and influence, Fu X stood out among the authors, and Pittenger MF took the top spot in co‐citations. According to the keywords from the analysis, future research should concentrate on the mechanisms through which stem cells promote wound healing. We conducted a thorough analysis of the general information, knowledge base and research hotspots in the field of stem cells and wound healing from 1999 to 2023 by using the VOSviewer, CiteSpace, and other bibliometric analysis tools. It not only provided valuable insights for scholars, but also served as a reliable reference that drives further development in the field and stimulates the interest of researchers.
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Affiliation(s)
- Nianzhe Sun
- Department of OrthopedicsXiangya Hospital, Central South UniversityChangshaChina
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
| | - Yu Sun
- Department of OrthopedicsXiangya Hospital, Central South UniversityChangshaChina
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
| | - Yixuan Xing
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
- Department of EmergencyXiangya Hospital, Central South UniversityChangshaChina
| | - Laiyu Xu
- Department of OrthopedicsThe First Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhouChina
| | - Zijie Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Liming Qing
- Department of OrthopedicsXiangya Hospital, Central South UniversityChangshaChina
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
| | - Panfeng Wu
- Department of OrthopedicsXiangya Hospital, Central South UniversityChangshaChina
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
| | - Juyu Tang
- Department of OrthopedicsXiangya Hospital, Central South UniversityChangshaChina
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
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20
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Tan F, Li X, Wang Z, Li J, Shahzad K, Zheng J. Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther 2024; 9:17. [PMID: 38212307 PMCID: PMC10784577 DOI: 10.1038/s41392-023-01704-0] [Citation(s) in RCA: 136] [Impact Index Per Article: 136.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/15/2023] [Accepted: 11/12/2023] [Indexed: 01/13/2024] Open
Abstract
Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.
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Affiliation(s)
- Fei Tan
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China.
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China.
- The Royal College of Surgeons in Ireland, Dublin, Ireland.
- The Royal College of Surgeons of England, London, UK.
| | - Xuran Li
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Zhao Wang
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
| | - Jiaojiao Li
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Khawar Shahzad
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Jialin Zheng
- Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital affiliated to Tongji University School of Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Nanocatalytic Medicine, Tongji University, Shanghai, China
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Li F, Gao C, Song G, Zhang K, Huang G, Liu H. Human Placenta-Derived Mesenchymal Stem Cells Combined With Artificial Dermal Scaffold Enhance Wound Healing in a Tendon-Exposed Wound of a Rabbit Model. Cell Transplant 2024; 33:9636897241228922. [PMID: 38334047 PMCID: PMC10858670 DOI: 10.1177/09636897241228922] [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: 08/22/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 02/10/2024] Open
Abstract
To overcome the difficulty of vascular regeneration in exposed tendon wounds, we combined human placenta-derived mesenchymal stem cells (hPMSCs) with an artificial dermal scaffold and assessed their role in promoting vascular regeneration and wound healing in vivo. hPMSCs were isolated from the human placenta and characterized based on their morphology, phenotypic profiles, and pluripotency. New Zealand rabbits were used to establish an exposed tendon wound model, and hPMSCs and artificial dermal scaffolds were transplanted into the wounds. The results of gross wound observations and pathological sections showed that hPMSCs combined with artificial dermal scaffold transplantation increased the vascularization area of the wound, promoted wound healing, and increased the survival rate of autologous skin transplantation. Following artificial dermal scaffold transplantation, hPMSCs accelerated the vascularization of the dermal scaffold, and the number of fibroblasts, collagen fibers, and neovascularization in the dermal scaffold after 1 week were much higher than those in the control group. Immunohistochemical staining further confirmed that the expression of the vascular endothelial cell marker, CD31, was significantly higher in the combined transplantation group than in the dermal scaffold transplantation group. Our findings demonstrated that hPMSCs seeded onto artificial dermal scaffold could facilitate vascularization of the dermal scaffold and improve tendon-exposed wound healing.
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Affiliation(s)
- Fang Li
- Cell Therapy Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Cong Gao
- Department of Burns and Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Guodong Song
- Department of Burns and Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Kun Zhang
- Cell Therapy Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Guobao Huang
- Department of Burns and Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hua Liu
- Cell Therapy Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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22
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Fan W, Zhou M, Zheng S, Liu Y, Pan S, Guo P, Xu M, Hu C, Ding A, Wang Z, Yin S, Zuo K, Xie X. Human umbilical cord mesenchymal stem cell-derived exosomes promote microcirculation in aged diabetic mice by TGF-β1 signaling pathway. Diabetol Metab Syndr 2023; 15:234. [PMID: 37968711 PMCID: PMC10652470 DOI: 10.1186/s13098-023-01191-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 10/12/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Microvascular dysfunction is one of the most common pathological characteristics in Type 2 diabetes. Human mesenchymal stem cell-derived exosomes (hUCMSCs-Exo) have diverse functions in improving microcirculation; however, the molecular mechanism of hUCMSCs-Exo in regulating burn-induced inflammation is not well understood. METHODS hUCMSCs-Exo were extracted by hypervelocity centrifugation method, and exosome morphology was observed by transmission electron microscopy, exosome diameter distribution was detected by particle size analysis, and exosome specific proteins were identified by Western blot.2. DB/DB mice were randomly divided into exosomes group and PBS group. Exosomes and PBS were injected into the tail vein, respectively, and the calf muscle tissue was taken 28 days later. 0.5% Evans blue fluorescence assessment microvascular permeability. The expression of CD31 was detected by immunofluorescence.The morphology and function of microvessels in muscle tissue of lower limbs was evaluated by transmission electron microscopy.3. TMT proteomics was used to detect the changes of differential protein expression in lower limb muscle tissues of the PBS group and the exosome group, and data analysis was performed to screen key signal molecules and their involved biological pathways. Key signal molecules CD105 were verified by Western blot. The expression of TGF-β1 in exosomes were evaluated by Western blot. RESULTS Electron microscopy showed that hUCMSCs-Exo presented a uniform vesicle structure, and NTA showed that its diameter was about 160 nm. Western blot showed positive expression of specific proteins CD9, CD81 and TSG101 on exosomes.2. There is no significant change in blood glucose and body weight before and after the exosome treatment. The exosome group can significantly reduce the exudation of Evans blue. Compared with the PBS group. Meanwhile, CD31 immunofluorescence showed that the red fluorescence of exosome treatment was significantly increased, which was higher than that of PBS group. Transmission electron microscopy showed smooth capillary lumen and smooth and complete surface of endothelial cells in the exosome group, while narrow capillary lumen and fingerlike protrusion of endothelial cells in the PBS group.3.Quantitative analysis of TMT proteomics showed that there were 82 differential proteins, including 49 down-regulated proteins and 33 up-regulated proteins. Go enrichment analysis showed that the differential proteins were involved in molecular function, biological process, cell components,among which CD105 was one of the up-regulated proteins. Through literature search, CD105 was found to be related to endothelial cell proliferation. Therefore, this study verified the changes of CD105 in the exosome group, and it was used as the mechanism study of this study. 4. Western blot analysis showed that the expression of CD105 protein in lower limb muscle tissue of exosome group was significantly increased compared with that of PBS group. Based on the fact that CD105 is a component of the TGF-β1 receptor complex and exosomes are rich in growth factors and cytokines, this study further examined the expression of TGF-β1 in exosomes, and the results showed that exosomes had high expression of TGF-β1. CONCLUSION By improving the integrity of microvascular endothelial cells, hUCMSCs-Exo can improve the permeability of microvessels in diabetic lower muscle tissue, further promote the proliferation of lower limb muscle cells and inhibit the apoptosis of tissue cells. The mechanism may be associated with exosomes rich in TGF-β1, which is likely to promote endothelial cell proliferation and improve permeability through binding to the endothelial CD105/TβR-II receptor complex, while promoting angiogenesis and protecting skeletal muscle cells from apoptosis.
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Affiliation(s)
- Weijian Fan
- Department of Interventional & Vascular Surgery, Hefei Second People's Hospital, Hefei Hospital Affiliated to Anhui Medical University, Anhui, 230011, China
| | - Mengdie Zhou
- Geriatric department, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, 201600, China
| | - Shaoqiu Zheng
- Department of Urinary Surgery Shanghai Pudong New District Zhoupu Hospital, Shanghai, 200100, China
| | - Yang Liu
- Department of Geriatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Songsong Pan
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Peng Guo
- Department of Vascular Surgery, The Fifth Affiliated Hospital of ZhengZhou University, ZhengZhou, 450052, China
| | - Minjie Xu
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Chao Hu
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Anle Ding
- AnHui University of Science and Technology, Huainan, 232001, China
| | - Zan Wang
- AnHui University of Science and Technology, Huainan, 232001, China
| | - Shiwu Yin
- Department of Interventional & Vascular Surgery, Hefei Second People's Hospital, Hefei Hospital Affiliated to Anhui Medical University, Anhui, 230011, China
| | - Keqiang Zuo
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Xiaoyun Xie
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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23
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Zhang S, Mulder C, Riddle S, Song R, Yue D. Mesenchymal stromal/stem cells and bronchopulmonary dysplasia. Front Cell Dev Biol 2023; 11:1247339. [PMID: 37965579 PMCID: PMC10642488 DOI: 10.3389/fcell.2023.1247339] [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: 06/25/2023] [Accepted: 10/17/2023] [Indexed: 11/16/2023] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants, leading to chronic respiratory disease. There has been an improvement in perinatal care, but many infants still suffer from impaired branching morphogenesis, alveolarization, and pulmonary capillary formation, causing lung function impairments and BPD. There is an increased risk of respiratory infections, pulmonary hypertension, and neurodevelopmental delays in infants with BPD, all of which can lead to long-term morbidity and mortality. Unfortunately, treatment options for Bronchopulmonary dysplasia are limited. A growing body of evidence indicates that mesenchymal stromal/stem cells (MSCs) can treat various lung diseases in regenerative medicine. MSCs are multipotent cells that can differentiate into multiple cell types, including lung cells, and possess immunomodulatory, anti-inflammatory, antioxidative stress, and regenerative properties. MSCs are regulated by mitochondrial function, as well as oxidant stress responses. Maintaining mitochondrial homeostasis will likely be key for MSCs to stimulate proper lung development and regeneration in Bronchopulmonary dysplasia. In recent years, MSCs have demonstrated promising results in treating and preventing bronchopulmonary dysplasia. Studies have shown that MSC therapy can reduce inflammation, mitochondrial impairment, lung injury, and fibrosis. In light of this, MSCs have emerged as a potential therapeutic option for treating Bronchopulmonary dysplasia. The article explores the role of MSCs in lung development and disease, summarizes MSC therapy's effectiveness in treating Bronchopulmonary dysplasia, and delves into the mechanisms behind this treatment.
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Affiliation(s)
- Shuqing Zhang
- School of Pharmacy, China Medical University, Shenyang, China
| | - Cassidy Mulder
- Liberty University College of Osteopathic Medicine, Lynchburg, VA, United States
| | - Suzette Riddle
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Rui Song
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | - Dongmei Yue
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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24
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Ning H, Tao H. Small RNA sequencing of exosomal microRNAs reveals differential expression of microRNAs in preeclampsia. Medicine (Baltimore) 2023; 102:e35597. [PMID: 37861520 PMCID: PMC10589583 DOI: 10.1097/md.0000000000035597] [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: 12/26/2022] [Accepted: 09/20/2023] [Indexed: 10/21/2023] Open
Abstract
Preeclampsia (PE) is one of the most common hypertensive disorders of pregnancy. It is a dangerous condition with a high mortality rate in mothers and fetuses and is associated with a lack of early diagnosis and effective treatment. While the etiology of the disease is complex and obscure, it is now clear that the placenta is central to disease progression. Exosomal microRNAs (miRNAs) are possible mediators that regulate placenta-related physiological and pathological processes. Placental mesenchymal stem cells have considerable potential to help us understand the pathogenesis and treatment of pregnancy-related diseases. Here, we investigate the exosomal miRNA profiles of human placenta-derived mesenchymal stem cells between healthy pregnant women and those with PE. We performed small RNA sequencing to obtain miRNA profiles, and conducted enrichment analysis of the miRNA target genes to identify differentially expressed miRNAs associated with PE. Overall, we detected 1795 miRNAs; among them, 206 were differentially expressed in women with PE, including 35 upregulated and 171 downregulated miRNAs, when compared with healthy pregnant women. Moreover, we identified possible functions and pathways associated with PE, including angiogenesis, cell proliferation, migration and invasion, and the coagulation-fibrinolysis balance. Eventually, we proposed hsa-miR-675-5p, hsa-miR-3614-5p, and hsa-miR-615-5p as potential regulators of the pathogenesis of PE, and constructed a miRNA-target gene network. Our study identifies possible candidate biomarkers for the diagnosis of PE, and introduces a new direction for further understanding the pathogenesis of PE.
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Affiliation(s)
- Hui Ning
- Department of Obstetrics, Qingdao Municipal Hospital, Qingdao, China
| | - Hong Tao
- Department of Obstetrics, Qingdao Municipal Hospital, Qingdao, China
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25
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Su J, Wei Q, Ma K, Wang Y, Hu W, Meng H, Li Q, Zhang Y, Zhang W, Li H, Fu X, Zhang C. P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts. BURNS & TRAUMA 2023; 11:tkad010. [PMID: 37860579 PMCID: PMC10583213 DOI: 10.1093/burnst/tkad010] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 01/01/2023] [Accepted: 02/14/2023] [Indexed: 10/21/2023]
Abstract
Background Persistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts (HDFs), partially leading to delayed skin wound healing. Extracellular vesicles (EVs) containing multiple pro-healing microRNAs (miRNAs) have been shown to exert therapeutic effects on diabetic wound healing. The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells (P-MSC-EVs) on diabetic wound healing and high glucose (HG)-induced senescent fibroblasts and to explore the underlying mechanisms. Methods P-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice, to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis. Next, a series of assays were conducted to evaluate the effects of low (2.28 x 1010 particles/ml) and high (4.56 x 1010 particles/ml) concentrations of P-MSC-EVs on the senescence, proliferation, migration, and apoptosis of HG-induced senescent HDFs in vitro. Then, miRNA microarrays and real-time quantitative PCR (RT-qPCR) were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment. Specific RNA inhibitors, miRNA mimics, and small interfering RNA (siRNA) were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs. Results Local injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths, with better-organized collagen deposition and decreased p16INK4a expression. In vitro, P-MSC-EVs enhanced the antisenescence, proliferation, migration, and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner. MiR-145-5p was found to be highly enriched in P-MSC-EVs. MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts. MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase (Erk)/protein kinase B (Akt) signaling pathway. Furthermore, local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing. Conclusions These results suggest that P-MSC-EVs accelerate diabetic wound healing by improving the function of senescent fibroblasts through the transfer of miR-145-5p, which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway. P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.
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Affiliation(s)
- Jianlong Su
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
- School of Medicine, NanKai University, 94 Weijin Road, Nankai District, Tianjin 300071, China
| | - Qian Wei
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Kui Ma
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Yaxi Wang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Wenzhi Hu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Hao Meng
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Qiankun Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Yuehou Zhang
- Burn and Plastic Surgery, Zhongda Hospital Affiliated Southeast University, Dingjiaqiao 87, Gulou District, Nanjing 210009, China
| | - Wenhua Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Haihong Li
- Department of Wound Repair, Institute of Wound Repair and Regeneration Medicine, Southern University of Science and Technology Hospital, Southern University of Science and Technology School of Medicine, 6019 Xililiuxian Road, Nanshan District, Shenzhen 518055, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
- School of Medicine, NanKai University, 94 Weijin Road, Nankai District, Tianjin 300071, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, 51 Fucheng Road, Haidian District, Beijing 100048, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, 51 Fucheng Road, Haidian District, Beijing 100048, China
| | - Cuiping Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, 51 Fucheng Road, Haidian District, Beijing 100048, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, 51 Fucheng Road, Haidian District, Beijing 100048, China
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Yu L, Qin J, Xing J, Dai Z, Zhang T, Wang F, Zhou J, Zhang X, Chen X, Gu Y. The mechanisms of exosomes in diabetic foot ulcers healing: a detailed review. J Mol Med (Berl) 2023; 101:1209-1228. [PMID: 37691076 DOI: 10.1007/s00109-023-02357-w] [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: 03/18/2023] [Revised: 08/03/2023] [Accepted: 08/06/2023] [Indexed: 09/12/2023]
Abstract
As time goes by, the morbidity of diabetes mellitus continues to rise, and the economic burden of diabetic foot ulcers as a common and serious complication of diabetes is increasing. However, currently there is no unified clinical treatment strategy for this complication, and the therapeutic efficacy is unsatisfactory. Recent studies have revealed that biological effects of exosomes involved in multiple stages of the process of wound closure are similar to source cells. Compared with source cells, exosomes possess lowly immunogenicity, highly stability and easily stored, etc. Accumulating evidence confirmed that exosomes promote diabetic wound healing through various pathways such as promoting angiogenesis, collagen fiber deposition, and inhibiting inflammation. The superior therapeutic efficacy of exosomes in accelerating diabetic cutaneous wound healing has attracted an increasing attention. Notably, the molecular mechanisms of exosomes vary among different sources in the chronic wound closure of diabetes. This review focuses on the specific roles and mechanisms of different cell- or tissue-derived exosomes relevant to wound healing. Additionally, the paper provides an overview of the current pre-clinical and clinical applications of exosomes, illustrates their special advantages in wound repair. Furthermore, we discuss the potential obstacles and various solutions for future research on exosomes in the management of diabetic foot ulcer. The aim is to offer novel insights and approaches for the treatment of diabetic foot ulcer.
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Affiliation(s)
- Lei Yu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People's Republic of China
| | - Jianxin Qin
- Department of Histology and Embryology, Medical School, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Jiajun Xing
- Department of Histology and Embryology, Medical School, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Zihao Dai
- Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People's Republic of China
| | - Tingting Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People's Republic of China
| | - Feng Wang
- Nantong Xingzhong Cell Engineering Co. LTD, Nantong, Jiangsu, 226001, People's Republic of China
| | - Jin Zhou
- Nantong Xingzhong Cell Engineering Co. LTD, Nantong, Jiangsu, 226001, People's Republic of China
| | - Xiaobai Zhang
- Department of Respiratory Medicine, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, China
| | - Xia Chen
- Department of Histology and Embryology, Medical School, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
| | - Yunjuan Gu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People's Republic of China.
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27
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Rao A, Shinde U, Das DK, Balasinor N, Madan T. Early prediction of pre-eclampsia using circulating placental exosomes: Newer insights. Indian J Med Res 2023; 158:385-396. [PMID: 37987999 DOI: 10.4103/ijmr.ijmr_2143_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Indexed: 11/22/2023] Open
Abstract
Pre-eclampsia (PE), a multifactorial de novo hypertensive pregnancy disorder, is one of the leading causes of foeto-maternal morbidity and mortality. Currently, antihypertensive drugs are the first-line therapy for PE and evidence suggests that low-dose aspirin initiated early in high risk pregnancies may reduce the risk of development or severity of PE. However, an early prediction of this disorder remains an unmet clinical challenge. Several potential serum biomarkers associated with maternal immunoregulation and placental angiogenesis have been evaluated but are ineffective and inconsistent for early prediction. Although placental biomarkers would be more specific and sensitive in predicting the risk of PE, accessing the placenta during pregnancy is not feasible. Circulating placental exosomes (pEXO), originating from foeto-maternal interface, are being evaluated as the placenta's surrogate and the best source of non-invasive placental biomarkers. pEXO appear in the maternal circulation starting from six weeks of gestation and its dynamic biological cargo across pregnancy is associated with successful pregnancy outcomes. Therefore, monitoring changes in pEXO expression profiles could provide new insights into the prediction, diagnosis and treatment of PE. This narrative review comprehensively summarizes the available literature on the candidate predictive circulating biomarkers evaluated for PE to date. In particular, the review elucidates the current knowledge of distinct molecular signatures emanating from pEXO in pre-eclamptic women to support the discovery of novel early predictive biomarkers for effective intervention and management of the disease.
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Affiliation(s)
- Aishwarya Rao
- Department of Innate Immunity, ICMR-National Institute for Research in Reproductive & Child Health, Mumbai, Maharashtra, India
| | - Uma Shinde
- Department of Neuroendocrinology, ICMR-National Institute for Research in Reproductive & Child Health, Mumbai, Maharashtra, India
| | - Dhanjit Kumar Das
- Department of Stem Cell Biology, ICMR-National Institute for Research in Reproductive & Child Health, Mumbai, Maharashtra, India
| | - Nafisa Balasinor
- Department of Neuroendocrinology, ICMR-National Institute for Research in Reproductive & Child Health, Mumbai, Maharashtra, India
| | - Taruna Madan
- Department of Innate Immunity, ICMR-National Institute for Research in Reproductive & Child Health, Mumbai, Maharashtra, India
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28
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Shekari F, Alibhai FJ, Baharvand H, Börger V, Bruno S, Davies O, Giebel B, Gimona M, Salekdeh GH, Martin‐Jaular L, Mathivanan S, Nelissen I, Nolte‐’t Hoen E, O'Driscoll L, Perut F, Pluchino S, Pocsfalvi G, Salomon C, Soekmadji C, Staubach S, Torrecilhas AC, Shelke GV, Tertel T, Zhu D, Théry C, Witwer K, Nieuwland R. Cell culture-derived extracellular vesicles: Considerations for reporting cell culturing parameters. JOURNAL OF EXTRACELLULAR BIOLOGY 2023; 2:e115. [PMID: 38939735 PMCID: PMC11080896 DOI: 10.1002/jex2.115] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/18/2023] [Accepted: 09/17/2023] [Indexed: 06/29/2024]
Abstract
Cell culture-conditioned medium (CCM) is a valuable source of extracellular vesicles (EVs) for basic scientific, therapeutic and diagnostic applications. Cell culturing parameters affect the biochemical composition, release and possibly the function of CCM-derived EVs (CCM-EV). The CCM-EV task force of the Rigor and Standardization Subcommittee of the International Society for Extracellular Vesicles aims to identify relevant cell culturing parameters, describe their effects based on current knowledge, recommend reporting parameters and identify outstanding questions. While some recommendations are valid for all cell types, cell-specific recommendations may need to be established for non-mammalian sources, such as bacteria, yeast and plant cells. Current progress towards these goals is summarized in this perspective paper, along with a checklist to facilitate transparent reporting of cell culturing parameters to improve the reproducibility of CCM-EV research.
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Affiliation(s)
- Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
- Advanced Therapy Medicinal Product Technology Development Center (ATMP‐TDC), Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
| | | | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in BiologyUniversity of Science and CultureTehranIran
| | - Verena Börger
- Institute for Transfusion MedicineUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Stefania Bruno
- Department of Medical Sciences and Molecular Biotechnology CenterUniversity of TorinoTurinItaly
| | - Owen Davies
- School of Sport, Exercise and Health SciencesLoughborough UniversityLoughboroughUK
| | - Bernd Giebel
- Institute for Transfusion MedicineUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Mario Gimona
- GMP UnitSpinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS) and Research Program “Nanovesicular Therapies” Paracelsus Medical UniversitySalzburgAustria
| | | | - Lorena Martin‐Jaular
- Institut Curie, INSERM U932 and Curie CoreTech Extracellular VesiclesPSL Research UniversityParisFrance
| | - Suresh Mathivanan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVICAustralia
| | - Inge Nelissen
- VITO (Flemish Institute for Technological Research), Health departmentBoeretangBelgium
| | - Esther Nolte‐’t Hoen
- Department of Biomolecular Health Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Lorraine O'Driscoll
- School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences InstituteTrinity College DublinDublinIreland
| | - Francesca Perut
- Biomedical Science and Technologies and Nanobiotechnology LabIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Stefano Pluchino
- Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
| | - Gabriella Pocsfalvi
- Institute of Biosciences and BioResourcesNational Research CouncilNaplesItaly
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae‐Oncology Group, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of MedicineThe University of QueenslandBrisbaneAustralia
| | - Carolina Soekmadji
- School of Biomedical Sciences, Faculty of MedicineUniversity of QueenslandBrisbaneAustralia
| | | | - Ana Claudia Torrecilhas
- Laboratório de Imunologia Celular e Bioquímica de Fungos e Protozoários, Departamento de Ciências FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)SPBrazil
| | - Ganesh Vilas Shelke
- Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMarylandUSA
| | - Tobias Tertel
- Institute for Transfusion MedicineUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Dandan Zhu
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVICAustralia
| | - Clotilde Théry
- Institut Curie, INSERM U932 and Curie CoreTech Extracellular VesiclesPSL Research UniversityParisFrance
| | - Kenneth Witwer
- Departments of Molecular and Comparative Pathobiology and Neurology and Richman Family Precision Medicine Center of Excellence in Alzheimer's DiseaseJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Rienk Nieuwland
- Laboratory of Experimental Clinical Chemistry, Department of Clinical Chemistry, Amsterdam University Medical CentersLocation AMC, University of AmsterdamAmsterdamThe Netherlands
- Amsterdam Vesicle Center, Amsterdam University Medical Centers, location AMCUniversity of AmsterdamAmsterdamThe Netherlands
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Russo E, Alberti G, Corrao S, Borlongan CV, Miceli V, Conaldi PG, Di Gaudio F, La Rocca G. The Truth Is Out There: Biological Features and Clinical Indications of Extracellular Vesicles from Human Perinatal Stem Cells. Cells 2023; 12:2347. [PMID: 37830562 PMCID: PMC10571796 DOI: 10.3390/cells12192347] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/14/2023] [Accepted: 09/19/2023] [Indexed: 10/14/2023] Open
Abstract
The potential of perinatal tissues to provide cellular populations to be used in different applications of regenerative medicine is well established. Recently, the efforts of researchers are being addressed regarding the evaluation of cell products (secreted molecules or extracellular vesicles, EVs) to be used as an alternative to cellular infusion. The data regarding the effective recapitulation of most perinatal cells' properties by their secreted complement point in this direction. EVs secreted from perinatal cells exhibit key therapeutic effects such as tissue repair and regeneration, the suppression of inflammatory responses, immune system modulation, and a variety of other functions. Although the properties of EVs from perinatal derivatives and their significant potential for therapeutic success are amply recognized, several challenges still remain that need to be addressed. In the present review, we provide an up-to-date analysis of the most recent results in the field, which can be addressed in future research in order to overcome the challenges that are still present in the characterization and utilization of the secreted complement of perinatal cells and, in particular, mesenchymal stromal cells.
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Affiliation(s)
- Eleonora Russo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Giusi Alberti
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Simona Corrao
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Cesar V. Borlongan
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA;
| | - Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Francesca Di Gaudio
- Department of Health Promotion, Maternal-Infantile Care, Excellence Internal and Specialist Medicine “G. D’Alessandro” (PROMISE), University of Palermo, 90127 Palermo, Italy;
| | - Giampiero La Rocca
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
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30
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Li L, Shucheng H, Fu L, Pei B, Xu W, Jiang X. Overexpression and potential roles of midkine via regulation of vascular endothelial growth factor A in psoriasis. Exp Dermatol 2023; 32:1383-1393. [PMID: 37218430 DOI: 10.1111/exd.14836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/27/2023] [Accepted: 05/05/2023] [Indexed: 05/24/2023]
Abstract
Midkine plays a critical role in angiogenesis by regulating the vascular endothelial growth factor (VEGF) signalling pathway, which is known to be associated with psoriasis pathogenesis. However, research on midkine-psoriasis relationship remains limited. The objective of this study was to detect midkine expression in psoriasis and investigate its potential role in the disease. Midkine expression was measured using immunohistochemistry and ELISA. Effects of midkine on HaCaT cell proliferation, VEGF-A production and signalling pathways were assessed using CCK8, RT-PCR and WB. Scratch and in vitro tube formation tests were used to evaluate the effects of HaCaT-cell-activated midkine on the migration and tube formation of human dermal microvascular endothelial cells. Murine psoriasiform models were injected with midkine recombinant protein and midkine monoclonal antibody to investigate skin lesions, tissue sections and dermal microvessel density. Levels of midkine significantly increased in both lesions and serum of patients with psoriasis. Serum expression of midkine decreased after treatment and a positive correlation was found between midkine and disease severity. Midkine promoted HaCaT cell proliferation and VEGF-A production. The Notch2/HES1/JAK2-STAT5A pathway expression increased after midkine treatment of HaCaT cells. The supernatant of HaCaT cells treated with midkine promoted HMEC-1 migration and angiogenesis in vitro. Recombinant midkine protein exacerbated psoriasiform lesions with increased expressions of VEGF-A and microvessel density, while midkine monoclonal antibody alleviated psoriasis lesions. Midkine may have a significant impact on psoriasis angiogenesis by regulating VEGF-A expression through the Notch2/HES1/JAK2-STAT5A pathway, highlighting a potential therapeutic target for psoriasis treatment.
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Affiliation(s)
- Lin Li
- Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, China
- Department of Dermatology, Chengdu Second People's Hospital, Chengdu, China
| | - Huidi Shucheng
- Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Lixin Fu
- Department of Dermatology, Chengdu Second People's Hospital, Chengdu, China
| | - Baoqiang Pei
- Department of Dermatology, Chengdu Second People's Hospital, Chengdu, China
| | - Wen Xu
- Department of Dermatology, Chengdu Second People's Hospital, Chengdu, China
| | - Xian Jiang
- Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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31
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Joshi NP, Madiwale SD, Sundrani DP, Joshi SR. Fatty acids, inflammation and angiogenesis in women with gestational diabetes mellitus. Biochimie 2023; 212:31-40. [PMID: 37059350 DOI: 10.1016/j.biochi.2023.04.005] [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: 11/14/2022] [Revised: 03/01/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnancy whose prevalence is on the rise. Reports suggest a likely association between inflammation and maternal GDM. A balance between pro and anti-inflammatory cytokines is necessary for the regulation of maternal inflammation system throughout pregnancy. Along with various inflammatory markers, fatty acids also act as pro-inflammatory molecules. However, studies reporting the role of inflammatory markers in GDM are contradictory, suggesting the need of more studies to better understand the role of inflammation in pregnancies complicated by GDM. Inflammatory response can be regulated by angiopoietins suggesting a link between inflammation and angiogenesis. Placental angiogenesis is a normal physiological process which is tightly regulated during pregnancy. Various pro and anti-angiogenic factors influence the regulation of the feto-placental vascular development. Studies evaluating the levels of angiogenic markers in women with GDM are limited and the findings are inconsistent. This review summarizes the available literature on fatty acids, inflammatory markers and angiogenesis in women with GDM. We also discuss the possible link between them and their influence on placental development in GDM.
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Affiliation(s)
- Nikita P Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Shweta D Madiwale
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Deepali P Sundrani
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Sadhana R Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India.
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32
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Zhang Y, Yang Y, Gao X, Gao W, Zhang L. Research progress on mesenchymal stem cells and their exosomes in systemic sclerosis. Front Pharmacol 2023; 14:1263839. [PMID: 37693906 PMCID: PMC10485262 DOI: 10.3389/fphar.2023.1263839] [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: 07/20/2023] [Accepted: 08/15/2023] [Indexed: 09/12/2023] Open
Abstract
Systemic sclerosis (SSc) is a connective tissue disease with an unknown etiology. Clinically, it is characterized by localized or diffuse skin thickening and fibrosis. The pathogenesis of SSc includes microvascular injury, autoimmune-mediated inflammation, and fibroblast activation. These processes interact and contribute to the diverse clinicopathology and presentation of SSc. Given the limited effectiveness and substantial side effects of traditional treatments, the treatment strategy for SSc has several disadvantages. Mesenchymal stem cells (MSCs) are expected to serve as effective treatment options owing to their significant immunomodulatory, antifibrotic, and pro-angiogenic effects. Exosomes, secreted by MSCs via paracrine signaling, mirror the effect of MSCs as well as offer the benefit of targeted delivery, minimal immunogenicity, robust reparability, good safety and stability, and easy storage and transport. This enables them to circumvent the limitations of the MSCs. When using exosomes, it is crucial to consider preparation methods, quality standards, and suitable drug delivery systems, among other technical issues. Therefore, this review aims to summarize the latest research progress on MSCs and exosomes in SSc, offering novel ideas for treating SSc.
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Affiliation(s)
| | | | | | | | - Liyun Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
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33
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Meshko B, Volatier TLA, Hadrian K, Deng S, Hou Y, Kluth MA, Ganss C, Frank MH, Frank NY, Ksander B, Cursiefen C, Notara M. ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation. Cells 2023; 12:1731. [PMID: 37443766 PMCID: PMC10341195 DOI: 10.3390/cells12131731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
The limbus, the vascularized junction between the cornea and conjunctiva, is thought to function as a barrier against corneal neovascularization. However, the exact mechanisms regulating this remain unknown. In this study, the limbal epithelial stem cell (LESC) marker ABCB5 was used to investigate the role of LESCs in corneal neovascularization. In an ABCB5KO model, a mild but significant increase of limbal lymphatic and blood vascular network complexity was observed in developing mice (4 weeks) but not in adult mice. Conversely, when using a cornea suture model, the WT animals exhibited a mild but significant increase in the number of lymphatic vessel sprouts compared to the ABCB5KO, suggesting a contextual anti-lymphangiogenic effect of ABCB5 on the limbal vasculature during development, but a pro-lymphangiogenic effect under inflammatory challenge in adulthood. In addition, conditioned media from ABCB5-positive cultured human limbal epithelial cells (ABCB5+) stimulated human blood and lymphatic endothelial cell proliferation and migration. Finally, a proteomic analysis demonstrated ABCB5+ cells have a pro(lymph)angiogenic as well as an anti-inflammatory profile. These data suggest a novel dual, context-dependent role of ABCB5+ LESCs, inhibiting developmental but promoting inflammatory (lymph)angiogenesis in adulthood and exerting anti-inflammatory effects. These findings are of high clinical relevance in relation to LESC therapy against blindness.
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Affiliation(s)
- Berbang Meshko
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Thomas L. A. Volatier
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Karina Hadrian
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Shuya Deng
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Yanhong Hou
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Mark Andreas Kluth
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany; (M.A.K.); (C.G.)
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany
| | - Christoph Ganss
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany; (M.A.K.); (C.G.)
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany
| | - Markus H. Frank
- Transplant Research Program, Boston Children’s Hospital, Boston, MA 02115, USA
- Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA;
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA 6027, Australia
| | - Natasha Y. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA;
- Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
- Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Bruce Ksander
- Massachusetts Eye & Ear Infirmary, Schepens Eye Research Institute, Boston, MA 02114, USA;
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
- Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Maria Notara
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
- Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
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Yuan YG, Wang JL, Zhang YX, Li L, Reza AMMT, Gurunathan S. Biogenesis, Composition and Potential Therapeutic Applications of Mesenchymal Stem Cells Derived Exosomes in Various Diseases. Int J Nanomedicine 2023; 18:3177-3210. [PMID: 37337578 PMCID: PMC10276992 DOI: 10.2147/ijn.s407029] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/31/2023] [Indexed: 06/21/2023] Open
Abstract
Exosomes are nanovesicles with a wide range of chemical compositions used in many different applications. Mesenchymal stem cell-derived exosomes (MSCs-EXOs) are spherical vesicles that have been shown to mediate tissue regeneration in a variety of diseases, including neurological, autoimmune and inflammatory, cancer, ischemic heart disease, lung injury, and liver fibrosis. They can modulate the immune response by interacting with immune effector cells due to the presence of anti-inflammatory compounds and are involved in intercellular communication through various types of cargo. MSCs-EXOs exhibit cytokine storm-mitigating properties in response to COVID-19. This review discussed the potential function of MSCs-EXOs in a variety of diseases including neurological, notably epileptic encephalopathy and Parkinson's disease, cancer, angiogenesis, autoimmune and inflammatory diseases. We provided an overview of exosome biogenesis and factors that regulate exosome biogenesis. Additionally, we highlight the functions and potential use of MSCs-EXOs in the treatment of the inflammatory disease COVID-19. Finally, we covered a strategies and challenges of MSCs-EXOs. Finally, we discuss conclusion and future perspectives of MSCs-EXOs.
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Affiliation(s)
- Yu-Guo Yuan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Jia-Lin Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Ya-Xin Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Ling Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Abu Musa Md Talimur Reza
- Department of Molecular Biology and Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Türkiye
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35
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Nguyen THN, Pham PV, Vu NB. Exosomes from adipose-derived stem cells promote angiogenesis and reduce necrotic grade in hindlimb ischemia mouse models. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:429-437. [PMID: 37009008 PMCID: PMC10008393 DOI: 10.22038/ijbms.2023.67936.14857] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 01/31/2023] [Indexed: 04/04/2023]
Abstract
Objectives Acute hindlimb ischemia is a peripheral arterial disease that severely affects the patient's health. Injection of stem cells-derived exosomes that promote angiogenesis is a promising therapeutic strategy to increase perfusion and repair ischemic tissues. This study aimed to evaluate the efficacy of adipose stem cell-derived exosomes injection (ADSC-Exos) in treating acute mouse hindlimb ischemia. Materials and Methods ADSC-Exos were collected via ultracentrifugation. Exosome-specific markers were analyzed via flow cytometry. The morphology of exosomes was detected by TEM. A dose of 100 ug exosomes/100 ul PBS was locally injected into acute mice ischemic hindlimb. The treatment efficacy was evaluated based on the oxygen saturation level, limb function, new blood vessel formation, muscle structure recovery, and limb necrosis grade. Results ADSC-exosomes expressed high positivity for markers CD9 (76.0%), CD63 (91.2%), and CD81 (99.6%), and have a cup shape. After being injected into the muscle, in the treatment group, many small and short blood vessels formed around the first ligation and grew down toward the second ligation. The SpO2 level, reperfusion, and recovery of the limb function are more positively improved in the treatment group. On day 28, the muscle's histological structure in the treatment group is similar to normal tissue. Approximately 33.33% of the mice had grade I and II lesions and there were no grade III and IV observed in the treatment group. Meanwhile, in the placebo group, 60% had grade I to IV lesions. Conclusion ADSC-Exos showed the ability to stimulate angiogenesis and significantly reduce the rate of limb necrosis.
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Affiliation(s)
- Trinh Hoang-Nhat Nguyen
- Stem Cell Institute, University of Science Ho Chi Minh City, Viet Nam
- Viet Nam National University, Ho Chi Minh City, Viet Nam
| | - Phuc Van Pham
- Stem Cell Institute, University of Science Ho Chi Minh City, Viet Nam
- Viet Nam National University, Ho Chi Minh City, Viet Nam
- Laboratory of Stem Cell Research and Application, University of Science Ho Chi Minh City, Viet Nam
| | - Ngoc Bich Vu
- Stem Cell Institute, University of Science Ho Chi Minh City, Viet Nam
- Viet Nam National University, Ho Chi Minh City, Viet Nam
- Corresponding author: Ngoc Bich Vu. Stem Cell Institute, University of Science Ho Chi Minh City, Viet Nam; Viet Nam National University, Ho Chi Minh City, Viet Nam.
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Moeinabadi-Bidgoli K, Rezaee M, Hossein-Khannazer N, Babajani A, Aghdaei HA, Arki MK, Afaghi S, Niknejad H, Vosough M. Exosomes for angiogenesis induction in ischemic disorders. J Cell Mol Med 2023; 27:763-787. [PMID: 36786037 PMCID: PMC10003030 DOI: 10.1111/jcmm.17689] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/19/2023] [Accepted: 01/26/2023] [Indexed: 02/15/2023] Open
Abstract
Ischaemic disorders are leading causes of morbidity and mortality worldwide. While the current therapeutic approaches have improved life expectancy and quality of life, they are unable to "cure" ischemic diseases and instate regeneration of damaged tissues. Exosomes are a class of extracellular vesicles with an average size of 100-150 nm, secreted by many cell types and considered a potent factor of cells for paracrine effects. Since exosomes contain multiple bioactive components such as growth factors, molecular intermediates of different intracellular pathways, microRNAs and nucleic acids, they are considered as cell-free therapeutics. Besides, exosomes do not rise cell therapy concerns such as teratoma formation, alloreactivity and thrombotic events. In addition, exosomes are stored and utilized more convenient. Interestingly, exosomes could be an ideal complementary therapeutic tool for ischemic disorders. In this review, we discussed therapeutic functions of exosomes in ischemic disorders including angiogenesis induction through various mechanisms with specific attention to vascular endothelial growth factor pathway. Furthermore, different delivery routes of exosomes and different modification strategies including cell preconditioning, gene modification and bioconjugation, were highlighted. Finally, pre-clinical and clinical investigations in which exosomes were used were discussed.
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Affiliation(s)
- Kasra Moeinabadi-Bidgoli
- Basic and Molecular Epidemiology of Gastroenterology Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Malihe Rezaee
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhesam Babajani
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastroenterology Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siamak Afaghi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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Alahari S, Ausman J, Porter T, Park C, Pettersson ABV, Klemetti MM, Zhang J, Post M, Caniggia I. Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia. Endocrinology 2023; 164:6997871. [PMID: 36683415 PMCID: PMC9939344 DOI: 10.1210/endocr/bqad013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023]
Abstract
Preeclampsia (PE) is a major obstetric complication that is challenging to predict. Currently, there are limited tools to assess placental health/function in crucial gestational periods for diagnosis and early prediction. The glycoprotein fibronectin (FN) is augmented in PE placentae, and associated with reduced activity of JMJD6, an oxygen sensor that regulates placental FN processing. Evidence implicates placenta-derived small extracellular vesicles (sEVs) in the pathogenesis of pregnancy-associated disorders. Here, we examined the utility of FN and JMJD6 in placental sEVs as putative markers for early- and late-onset PE (E-PE and L-PE). Maternal plasma was obtained from venous blood collected longitudinally during pregnancy (10-14, 16-22, and 26-32 weeks of gestation and at delivery) in normotensive term control, preterm control, L-PE, E-PE, and gestational hypertensive individuals. Placenta-derived sEVs were isolated and their FN and JMJD6 content and JMJD6 activity were measured. In women that went on to develop preeclampsia, FN content of circulating placental sEVs was significantly elevated as early as 10 to 14 weeks of gestation and remained augmented until the time of delivery. This was accompanied by a depletion in JMJD6 content. Multivariate receiver operating characteristic analysis revealed high predictive power for FN and JMJD6 as early markers of E-PE and L-PE. In vitro, hypoxia or JMJD6 loss promoted FN accumulation in sEVs that was reverted on restoring cellular iron balance with the natural compound, Hinokitiol. Elevated FN, along with diminished JMJD6 in circulating placental sEVs, serves as an early molecular signature for the detection of different hypertensive disorders of pregnancy and their severity.
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Affiliation(s)
- Sruthi Alahari
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3H7, Canada
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Jonathan Ausman
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3H7, Canada
| | - Tyler Porter
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3H7, Canada
| | - Chanho Park
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3H7, Canada
| | - Ante B V Pettersson
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Miira M Klemetti
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3H7, Canada
| | - Jianhong Zhang
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3H7, Canada
| | - Martin Post
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Isabella Caniggia
- Correspondence: Isabella Caniggia, MD, PhD, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, 25 Orde Street, Room 6-1004-3, Toronto, ON M5T 3H7, Canada.
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Li N, Gu Y, Tang J, Li Y, Chen D, Xu Z. Circulating Non-coding RNAs and Exosomes: Liquid Biopsies for Monitoring Preeclampsia. Methods Mol Biol 2023; 2695:263-277. [PMID: 37450125 DOI: 10.1007/978-1-0716-3346-5_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Preeclampsia (PE) remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. The early prediction or accurate diagnosis of PE is a concern of researchers. Liquid biopsy can be analyzed for cell-free nucleic acids and exosomes. Because circulating non-coding RNAs (ncRNAs) and peripheral blood exosomes can be detected in the peripheral blood of women in early pregnancy, these vesicles and their contents have become the focus of research on early predictive and diagnostic biomarkers for preeclampsia. In this review, we focus on recent studies addressing the roles of circulating ncRNAs and exosomes in PE, with particular attention paid to the potential application value of placenta-derived exosomes and circulating ncRNAs as PE-specific biomarkers.
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Affiliation(s)
- Na Li
- Lab of Perinatal Medicine, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu, China
| | - Ying Gu
- Lab of Perinatal Medicine, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu, China
| | - Jiaqi Tang
- Institute for Fetology, First Hospital of Soochow University, Suzhou, China
| | - Yongmei Li
- Department of Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
| | - Daozhen Chen
- Lab of Perinatal Medicine, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu, China
| | - Zhice Xu
- Lab of Perinatal Medicine, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu, China
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Khan SU, Khan MI, Khan MU, Khan NM, Bungau S, Hassan SSU. Applications of Extracellular Vesicles in Nervous System Disorders: An Overview of Recent Advances. Bioengineering (Basel) 2022; 10:51. [PMID: 36671622 PMCID: PMC9854809 DOI: 10.3390/bioengineering10010051] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/19/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Diseases affecting the brain and spinal cord fall under the umbrella term "central nervous system disease". Most medications used to treat or prevent chronic diseases of the central nervous system cannot cross the blood-brain barrier (BBB) and hence cannot reach their intended target. Exosomes facilitate cellular material movement and signal transmission. Exosomes can pass the blood-brain barrier because of their tiny size, high delivery efficiency, minimal immunogenicity, and good biocompatibility. They enter brain endothelial cells via normal endocytosis and reverse endocytosis. Exosome bioengineering may be a method to produce consistent and repeatable isolation for clinical usage. Because of their tiny size, stable composition, non-immunogenicity, non-toxicity, and capacity to carry a wide range of substances, exosomes are indispensable transporters for targeted drug administration. Bioengineering has the potential to improve these aspects of exosomes significantly. Future research into exosome vectors must focus on redesigning the membrane to produce vesicles with targeting abilities to increase exosome targeting. To better understand exosomes and their potential as therapeutic vectors for central nervous system diseases, this article explores their basic biological properties, engineering modifications, and promising applications.
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Affiliation(s)
- Safir Ullah Khan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Muhammad Imran Khan
- School of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Munir Ullah Khan
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for X Polymers, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | | | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Syed Shams ul Hassan
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
- Department of Natural Product Chemistry, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
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Yang L, Rong GC, Wu QN. Diabetic foot ulcer: Challenges and future. World J Diabetes 2022; 13:1014-1034. [PMID: 36578870 PMCID: PMC9791573 DOI: 10.4239/wjd.v13.i12.1014] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/07/2022] [Accepted: 11/29/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetic foot ulcers (DFUs) have become one of the important causes of mortality and morbidity in patients with diabetes, and they are also a common cause of hospitalization, which places a heavy burden on patients and society. The prevention and treatment of DFUs requires multidisciplinary management. By controlling various risk factors, such as blood glucose levels, blood pressure, lipid levels and smoking cessation, local management of DFUs should be strengthened, such as debridement, dressing, revascularization, stem cell decompression and oxygen therapy. If necessary, systemic anti-infection treatment should be administered. We reviewed the progress in the clinical practice of treating DFUs in recent years, such as revascularization, wound repair, offloading, stem cell transplantation, and anti-infection treatment. We also summarized and prospectively analyzed some new technologies and measurements used in the treatment of DFUs and noted the future challenges and directions for the development of DFU treatments.
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Affiliation(s)
- Li Yang
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
| | - Gui-Chuan Rong
- Department of Gynaecology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
| | - Qi-Nan Wu
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
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Ortega MA, Fraile-Martínez O, García-Montero C, Paradela A, Asunción Sánchez-Gil M, Rodriguez-Martin S, De León-Luis JA, Pereda-Cerquella C, Bujan J, Guijarro LG, Alvarez-Mon M, García-Honduvilla N. Unfolding the role of placental-derived Extracellular Vesicles in Pregnancy: From homeostasis to pathophysiology. Front Cell Dev Biol 2022; 10:1060850. [PMID: 36478738 PMCID: PMC9720121 DOI: 10.3389/fcell.2022.1060850] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 11/02/2022] [Indexed: 08/11/2023] Open
Abstract
The human placenta is a critical structure with multiple roles in pregnancy, including fetal nutrition and support, immunological, mechanical and chemical barrier as well as an endocrine activity. Besides, a growing body of evidence highlight the relevance of this organ on the maternofetal wellbeing not only during gestation, but also from birth onwards. Extracellular vesicles (EVs) are complex macromolecular structures of different size and content, acting as carriers of a diverse set of molecules and information from donor to recipient cells. Since its early development, the production and function of placental-derived EVs are essential to ensure an adequate progress of pregnancy. In turn, the fetus receives and produce their own EVs, highlighting the importance of these components in the maternofetal communication. Moreover, several studies have shown the clinical relevance of EVs in different obstetric pathologies such as preeclampsia, infectious diseases or gestational diabetes, among others, suggesting that they could be used as pathophysiological biomarkers of these diseases. Overall, the aim of this article is to present an updated review of the published basic and translational knowledge focusing on the role of placental-derived EVs in normal and pathological pregnancies. We suggest as well future lines of research to take in this novel and promising field.
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Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, Alcala de Henares, Spain
| | - Oscar Fraile-Martínez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | | | - María Asunción Sánchez-Gil
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- University Defense Center of Madrid (CUD), Madrid, Spain
| | - Sonia Rodriguez-Martin
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Service of Pediatric, Hospital Universitario Principe de Asturias, Alcalá de Henares, Spain
| | - Juan A. De León-Luis
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, Madrid, Spain
- Health Research Institute Gregorio Marañón, Madrid, Spain
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Ma-drid, Madrid, Spain
| | - Claude Pereda-Cerquella
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
| | - Julia Bujan
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Luis G. Guijarro
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Unit of Biochemistry and Molecular Biology, Centro de Investigación Biomédica en Red en El Área Temática de Enfermedades Hepáticas (CIBEREHD), Department of System Biology, University of Alcalá, Alcala de Henares, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine, Centro de Investigación Biomédica en Red en El Área Temática de Enfermedades Hepáticas (CIBEREHD), University Hospital Príncipe de Asturias, Alcala de Henares, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- University Defense Center of Madrid (CUD), Madrid, Spain
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Divband S, Tasharrofi N, Abroun S, Zomorrod MS. Human Umbilical Cord Mesenchymal Stem Cells-Derived Small Extracellular Vesicles Can Be Considered as Cell-Free Therapeutics for Angiogenesis Promotion. CELL JOURNAL 2022; 24:689-696. [PMID: 36377219 PMCID: PMC9663965 DOI: 10.22074/cellj.2022.8275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Indexed: 12/01/2022]
Abstract
OBJECTIVE Angiogenesis has critical roles in several physiological processes. Restoring angiogenesis in some pathological conditions such as a few vascular diseases can be a therapeutic approach to controlling this issue. Mesenchymal stem cells (MSCs) secrete specific intracellular products known as extracellular vesicles (EVs) with high therapeutic potential which compared to their source cells, do not have the limitations of cell therapy. The angiogenic effect of the human umbilical cord MSCs (hUCMSCs)-derived small EVs are evaluated in the present work. Aim of this research is to show that hUCMSCs-derived small EVs cause differentiation of genes involved in angiogenesis like FGFR-1, FGF, VEGF, and VEGFR-2. MATERIALS AND METHODS In this experimental study, MSCs were isolated from the human umbilical cord, and after confirming their identities, their secreted EVs (including exosomes) were extracted by ultracentrifugation. The isolated small EVs were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), bicinchoninic acid assay (BCA), and Western Blotting. Then, the human umbilical vein endothelial cells (HUVECs) were treated with derived small EVs for 72 hours, and the expression of the angiogenic factors including FGFR-1, FGF, VEGF, and VEGFR-2 was evaluated by quantitative real-time-polymerase chain reaction (qPCR). Angiogenesis was also evaluated via a tube formation assay. RESULTS The results demonstrated that FGFR-1, FGF, VEGF, and VEGFR-2 could be elevated 2, 2, 3.5, and 2 times, respectively, in EVs treated HUVECs, and derivative EVs can encourage tube formation in HUVECs. CONCLUSION These findings imply that hUCMSCs-derived small EVs are valuable resources in promoting angiogenesis and are very promising in cell-free therapy.
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Affiliation(s)
- Somayeh Divband
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nooshin Tasharrofi
- Faculty of Pharmacy, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Saeid Abroun
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mina Soufi Zomorrod
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran,P.O.Box: 14115-111Department of Hematology and Cell TherapyFaculty of Medical SciencesTarbiat Modares
UniversityTehranIran
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Silini AR, Ramuta TŽ, Pires AS, Banerjee A, Dubus M, Gindraux F, Kerdjoudj H, Maciulatis J, Weidinger A, Wolbank S, Eissner G, Giebel B, Pozzobon M, Parolini O, Kreft ME. Methods and criteria for validating the multimodal functions of perinatal derivatives when used in oncological and antimicrobial applications. Front Bioeng Biotechnol 2022; 10:958669. [PMID: 36312547 PMCID: PMC9607958 DOI: 10.3389/fbioe.2022.958669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/26/2022] [Indexed: 11/18/2022] Open
Abstract
Perinatal derivatives or PnDs refer to tissues, cells and secretomes from perinatal, or birth-associated tissues. In the past 2 decades PnDs have been highly investigated for their multimodal mechanisms of action that have been exploited in various disease settings, including in different cancers and infections. Indeed, there is growing evidence that PnDs possess anticancer and antimicrobial activities, but an urgent issue that needs to be addressed is the reproducible evaluation of efficacy, both in vitro and in vivo. Herein we present the most commonly used functional assays for the assessment of antitumor and antimicrobial properties of PnDs, and we discuss their advantages and disadvantages in assessing the functionality. This review is part of a quadrinomial series on functional assays for the validation of PnDs spanning biological functions such as immunomodulation, anticancer and antimicrobial, wound healing, and regeneration.
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Affiliation(s)
- Antonietta R. Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Taja Železnik Ramuta
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Salomé Pires
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Asmita Banerjee
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Marie Dubus
- Université de Reims Champagne Ardenne, EA 4691 Biomatériaux et Inflammation en Site Osseux (BIOS), Reims, France
| | - Florelle Gindraux
- Service de Chirurgie Orthopédique, Traumatologique et Plastique, CHU Besançon and Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, Université Bourgogne Franche-Comté, Besançon, France
| | - Halima Kerdjoudj
- Université de Reims Champagne Ardenne, EA 4691 Biomatériaux et Inflammation en Site Osseux (BIOS), Reims, France
| | - Justinas Maciulatis
- The Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Adelheid Weidinger
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Günther Eissner
- Systems Biology Ireland, UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michela Pozzobon
- Stem Cells and Regenerative Medicine Lab, Department of Women’s and Children’s Health, University of Padova, Fondazione Istituto di Ricerca Pediatrica Città Della Speranza, Padoa, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica Del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
| | - Mateja Erdani Kreft
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana, Ljubljana, Slovenia
- *Correspondence: Mateja Erdani Kreft,
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Xia Y, Yang R, Hou Y, Wang H, Li Y, Zhu J, Fu C. Application of mesenchymal stem cell-derived exosomes from different sources in intervertebral disc degeneration. Front Bioeng Biotechnol 2022; 10:1019437. [PMID: 36277386 PMCID: PMC9585200 DOI: 10.3389/fbioe.2022.1019437] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/26/2022] [Indexed: 12/12/2022] Open
Abstract
Intervertebral disc degeneration (IVDD) is a main cause of lower back pain, leading to psychological and economic burdens to patients. Physical therapy only delays pain in patients but cannot eliminate the cause of IVDD. Surgery is required when the patient cannot tolerate pain or has severe neurological symptoms. Although surgical resection of IVD or decompression of the laminae eliminates the diseased segment, it damages adjacent normal IVD. There is also a risk of re-protrusion after IVD removal. Cell therapy has played a crucial role in the development of regenerative medicine. Cell transplantation promotes regeneration of degenerative tissue. However, owing to the lack of vascular structure in IVD, sufficient nutrients cannot be provided for transplanted mesenchymal stem cells (MSCs). In addition, dead cells release harmful substances that aggravate IVDD. Extracellular vesicles (EVs) have been extensively studied as an emerging therapeutic approach. EVs generated by paracrine MSCs retain the potential of MSCs and serve as carriers to deliver their contents to target cells to regulate target cell activity. Owing to their double-layered membrane structure, EVs have a low immunogenicity and no immune rejection. Therefore, EVs are considered an emerging therapeutic modality in IVDD. However, they are limited by mass production and low loading rates. In this review, the structure of IVD and advantages of EVs are introduced, and the application of MSC-EVs in IVDD is discussed. The current limitations of EVs and future applications are described.
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Affiliation(s)
- Yuanliang Xia
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ruohan Yang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yulin Hou
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, China
| | - Hengyi Wang
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yuehong Li
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Jianshu Zhu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Changfeng Fu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Changfeng Fu,
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Therapeutic Efficacy of Adipose-Derived Stem Cells Versus Bone Marrow Stromal Cells for Irradiated Mandibular Fracture Repair. Ann Plast Surg 2022; 89:459-464. [PMID: 36149985 DOI: 10.1097/sap.0000000000003301] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Mesenchymal stem cells have immense potential in applications of bone healing and regeneration. However, few studies have evaluated the therapeutic efficacy of adipose-derived stem cells (ASCs) and bone marrow stromal cells (BMSCs) in irradiated bone. The purpose of this study is to compare the ability of ASCs versus BMSCs to enhance healing outcomes in a murine model of irradiated mandibular fracture repair. METHODS Forty-eight isogenic male Lewis rats underwent radiation therapy followed by mandibular osteotomy with intraoperative placement of either ASCs or BMSCs. Animals were killed on postoperative day 40. Mandibles were analyzed for union rate, biomechanical strength, vascularity, and mineralization. Groups were compared at P < 0.05 significance. RESULTS The ASC and BMSC groups demonstrated 92% and 75% union rates. Compared with the BMSC group, the ASC group demonstrated a trending increase in maximum load ( P = 0.095) on biomechanical strength analysis and a significant increase in vessel number ( P = 0.001), vessel thickness ( P = 0.035), and vessel volume fraction ( P = 0.007) on micro-computed tomography angiography analysis. No significant differences in bone mineralization were identified on micro-computed tomography analysis. CONCLUSION This study demonstrates the superior therapeutic efficacy of ASCs over BMSCs in irradiated fracture healing as evidenced by union rate, vascular morphometry, and a trend in biomechanical strength. We posit that the robust vascular response induced by ASCs better recapitulates the sequence and synchronicity of physiologic bone healing compared with BMSCs, thereby improving the reliability of irradiated fracture repair.
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Shi MY, Liu L, Yang FY. Strategies to improve the effect of mesenchymal stem cell therapy on inflammatory bowel disease. World J Stem Cells 2022; 14:684-699. [PMID: 36188115 PMCID: PMC9516464 DOI: 10.4252/wjsc.v14.i9.684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis and is an idiopathic, chronic inflammatory disease of the colonic mucosa. The occurrence of IBD, causes irreversible damage to the colon and increases the risk of carcinoma. The routine clinical treatment of IBD includes drug treatment, endoscopic treatment and surgery. The vast majority of patients are treated with drugs and biological agents, but the complete cure of IBD is difficult. Mesenchymal stem cells (MSCs) have become a new type of cell therapy for the treatment of IBD due to their immunomodulatory and nutritional functions, which have been confirmed in many clinical trials. This review discusses some potential mechanisms of MSCs in the treatment of IBD, summarizes the experimental results, and provides new insights to enhance the therapeutic effects of MSCs in future applications.
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Affiliation(s)
- Meng-Yue Shi
- School of Medicine, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Fu-Yuan Yang
- Health Science Center, Yangtze University, Jingzhou 434020, Hubei Province, China
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Lu Y, Zhang J, Zeng F, Wang P, Guo X, Wang H, Qin Z, Tao T. Human PMSCs-derived small extracellular vesicles alleviate neuropathic pain through miR-26a-5p/Wnt5a in SNI mice model. J Neuroinflammation 2022; 19:221. [PMID: 36071475 PMCID: PMC9450435 DOI: 10.1186/s12974-022-02578-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 08/27/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSCs)-derived small Extracellular Vesicles (sEVs) are considered as a new cell-free therapy for pain caused by nerve injury, but whether human placental mesenchymal stem cell-derived sEVs relieve pain in sciatic nerve injury and its possible mechanism are still unclear. In this study, we investigated the roles of hPMSCs-derived sEVs and related mechanisms in neuropathic pain. METHODS The spared nerve injury (SNI) mouse model was employed. Intrathecal injection of sEVs or miR-26a-5p agomir was performed on the seventh day of modeling, to study its anti-nociceptive effect. sEVs' miRNA sequencing (miRNA-Seq) and bioinformatics analysis were performed to study the downstream mechanisms of miRNAs. RT-qPCR, protein assay and immunofluorescence were used for further validation. RESULTS A single intrathecal injection of sEVs durably reversed mechanical hypersensitivity in the left hind paw of mice with partial sciatic nerve ligation. Immunofluorescence studies found that PKH26-labeled sEVs were visible in neurons and microglia in the dorsal horn of the ipsilateral L4/5 spinal cord and more enriched in the ipsilateral. According to miRNA-seq results, we found that intrathecal injection of miR-26a-5p agomir, the second high counts microRNA in hPMSCs derived sEVs, significantly suppressed neuropathic pain and neuroinflammation in SNI mice. Bioinformatics analysis and dual-luciferase reporter gene analysis identified Wnt5a as a direct downstream target gene of miR-26a-5p. The results showed that overexpression of miR-26a-5p in vivo could significantly reduce the expression level of Wnt5a. In addition, Foxy5, a mimetic peptide of Wnt5a, can significantly reverse the inhibitory effect of miR-26a-5p on neuroinflammation and neuropathic pain, and at the same time, miR-26a-5p can rescue the effect of Foxy5 by overexpression. CONCLUSIONS We reported that hPMSCs derived sEVs as a promising therapy for nerve injury induced neuropathic pain. In addition, we showed that the miR-26a-5p in the sEVs regulated Wnt5a/Ryk/CaMKII/NFAT partly take part in the analgesia through anti-neuroinflammation, which suggests an alleviating pain effect through non-canonical Wnt signaling pathway in neuropathic pain model in vivo.
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Affiliation(s)
- Yitian Lu
- Department of Anesthesiology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, People's Republic of China.,Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Jintao Zhang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.,Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Fanning Zeng
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Peng Wang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Xiangna Guo
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Haitao Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Zaisheng Qin
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
| | - Tao Tao
- Department of Anesthesiology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, People's Republic of China.
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Zhang S, Tuk B, van de Peppel J, Kremers GJ, Koedam M, Pesch GR, Rahman Z, Hoogenboezem RM, Bindels EMJ, van Neck JW, Boukany PE, van Leeuwen JPTM, van der Eerden BCJ. Microfluidic evidence of synergistic effects between mesenchymal stromal cell-derived biochemical factors and biomechanical forces to control endothelial cell function. Acta Biomater 2022; 151:346-359. [PMID: 35995408 DOI: 10.1016/j.actbio.2022.08.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 07/20/2022] [Accepted: 08/12/2022] [Indexed: 11/01/2022]
Abstract
A functional vascular system is a prerequisite for bone repair as disturbed angiogenesis often causes non-union. Paracrine factors released from human bone marrow derived mesenchymal stromal cells (BMSCs) have angiogenic effects on endothelial cells. However, whether these paracrine factors participate in blood flow dynamics within bone capillaries remains poorly understood. Here, we used two different microfluidic designs to investigate critical steps during angiogenesis and found pronounced effects of endothelial cell proliferation as well as chemotactic and mechanotactic migration induced by BMSC conditioned medium (CM). The application of BMSC-CM in dynamic cultures demonstrates that bioactive factors in combination with fluidic flow-induced biomechanical signals significantly enhanced endothelial cell migration. Transcriptional analyses of endothelial cells demonstrate the induction of a unique gene expression profile related to tricarboxylic acid cycle and energy metabolism by the combination of BMSC-CM factors and shear stress, which opens an interesting avenue to explore during fracture healing. Our results stress the importance of in vivo - like microenvironments simultaneously including biochemical, biomechanical and oxygen levels when investigating key events during vessel repair. STATEMENT OF SIGNIFICANCE: Our results demonstrate the importance of recapitulating in vivo - like microenvironments when investigating key events during vessel repair. Endothelial cells exhibit enhanced angiogenesis characteristics when simultaneous exposing them to hMSC-CM, mechanical forces and biochemical signals simultaneously. The improved angiogenesis may not only result from the direct effect of growth factors, but also by reprogramming of endothelial cell metabolism. Moreover, with this model we demonstrated a synergistic impact of mechanical forces and biochemical factors on endothelial cell behavior and the expression of genes involved in the TCA cycle and energy metabolism, which opens an interesting new avenue to stimulate angiogenesis during fracture healing.
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Affiliation(s)
- Shuang Zhang
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Bastiaan Tuk
- Department of Plastic and Reconstructive Surgery, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Jeroen van de Peppel
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Gert-Jan Kremers
- Erasmus Optical Imaging Center, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Marijke Koedam
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Georg R Pesch
- Department of Chemical Engineering, Delft University of Technology; Delft, the Netherlands
| | - Zaid Rahman
- Department of Chemical Engineering, Delft University of Technology; Delft, the Netherlands
| | - Remco M Hoogenboezem
- Department of Hematology, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Eric M J Bindels
- Department of Hematology, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Johan W van Neck
- Department of Plastic and Reconstructive Surgery, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Pouyan E Boukany
- Department of Chemical Engineering, Delft University of Technology; Delft, the Netherlands
| | - Johannes P T M van Leeuwen
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands
| | - Bram C J van der Eerden
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands.
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Gao Z, Wang N, Liu X. Human placenta mesenchymal stem cell-derived exosome shuttling microRNA-130b-3p from gestational diabetes mellitus patients targets ICAM-1 and perturbs human umbilical vein endothelial cell angiogenesis. Acta Diabetol 2022; 59:1091-1107. [PMID: 35676597 DOI: 10.1007/s00592-022-01910-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/18/2022] [Indexed: 11/01/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the roles of miR-130b-3p and ICAM-1 in gestational diabetes mellitus (GDM) and their potential association. METHODS Human placenta mesenchymal stem cells (PlaMSCs) were isolated from GDM patients, and the effects of the PlaMSCs from GDM patients (GDM-MSCs) and the exosomes secreted by GDM-MSCs on human umbilical vein endothelial cell (HUVEC) proliferation, migration, and angiogenesis were detected. Next, GDM-MSCs were transfected with miR-130b-3p antagomir to modify miR-130b-3p expression in GDM-MSCs-derived exosomes, and the exosomes with modified miR-130b-3p expression were cultured with HUVECs to evaluate exosomal miR-130b-3p on HUVEC function. Furthermore, a target gene of miR-130b-3p was predicted and assessed. The miR-130b-3p-modified exosomes were cultured with HUVECs transfected with ICAM-1 shRNA to determine the effect of miR-130b-3p-ICAM-1 crosstalk on HUVEC function. Additionally, a GDM mouse model was conducted to further study the effect of miR-130b-3p in GDM in vivo. RESULTS GDM-MSCs inhibited HUVEC proliferation and angiogenesis. The elevated expression of miR-130b-3p was found in GDM-MSCs-derived exosomes. GDM-MSCs-derived exosomes repressed the proliferation and angiogenesis of HUVECs and miR-130b-3p inhibition could restrain the inhibition of the exosomes on HUVEC function. Mechanistically, miR-130b-3p downregulated ICAM-1 expression in a targeted manner, and thereby enhanced HUVEC proliferation, migration, and angiogenesis and increased the expression of angiogenesis-related factors. Moreover, miR-130b-3p inhibition promoted placental angiogenesis in GDM mice and upregulated ICAM-1 expression. CONCLUSION Conclusively, GDM-MSCs-derived exosomes shuttling miR-130b-3p repressed proliferation, migration, and angiogenesis of HUVECs by regulating ICAM-1 expression.
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Affiliation(s)
- Zhou Gao
- Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Nan Wang
- Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Xinli Liu
- Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China.
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Zeng J, Lu C, Huang H, Huang J. Effect of Recombinant Netrin-1 Protein Combined with Peripheral Blood Mesenchymal Stem Cells on Angiogenesis in Rats with Arteriosclerosis Obliterans. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3361605. [PMID: 35928912 PMCID: PMC9345694 DOI: 10.1155/2022/3361605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/30/2022] [Accepted: 07/02/2022] [Indexed: 01/06/2023]
Abstract
This work was aimed to explore the effect of recombinant netrin-1 protein and peripheral blood mesenchymal stem cells (MSCs) on the angiogenesis ability of atherosclerosis. 28 Sprague Dawley (SD) rats were taken as research models. The arterial occlusion models were created by surgery and then divided into the saline control group (n =7), netrin-1 treatment group (n =7), MSCs treatment group (n =7), and netrin-1 + MSCs combined treatment group (n =7). The peripheral blood MSCs were extracted from the peritoneal cavity of diseased SD rats and cultured alone or in combination with netrin-1. The individually cultured MSCs and netrin-1 were locally injected into the ischemic tissues of SD rats. The Tarlov scoring was performed at the first, second, and third week of treatment, respectively. The expression of vascular endothelial growth factor (VEGF) was also measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the capillary density was measured by immunofluorescence staining. The mean maximum contractility of the gastrocnemius muscle in each group was determined in the third week after treatment. The Tarlov score of the netrin-1 + MSCs group was significantly higher than that of the control group (P < 0.05) at the second week. To the 4th week of treatment, the Tarlov score of the netrin-1 + MSCs group was highly increased compared to the netrin-1 group and the MSCs group (P < 0.05). The expression of VEGF in the treatment groups was greatly increased each week compared to the control group (P < 0.05). Compared with the netrin-1 and the MSCs groups, the VEGF was also notably increased in the netrin-1 + MSCs group (P <0.05). The capillary densities of the treatment groups were observably greater than that of the control group in the second and third weeks (P <0.05), while the capillary density in the netrin-1 + MSCs group was also significantly increased than those in the netrin-1 group and the MSCs group (P < 0.05). The mean maximum contractility of the netrin-1 + MSCs group was remarkably higher than that of the other groups (P < 0.05). The netrin-1 + MSCs group achieved the higher Tarlov score, higher VEGF expression, higher capillary density, and better muscle recovery than netrin-1 and MSCs treatments.
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Affiliation(s)
- Jie Zeng
- Department of Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072 Sichuan, China
| | - Cong Lu
- Department of Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072 Sichuan, China
| | - Hui Huang
- Department of Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072 Sichuan, China
| | - Jianxin Huang
- Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072 Sichuan, China
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