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Poudineh M, Mohammadyari F, Parsamanesh N, Jamialahmadi T, Kesharwani P, Sahebkar A. Cell and gene therapeutic approaches in non-alcoholic fatty liver disease. Gene 2025; 956:149466. [PMID: 40189164 DOI: 10.1016/j.gene.2025.149466] [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: 01/06/2025] [Revised: 03/14/2025] [Accepted: 03/31/2025] [Indexed: 04/11/2025]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a range of conditions marked by the buildup of triglycerides in liver cells, accompanied by inflammation, which contributes to liver damage, clinical symptoms, and histopathological alterations. Multiple molecular pathways contribute to NAFLD pathogenesis, including immune dysregulation, endoplasmic reticulum stress, and tissue injury. Both the innate and adaptive immune systems play crucial roles in disease progression, with intricate crosstalk between liver and immune cells driving NAFLD development. Among emerging therapeutic strategies, cell and gene-based therapies have shown promise. This study reviews the pathophysiological mechanisms of NAFLD and explores the therapeutic potential of cell-based interventions, highlighting their immunomodulatory effects, inhibition of hepatic stellate cells, promotion of hepatocyte regeneration, and potential for hepatocyte differentiation. Additionally, we examine gene delivery vectors designed to target NAFLD, focusing on their role in engineering hepatocytes through gene addition or editing to enhance therapeutic efficacy.
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Affiliation(s)
| | | | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran; Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Tananz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh 470003, India.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Pan M, Xu Y, Wang Y, Jiang Y, Xie Y, Tai C, Wang W, Wang B. The therapeutic efficacy comparison of MSCs derived different tissues unveilings anti-apoptosis more crucial than angiogenesis in treating acute myocardial infarction. Stem Cell Res Ther 2025; 16:236. [PMID: 40361236 PMCID: PMC12077008 DOI: 10.1186/s13287-025-04378-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Myocardial infarction (MI) is a severe disease that often associated with impaired angiogenesis and increased myocardial apoptosis. Mesenchymal stromal cells (MSCs) have been a promising candidate for treating myocardial infarction. However, functional heterogeneity of MSCs leads to inconsistent therapeutic efficiency and the current MSCs-based therapy lacks the concept and implementation of precision medicine. In this study, we compared the cardioprotective effect of UCMSCs and ADMSCs targeting the angiogenesis in a mouse MI model and screened out optimum MSCs candidate for precise clinical application. METHODS The gene expression profiles of UCMSCs and ADMSCs were investigated through RNA sequencing analysis. To compare their angiogenic potential, we performed tube formation assay, Matrigel plug assays, and aortic ring assay, and analyzed pro-angiogenic genes via qPCR. Subsequently, UCMSCs and ADMSCs were respectively injected into myocardium after MI surgery in mice. On day 28 post-MI, echocardiography was performed to assess cardiac function. Histological analysis was performed to assess MSCs retention, angiogenesis, and myocardial apoptosis. Additionally, the anti-apoptosis effects mediated by MSCs were further evaluated using flow cytometry in hypoxia H9C2 and HL-1 cells. RESULTS The RNA sequencing analysis revealed differences in gene expression related to angiogenesis and apoptosis pathways between UCMSCs and ADMSCs. UCMSCs presented greater pro-angiogenesis activity than ADMSCs in vitro and in vivo. Both of UCMSCs and ADMSCs improved cardiac function, decreased infarction area and inhibited cardiomyocyte apoptosis while promoting angiogenesis post-MI in mice. Notably, ADMSCs exerted a better cardioprotective function than UCMSCs and stronger anti-apoptotic effect on residual cardiomyocytes. CONCLUSIONS The protection of residual cells survival played a more prominent role than angiogenesis in MSCs-based therapy for acute MI. Our study provides new insights into therapeutic strategies and suggests that the optimal type of MSCs can be screened based on their tissue heterogeneity for precise clinical applications in acute MI.
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Affiliation(s)
- Mingjie Pan
- Clinical Medicine Research Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Yueyue Xu
- The Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Clinical Medical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Yue Jiang
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Yuanyuan Xie
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Chenxu Tai
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Wenqing Wang
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Clinical Medical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China.
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Hoseini SM, Montazeri F. The influence of cell source on the senescence of human mesenchymal stem/stromal cells. Hum Cell 2025; 38:87. [PMID: 40221541 DOI: 10.1007/s13577-025-01213-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
While mesenchymal stem/stromal cells (MSCs) exhibit the ability to self-renew, they are not immortal; they eventually reach a point of irreversible growth cessation and functional deterioration following a limited series of population doublings, referred to as replicative senescence. When evaluated according to the criteria set by the International Society for Cell Therapy (ISCT), MSCs show significant differences in their senescence patterns and other characteristics related to their phenotype and function. These differences are attributed to the source of the MSCs and the conditions in which they are grown. MSCs derived from fetal or adult sources have variations in their genome stability, as well as in the expression and epigenetic profile of the cells, which in turn affects their secretome. Understanding the key factors of MSC senescence based on cell source can help to develop effective strategies for regulating senescence and improving the therapeutic potential.
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Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, No. 1. Safaeyeh. Bou-Al Ave., Yazd, 8916877391, Iran.
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Kamrani S, Naseramini R, Khani P, Razavi ZS, Afkhami H, Atashzar MR, Nasri F, Alavimanesh S, Saeidi F, Ronaghi H. Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword. Cancer Cell Int 2025; 25:117. [PMID: 40140850 PMCID: PMC11948648 DOI: 10.1186/s12935-025-03741-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/08/2025] [Indexed: 03/28/2025] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy defined by the abnormal proliferation and accumulation of plasma cells (PC) within the bone marrow (BM). While multiple myeloma impacts the bone, it is not classified as a primary bone cancer. The bone marrow microenvironment significantly influences the progression of myeloma and its treatment response. Mesenchymal stromal cells (MSCs) in this environment engage with myeloma cells and other bone marrow components via direct contact and the secretion of soluble factors. This review examines the established roles of MSCs in multiple facets of MM pathology, encompassing their pro-inflammatory functions, contributions to tumor epigenetics, effects on immune checkpoint inhibitors (ICIs), influence on reprogramming, chemotherapy resistance, and senescence. This review investigates the role of MSCs in the development and progression of MM.
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Affiliation(s)
- Sina Kamrani
- Department of Orthopedic, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Reza Naseramini
- Department of Orthopedic, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Pouria Khani
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Mohammad Reza Atashzar
- Department of Immunology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzad Nasri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sajad Alavimanesh
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Farzane Saeidi
- Department of Medical Genetics, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Hossein Ronaghi
- Department of Orthopedic, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
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Gao P, Kajiya M, Motoike S, Ikeya M, Yang J. Application of mesenchymal stem/stromal cells in periodontal regeneration: Opportunities and challenges. JAPANESE DENTAL SCIENCE REVIEW 2024; 60:95-108. [PMID: 38314143 PMCID: PMC10837070 DOI: 10.1016/j.jdsr.2024.01.001] [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: 08/08/2023] [Revised: 12/06/2023] [Accepted: 01/15/2024] [Indexed: 02/06/2024] Open
Abstract
Guided tissue regeneration (GTR) has been widely used in the periodontal treatment of intrabony and furcation defects for nearly four decades. The treatment outcomes have shown effectiveness in reducing pocket depth, improving attachment gain and bone filling in periodontal tissue. Although applying GTR could reconstruct the periodontal tissue, the surgical indications are relatively narrow, and some complications and race ethic problems bring new challenges. Therefore, it is challenging to achieve a consensus concerning the clinical benefits of GTR. With the appearance of stem cell-based regenerative medicine, mesenchymal stem/stromal cells (MSCs) have been considered a promising cell resource for periodontal regeneration. In this review, we highlight preclinical and clinical periodontal regeneration using MSCs derived from distinct origins, including non-odontogenic and odontogenic tissues and induced pluripotent stem cells, and discuss the transplantation procedures, therapeutic mechanisms, and concerns to evaluate the effectiveness of MSCs.
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Affiliation(s)
- Pan Gao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of General Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Mikihito Kajiya
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Souta Motoike
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Makoto Ikeya
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
| | - Jingmei Yang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
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Pal D, Das P, Roy S, Mukherjee P, Halder S, Ghosh D, Nandi SK. Recent trends of stem cell therapies in the management of orthopedic surgical challenges. Int J Surg 2024; 110:6330-6344. [PMID: 38716973 PMCID: PMC11487011 DOI: 10.1097/js9.0000000000001524] [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: 12/29/2023] [Accepted: 04/14/2024] [Indexed: 10/20/2024]
Abstract
Emerged health-related problems especially with increasing population and with the wider occurrence of these issues have always put the utmost concern and led medicine to outgrow its usual mode of treatment, to achieve better outcomes. Orthopedic interventions are one of the most concerning hitches, requiring advancement in several issues, that show complications with conventional approaches. Advanced studies have been undertaken to address the issue, among which stem cell therapy emerged as a better area of growth. The capacity of the stem cells to renovate themselves and adapt into different cell types made it possible to implement its use as a regenerative slant. Harvesting the stem cells, particularly mesenchymal stem cells (MSCs) is easier and can be further grown in vitro . In this review, we have discussed orthopedic-related issues including bone defects and fractures, nonunions, ligament and tendon injuries, degenerative changes, and associated conditions, which require further approaches to execute better outcomes, and the advanced strategies that can be tagged along with various ways of application of MSCs. It aims to objectify the idea of stem cells, with a major focus on the application of MSCs from different sources in various orthopedic interventions. It also discusses the limitations, and future scopes for further approaches in the field of regenerative medicine. The involvement of MSCs may transition the procedures in orthopedic interventions from predominantly surgical substitution and reconstruction to bio-regeneration and prevention. Nevertheless, additional improvements and evaluations are required to explore the effectiveness and safety of mesenchymal stem cell treatment in orthopedic regenerative medicine.
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Affiliation(s)
| | - Pratik Das
- Department of Veterinary Surgery and Radiology
| | - Subhasis Roy
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal
| | - Prasenjit Mukherjee
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal
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Ratushnyy A, Ezdakova M, Matveeva D, Tyrina E, Buravkova L. Regulatory Effects of Senescent Mesenchymal Stem Cells: Endotheliocyte Reaction. Cells 2024; 13:1345. [PMID: 39195236 PMCID: PMC11352319 DOI: 10.3390/cells13161345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/01/2024] [Accepted: 08/08/2024] [Indexed: 08/29/2024] Open
Abstract
Currently, there is a growing focus on aging and age-related diseases. The processes of aging are based on cell senescence, which results in changes in intercellular communications and pathological alterations in tissues. In the present study, we investigate the influence of senescent mesenchymal stem cells (MSCs) on endothelial cells (ECs). In order to induce senescence in MSCs, we employed a method of stress-induced senescence utilizing mitomycin C (MmC). Subsequent experiments involved the interaction of ECs with MSCs in a coculture or the treatment of ECs with the secretome of senescent MSCs. After 48 h, we assessed the EC state. Our findings revealed that direct interaction led to a decrease in EC proliferation and migratory activity of the coculture. Furthermore, there was an increase in the activity of the lysosomal compartment, as well as an upregulation of the genes P21, IL6, IL8, ITGA1, and ITGB1. Treatment of ECs with the "senescent" secretome resulted in less pronounced effects, although a decrease in proliferation and an increase in ICAM-1 expression were observed. The maintenance of high levels of typical "senescent" cytokines and growth factors after 48 h suggests that the addition of the "senescent" secretome may have a prolonged effect on the cells. It is noteworthy that in samples treated with the "senescent" secretome, the level of PDGF-AA was higher, which may explain some of the pro-regenerative effects of senescent cells. Therefore, the detected changes may underlie both the negative and positive effects of senescence. The findings provide insight into the effects of cell senescence in vitro, where many of the organism's regulatory mechanisms are absent.
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Affiliation(s)
- Andrey Ratushnyy
- Institute of Biomedical Problems, Russian Academy of Sciences, Khoroshevskoye Shosse, 76a, 123007 Moscow, Russia; (M.E.); (D.M.); (E.T.); (L.B.)
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Qu Y, Wang Z, Dong L, Zhang D, Shang F, Li A, Gao Y, Bai Q, Liu D, Xie X, Ming L. Natural small molecules synergize mesenchymal stem cells for injury repair in vital organs: a comprehensive review. Stem Cell Res Ther 2024; 15:243. [PMID: 39113141 PMCID: PMC11304890 DOI: 10.1186/s13287-024-03856-4] [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: 06/13/2024] [Accepted: 07/17/2024] [Indexed: 08/10/2024] Open
Abstract
Mesenchymal stem cells (MSCs) therapy is a highly researched treatment that has the potential to promote immunomodulation and anti-inflammatory, anti-apoptotic, and antimicrobial activities. It is thought that it can enhance internal organ function, reverse tissue remodeling, and achieve significant organ repair and regeneration. However, the limited infusion, survival, and engraftment of transplanted MSCs diminish the effectiveness of MSCs-based therapy. Consequently, various preconditioning methods have emerged as strategies for enhancing the therapeutic effects of MSCs and achieving better clinical outcomes. In particular, the use of natural small molecule compounds (NSMs) as a pretreatment strategy is discussed in this narrative review, with a focus on their roles in regulating MSCs for injury repair in vital internal organs. Additionally, the discussion focuses on the future directions and challenges of transforming mesenchymal stem cell research into clinical applications.
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Affiliation(s)
- Yanling Qu
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Zhe Wang
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Lingjuan Dong
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Dan Zhang
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Fengqing Shang
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510000, China
| | - Afeng Li
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Yanni Gao
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Qinhua Bai
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Dan Liu
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Xiaodong Xie
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu Province, China.
| | - Leiguo Ming
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China.
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu Province, China.
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Lee SB, Abdal Dayem A, Kmiecik S, Lim KM, Seo DS, Kim HT, Kumar Biswas P, Do M, Kim DH, Cho SG. Efficient improvement of the proliferation, differentiation, and anti-arthritic capacity of mesenchymal stem cells by simply culturing on the immobilized FGF2 derived peptide, 44-ERGVVSIKGV-53. J Adv Res 2024; 62:119-141. [PMID: 37777063 PMCID: PMC11331723 DOI: 10.1016/j.jare.2023.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 08/23/2023] [Accepted: 09/26/2023] [Indexed: 10/02/2023] Open
Abstract
INTRODUCTION The stem cell microenvironment has been evidenced to robustly affect its biological functions and clinical grade. Natural or synthetic growth factors, especially, are essential for modulating stem cell proliferation, metabolism, and differentiation via the interaction with specific extracellular receptors. Fibroblast growth factor-2 (FGF-2) possesses pleiotropic functions in various tissues and organs. It interacts with the FGF receptor (FGFR) and activates FGFR signaling pathways, which involve numerous biological functions, such as angiogenesis, wound healing, cell proliferation, and differentiation. OBJECTIVES Here, we aim to explore the molecular functions, mode of action, and therapeutic activity of yet undetermined function, FGF-2-derived peptide, FP2 (44-ERGVVSIKGV-53) in promoting the proliferation, differentiation, and therapeutic application of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) in comparison to other test peptides, canofin1 (FP1), hexafin2 (FP3), and canofin3 (FP4) with known functions. METHODS The immobilization of test peptides that are fused with mussel adhesive proteins (MAP) on the culture plate was carried out via EDC/NHS chemistry. Cell Proliferation assay, colony-forming unit, western blotting analysis, gene expression analysis, RNA-Seq. analysis, osteogenic, and chondrogenic differentiation capacity were applied to test the activity of the test peptides. We additionally utilized three-dimensional (3D) structural analysis and artificial intelligence (AI)-based AlphaFold2 and CABS-dock programs for receptor interaction prediction of the peptide receptor. We also verified the in vivo therapeutic capacity of FP2-cultured hWJ-MSCs using an osteoarthritis mice model. RESULTS Culture of hWJ-MSC onto an FP2-immobilized culture plate showed a significant increase in cell proliferation (n = 3; *p < 0.05, **p < 0.01) and the colony-forming unit (n = 3; *p < 0.05, **p < 0.01) compared with the test peptides. FP2 showed a significantly upregulated phosphorylation of FRS2α and FGFR1 and activated the AKT and ERK signaling pathways (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). Interestingly, we detected efficient FP2 receptor binding that was predicted using AI-based tools. Treatment with an AKT inhibitor significantly abrogated the FP2-mediated enhancement of cell differentiation (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). Intra-articular injection of FP2-cultured MSCs significantly mitigated arthritis symptoms in an osteoarthritis mouse model, as shown through the functional tests (n = 10; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001), modulation of the expression level of the pro-inflammatory and anti-inflammatory genes, and improved osteochondral regeneration as demonstrated by tissue sections. CONCLUSION Our study identified the FGF-2-derived peptide FP2 as a promising candidate peptide to improve the therapeutic potential of hWJ-MSCs, especially in bone and cartilage regeneration.
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Affiliation(s)
- Soo Bin Lee
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Ahmed Abdal Dayem
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sebastian Kmiecik
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, 02-089 Warsaw, Poland
| | - Kyung Min Lim
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; R&D Team, StemExOne Co., Ltd., 307 KU Technology Innovation Bldg, 120, Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Dong Sik Seo
- Stem Cell Research Center of AMOLIFESCIENCE Co., Ltd, 91, Gimpo-daero 1950 Beon-gil, Tongjin-eup, Gimpo-si, Gyeonggi-do 10014, Republic of Korea
| | - Hyeong-Taek Kim
- Stem Cell Research Center of AMOLIFESCIENCE Co., Ltd, 91, Gimpo-daero 1950 Beon-gil, Tongjin-eup, Gimpo-si, Gyeonggi-do 10014, Republic of Korea
| | - Polash Kumar Biswas
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Minjae Do
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205 USA
| | - Deok-Ho Kim
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205 USA
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; R&D Team, StemExOne Co., Ltd., 307 KU Technology Innovation Bldg, 120, Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
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Lyu Z, Xin M, Oyston DR, Xue T, Kang H, Wang X, Wang Z, Li Q. Cause and consequence of heterogeneity in human mesenchymal stem cells: Challenges in clinical application. Pathol Res Pract 2024; 260:155354. [PMID: 38870711 DOI: 10.1016/j.prp.2024.155354] [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: 02/22/2024] [Revised: 04/25/2024] [Accepted: 05/14/2024] [Indexed: 06/15/2024]
Abstract
Human mesenchymal stem cells (hMSCs) are mesoderm-derived adult stem cells with self-proliferation capacity, pluripotent differentiation potency, and excellent histocompatibility. These advantages make hMSCs a promising tool in clinical application. However, the majority of clinical trials using hMSC therapy for diverse human diseases do not achieve expectations, despite the prospective pre-clinical outcomes in animal models. This is partly attributable to the intrinsic heterogeneity of hMSCs. In this review, the cause of heterogeneity in hMSCs is systematically discussed at multiple levels, including isolation methods, cultural conditions, donor-to-donor variation, tissue sources, intra-tissue subpopulations, etc. Additionally, the effect of hMSCs heterogeneity on the contrary role in tumor progression and immunomodulation is also discussed. The attempts to understand the cellular heterogeneity of hMSCs and its consequences are important in supporting and improving therapeutic strategies for hMSCs.
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Affiliation(s)
- Zhao Lyu
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Miaomiao Xin
- Assisted Reproductive Center, Women's & Children's Hospital of Northwest, Xi'an, Shaanxi, China; University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, Vodnany, Czech Republic
| | - Dale Reece Oyston
- Department of Evolution, Ecology and Behaviour, University of Liverpool, Liverpool, UK
| | - Tingyu Xue
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Hong Kang
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Xiangling Wang
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Zheng Wang
- Medical Center of Hematology, the Second Affiliated Hospital, Army Medical University, Chongqing, Sichuan, China.
| | - Qian Li
- Changsha Medical University, Changsha, Hunan, China.
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Shojaporian S, Mahmoudian-Sani MR, Khodadadi A, Dehcheshmeh MG, Amari A. Effect of Priming With Toll-Like Receptor 3 Agonist on Expression of Long Noncoding RNAs in Human Wharton Jelly Mesenchymal Stem Cells. EXP CLIN TRANSPLANT 2024; 22:551-558. [PMID: 39223813 DOI: 10.6002/ect.2024.0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
OBJECTIVES Mesenchymal stem cells are gaining attention in medicine because of their anti-inflammatory and immunosuppressive properties. Inflammatory conditions can modulate immune responses in mesenchymal stem cells.We investigated the expression of long noncoding RNAs (RMRP, MALT1, NKILA,THRIL, and Linc-MAF-4) in humanWharton jelly mesenchymal stem cells primed with polyinosinicpolycytidylic acid. MATERIALS AND METHODS Mesenchymal stem cells were isolated from human Wharton jelly by the explant method. To determine the stem nature of the cells, we performed a differentiation test on bone and fat cells. We used flow cytometry analysis to determine surface markers. Umbilical cord mesenchymal stem cells (1 × 105) were cultured in T75 culture flasks in Dulbecco's modified Eagle medium containing 10% fetal bovine serum. After cells reached approximately 80% confluency, cells were exposed to 50 µg/mL of polyinosinic-polycytidylic acid, a Toll-like receptor 3 ligand, for 24, 48, and 72 hours. The control group were cells not exposed to polyinosinic-polycytidylic acid. Real-time polymerase chain reaction evaluated RMRP, MALAT1, NKILA, THRIL, and Linc-MAF-4 long noncoding RNAs. RESULTS We observed significantly increased expression of NKILA inWharton jelly mesenchymal stem cells stimulated with polyinosinic-polycytidylic acid at 72 hours compared with expression level in the control group (P < .001). CONCLUSIONS Results indicated that a potential mechanism by which the Toll-like receptor 3 ligand improves immunosuppression of mesenchymal stem cells can be attributed to the regulatory role of long noncoding RNAs, possibly through increased expression of anti-inflammatory long noncoding RNAs such as NKILA.
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Affiliation(s)
- Samira Shojaporian
- >From the Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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12
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Park HS, Lee BC, Chae DH, Yu A, Park JH, Heo J, Han MH, Cho K, Lee JW, Jung JW, Dunbar CE, Oh MK, Yu KR. Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation. Stem Cell Res Ther 2024; 15:145. [PMID: 38764093 PMCID: PMC11103961 DOI: 10.1186/s13287-024-03731-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 04/10/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated. METHODS In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs. RESULTS Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs. CONCLUSION In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.
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Affiliation(s)
- Hyun Sung Park
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Byung-Chul Lee
- Department of Biological Sciences, Sookmyung Women's University, Seoul, Korea
- Research Institute of Women's Health, Sookmyung Women's University, Seoul, Korea
| | - Dong-Hoon Chae
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Aaron Yu
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Jae Han Park
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Jiyoung Heo
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Myoung Hee Han
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Keonwoo Cho
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Joong Won Lee
- Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Korea
| | - Ji-Won Jung
- Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Korea
| | - Cynthia E Dunbar
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Mi-Kyung Oh
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea.
| | - Kyung-Rok Yu
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea.
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13
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Jasim SA, Aziz DZ, Mustafa YF, Margiana R, Al-Alwany AA, Hjazi A, Alawadi A, Yumashev A, Alsalamy A, Fenjan MN. Role of genetically engineered mesenchymal stem cell exosomes and LncRNAs in respiratory diseases treatment. Pathol Res Pract 2024; 254:155135. [PMID: 38295461 DOI: 10.1016/j.prp.2024.155135] [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: 12/12/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
The term acute respiratory disease encompasses a wide range of acute lung diseases, which in recent years have been ranked among the top three deadly diseases in the world. Since conventional treatment methods, including the use of anti-inflammatory drugs, have had no significant effect on the treatment process of these diseases, the attention of the medical community has been drawn to alternative methods. Mesenchymal stem cells (MSC) are multipotential stem/progenitor cells that have extensive immunomodulatory and anti-inflammatory properties and also play a critical role in the microenvironment of injured tissue. MSC secretomes (containing large extracellular vesicles, microvesicles, and exosomes) are a newly introduced option for cell-free therapies that can circumvent the hurdles of cell-based therapies while maintaining the therapeutic role of MSC themselves. The therapeutic capabilities of MSCs have been showed in many acute respiratory diseases, including chronic respiratory disease (CRD), novel coronavirus 2019 (COVID -19), and pneumonia. MSCs offer novel therapeutic approaches for chronic and acute lung diseases due to their anti-inflammatory and immunomodulatory properties. In this review, we summarize the current evidence on the efficacy and safety of MSC-derived products in preclinical models of lung diseases and highlight the biologically active compounds present in the MSC secretome and their mechanisms involved in anti-inflammatory activity and tissue regeneration.
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Affiliation(s)
| | - Dhifaf Zeki Aziz
- College of Science, Department of pathological Analyses, University of Kufa, Al-Najaf, Iraq.
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq.
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | | | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Saudi Arabia.
| | - Ahmed Alawadi
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Babylon, Iraq
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Russia.
| | - Ali Alsalamy
- College of technical engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq.
| | - Mohammed N Fenjan
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq.
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14
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Namestnikova DD, Kovalenko DB, Pokusaeva IA, Chudakova DA, Gubskiy IL, Yarygin KN, Baklaushev VP. Mesenchymal stem cells in the treatment of ischemic stroke. КЛИНИЧЕСКАЯ ПРАКТИКА 2024; 14:49-64. [DOI: 10.17816/clinpract624157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2025] Open
Abstract
Over the past two decades, multiple preclinical studies have shown that transplantation of mesenchymal stem cells leads to a pronounced positive effect in animals with experimental stroke. Based on the promising results of preclinical studies, several clinical trials on the transplantation of mesenchymal stem cells to stroke patients have also been conducted. In this review, we present and analyze the results of completed clinical trials dedicated to the mesenchymal stem cells transplantation in patients with ischemic stroke. According to the obtained results, it can be concluded that transplantation of mesenchymal stem cells is safe and feasible from the economic and biomedical point of view. For the further implementa-tion of this promising approach into the clinical practice, randomized, placebo-controlled, multicenter clinical trials are needed with a large sample of patients and optimized cell transplantation protocols and patient inclusion criteria. In this review we also discuss possi-ble strategies to enhance the effectiveness of cell therapy with the use of mesenchymal stem cells.
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Affiliation(s)
- Daria D. Namestnikova
- Federal Center of Brain Research and Neurotechnologies
- Pirogov Russian National Research Medical University
| | | | | | | | - Ilya L. Gubskiy
- Federal Center of Brain Research and Neurotechnologies
- Pirogov Russian National Research Medical University
| | | | - Vladimir P. Baklaushev
- Federal Center of Brain Research and Neurotechnologies
- Pirogov Russian National Research Medical University
- Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency
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15
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Seyyedin S, Ezzatabadipour M, Nematollahi-Mahani SN. The Role of Various Factors in Neural Differentiation of Human Umbilical Cord Mesenchymal Stem Cells with a Special Focus on the Physical Stimulants. Curr Stem Cell Res Ther 2024; 19:166-177. [PMID: 36734908 DOI: 10.2174/1574888x18666230124151311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/05/2022] [Accepted: 11/25/2022] [Indexed: 02/04/2023]
Abstract
Human umbilical cord matrix-derived mesenchymal stem cells (hUCMs) are considered as ideal tools for cell therapy procedures and regenerative medicine. The capacity of these cells to differentiate into neural lineage cells make them potentially important in the treatment of various neurodegenerative diseases. An electronic search was performed in Web of Science, PubMed/MEDLINE, Scopus and Google Scholar databases for articles published from January 1990 to March 2022. This review discusses the current knowledge on the effect of various factors, including physical, chemical and biological stimuli which play a key role in the differentiation of hUCMs into neural and glial cells. Moreover, the currently understood molecular mechanisms involved in the neural differentiation of hUCMs under various environmental stimuli are reviewed. Various stimuli, especially physical stimuli and specifically different light sources, have revealed effects on neural differentiation of mesenchymal stem cells, including hUCMs; however, due to the lack of information about the exact mechanisms, there is still a need to find optimal conditions to promote the differentiation capacity of these cells which in turn can lead to significant progress in the clinical application of hUCMs for the treatment of neurological disorders.
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Affiliation(s)
- Sajad Seyyedin
- Department of Anatomical Sciences, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Massood Ezzatabadipour
- Department of Anatomical Sciences, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Seyed Noureddin Nematollahi-Mahani
- Department of Anatomical Sciences, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran
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16
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Yang RL, Chen SY, Fu SP, Zhao DZ, Wan WH, Yang K, Lei W, Yang Y, Zhang Q, Zhang T. Antioxidant mechanisms of mesenchymal stem cells and their therapeutic potential in vitiligo. Front Cell Dev Biol 2023; 11:1293101. [PMID: 38178870 PMCID: PMC10764575 DOI: 10.3389/fcell.2023.1293101] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 12/08/2023] [Indexed: 01/06/2024] Open
Abstract
Vitiligo is a skin pigmentation disorder caused by melanocyte damage or abnormal function. Reac-tive oxygen species Reactive oxygen species can cause oxidative stress damage to melanocytes, which in turn induces vitiligo. Traditional treatments such as phototherapy, drugs, and other methods of treatment are long and result in frequent recurrences. Currently, mesenchymal stem cells (MSCs) are widely used in the research of various disease treatments due to their excellent paracrine effects, making them a promising immunoregulatory and tissue repair strategy. Furthermore, an increasing body of evi-dence suggests that utilizing the paracrine functions of MSCs can downregulate oxidative stress in the testes, liver, kidneys, and other affected organs in animal models of certain diseases. Addition-ally, MSCs can help create a microenvironment that promotes tissue repair and regeneration in are-as with oxidative stress damage, improving the disordered state of the injured site. In this article, we review the pathogenesis of oxidative stress in vitiligo and promising strategies for its treatment.
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Affiliation(s)
- Rui-lin Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Si-yu Chen
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Sheng-ping Fu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - De-zhi Zhao
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wei-hong Wan
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Kang Yang
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wei Lei
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ying Yang
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qian Zhang
- Department of Human Anatomy, Zunyi Medical University, Zunyi, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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17
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Chauhan A, Agarwal S, Masih M, Gautam PK. The Multifunction Role of Tumor-Associated Mesenchymal Stem Cells and Their Interaction with Immune Cells in Breast Cancer. Immunol Invest 2023; 52:856-878. [PMID: 37615117 DOI: 10.1080/08820139.2023.2249025] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Mesenchymal stem cells (MSCs) are a heterogeneous group of progenitor cells that play a multifunctional role including tissue regeneration, self-renewal properties, and differentiate into cells of mesodermal lineage such as adipocytes, osteoblasts, and chondrocytes. MSCs come into contact with tumor microenvironment (TME) and differentiate into tumor-associated MSCs (TA-MSCs). Various substances such as chemokines, cytokines, growth factors, and others are released by tumor cells to recruit MSCs. TA-MSCs induced epithelial-mesenchymal transition (EMT) program which mediates tumor growth progression, migration, and invasion. Role of MSCs in the tumor progression, stemness, malignancy, and treatment resistance in the breast cancer TME. Immunomodulation by MSCs is mediated by a combination of cell contact-dependent mechanisms and soluble substances. Monocytes/macrophages, dendritic cells, T cells, B cells, and NK cells all show signs of MSCs' immunomodulatory capability. In a complicated interplay initiated by MSCs, anti-inflammatory monocytes/macrophages and regulatory T cells (Tregs) play a key role, as they unveil their full immunomodulatory potential. MSC- secreted cytokines are commonly blamed for the interaction between MSCs, monocytes, and Tregs. Here, we review the current knowledge of cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the role MSCs play in breast cancer progression and its TME.Abbreviation MSC: Mesenchymal Stem Cells; TME: Tumor Microenvironment; TAMS; Tumour-associated Macrophages; ECM: Extracellular matrix; CAFs: Cancer-associated Fibroblasts; CFUs: Colony-forming unit Fibroblasts; Tregs: T regulatory cells; Bregs; Regulatory B cells; IFN-γ: Interferon-gamma; TNF-α: Tumour Necrosis Factor-alpha; IL: Interleukin; TGF-β: transforming growth factorβ; PGE2: Prostaglandin E2; CXCR: Chemokine Receptor; Blimp-1; B lymphocyte-induced maturation protein-1; CCL: Chemokine motif ligand; EMT: Epithelial-mesenchymal transition.
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Affiliation(s)
- Anita Chauhan
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Sonam Agarwal
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Marilyn Masih
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Pramod Kumar Gautam
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
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18
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Tian X, Pan M, Zhou M, Tang Q, Chen M, Hong W, Zhao F, Liu K. Mitochondria Transplantation from Stem Cells for Mitigating Sarcopenia. Aging Dis 2023; 14:1700-1713. [PMID: 37196123 PMCID: PMC10529753 DOI: 10.14336/ad.2023.0210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 02/10/2023] [Indexed: 05/19/2023] Open
Abstract
Sarcopenia is defined as the age-related loss of muscle mass and function that can lead to prolonged hospital stays and decreased independence. It is a significant health and financial burden for individuals, families, and society as a whole. The accumulation of damaged mitochondria in skeletal muscle contributes to the degeneration of muscles with age. Currently, the treatment of sarcopenia is limited to improving nutrition and physical activity. Studying effective methods to alleviate and treat sarcopenia to improve the quality of life and lifespan of older people is a growing area of interest in geriatric medicine. Therapies targeting mitochondria and restoring mitochondrial function are promising treatment strategies. This article provides an overview of stem cell transplantation for sarcopenia, including the mitochondrial delivery pathway and the protective role of stem cells. It also highlights recent advances in preclinical and clinical research on sarcopenia and presents a new treatment method involving stem cell-derived mitochondrial transplantation, outlining its advantages and challenges.
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Affiliation(s)
- Xiulin Tian
- Department of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Mengxiong Pan
- Department of Neurology, First People’s Hospital of Huzhou, Huzhou, Zhejiang, China.
| | - Mengting Zhou
- Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Qiaomin Tang
- Department of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Miao Chen
- Department of Neurology, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, Zhejiang, China.
| | - Wenwu Hong
- Department of Neurology, Tiantai People’s Hospital of Zhejiang Province, Tiantai, Taizhou, Zhejiang, China.
| | - Fangling Zhao
- Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Kaiming Liu
- Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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19
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Heyman E, Meeremans M, Van Poucke M, Peelman L, Devriendt B, De Schauwer C. Validation of multiparametric panels for bovine mesenchymal stromal cell phenotyping. Cytometry A 2023; 103:744-755. [PMID: 37173856 DOI: 10.1002/cyto.a.24737] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 04/13/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023]
Abstract
Bovine mesenchymal stromal cells (MSCs) display important features that render them valuable for cell therapy and tissue engineering strategies, such as self-renewal, multi-lineage differentiation, as well as immunomodulatory properties. These cells are also promising candidates to produce cultured meat. For all these applications, it is imperative to unequivocally identify this cell population. The isolation and in vitro tri-lineage differentiation of bovine MSCs is already described, but data on their immunophenotypic characterization is not yet complete. The currently limited availability of monoclonal antibodies (mAbs) specific for bovine MSC markers strongly hampers this research. Following the minimal criteria defined for human MSCs, bovine MSCs should express CD73, CD90, and CD105 and lack expression of CD14 or CD11b, CD34, CD45, CD79α, or CD19, and MHC-II. Additional surface proteins which have been reported to be expressed include CD29, CD44, and CD106. In this study, we aimed to immunophenotype bovine adipose tissue (AT)-derived MSCs using multi-color flow cytometry. To this end, 13 commercial Abs were screened for recognizing bovine epitopes using the appropriate positive controls. Using flow cytometry and immunofluorescence microscopy, cross-reactivity was confirmed for CD34, CD73, CD79α, and CD90. Unfortunately, none of the evaluated CD105 and CD106 Abs cross-reacted with bovine cells. Subsequently, AT-derived bovine MSCs were characterized using multi-color flow cytometry based on their expression of nine markers. Bovine MSCs clearly expressed CD29 and CD44, and lacked expression of CD14, CD45, CD73, CD79α, and MHCII, while a variable expression was observed for CD34 and CD90. In addition, the mRNA transcription level of different markers was analyzed using reverse transcription quantitative polymerase chain reaction. Using these panels, bovine MSCs can be properly immunophenotyped which allows a better characterization of this heterogenous cell population.
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Affiliation(s)
- Emma Heyman
- Veterinary Stem Cell Research Unit, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - M Meeremans
- Veterinary Stem Cell Research Unit, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - M Van Poucke
- Laboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - L Peelman
- Laboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - B Devriendt
- Laboratory of Immunology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Catharina De Schauwer
- Veterinary Stem Cell Research Unit, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
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20
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Uzieliene I, Bialaglovyte P, Miksiunas R, Lebedis I, Pachaleva J, Vaiciuleviciute R, Ramanaviciene A, Kvederas G, Bernotiene E. Menstrual Blood-Derived Stem Cell Paracrine Factors Possess Stimulatory Effects on Chondrogenesis In Vitro and Diminish the Degradation of Articular Cartilage during Osteoarthritis. Bioengineering (Basel) 2023; 10:1001. [PMID: 37760103 PMCID: PMC10525204 DOI: 10.3390/bioengineering10091001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/16/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Articular cartilage is an avascular tissue with a limited capacity for self-regeneration, leading the tissue to osteoarthritis (OA). Mesenchymal stem cells (MSCs) are promising for cartilage tissue engineering, as they are capable of differentiating into chondrocyte-like cells and secreting a number of active molecules that are important for cartilage extracellular matrix (ECM) synthesis. The aim of this study was to evaluate the potential of easily accessible menstrual blood-derived MSC (MenSC) paracrine factors in stimulating bone marrow MSC (BMMSCs) chondrogenic differentiation and to investigate their role in protecting cartilage from degradation in vitro. MenSCs and BMMSCs chondrogenic differentiation was induced using four different growth factors: TGF-β3, activin A, BMP-2, and IGF-1. The chondrogenic differentiation of BMMSCs was stimulated in co-cultures with MenSCs and cartilage explants co-cultured with MenSCs for 21 days. The chondrogenic capacity of BMMSCs was analyzed by the secretion of four growth factors and cartilage oligomeric matrix protein, as well as the release and synthesis of cartilage ECM proteins, and chondrogenic gene expression in cartilage explants. Our results suggest that MenSCs stimulate chondrogenic response in BMMSCs by secreting activin A and TGF-β3 and may have protective effects on cartilage tissue ECM by decreasing the release of GAGs, most likely through the modulation of activin A related molecular pathway. In conclusion, paracrine factors secreted by MenSCs may turn out to be a promising therapeutical approach for cartilage tissue protection and repair.
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Affiliation(s)
- Ilona Uzieliene
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania; (P.B.); (R.M.); (I.L.); (J.P.); (R.V.); (E.B.)
| | - Paulina Bialaglovyte
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania; (P.B.); (R.M.); (I.L.); (J.P.); (R.V.); (E.B.)
| | - Rokas Miksiunas
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania; (P.B.); (R.M.); (I.L.); (J.P.); (R.V.); (E.B.)
| | - Ignas Lebedis
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania; (P.B.); (R.M.); (I.L.); (J.P.); (R.V.); (E.B.)
| | - Jolita Pachaleva
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania; (P.B.); (R.M.); (I.L.); (J.P.); (R.V.); (E.B.)
| | - Raminta Vaiciuleviciute
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania; (P.B.); (R.M.); (I.L.); (J.P.); (R.V.); (E.B.)
| | - Almira Ramanaviciene
- Department of Immunology, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania;
- NanoTechnas—Center on Nanotechnology and Materials Sciences, Faculty of Chemistry and Geosciences, Vilnius University, LT-03225 Vilnius, Lithuania
| | - Giedrius Kvederas
- The Clinic of Rheumatology, Traumatology Orthopaedics and Reconstructive Surgery, Institute of Clinical Medicine of the Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania;
| | - Eiva Bernotiene
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania; (P.B.); (R.M.); (I.L.); (J.P.); (R.V.); (E.B.)
- Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, VilniusTech, Vilnius Gediminas Technical University, 10223 Vilnius, Lithuania
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21
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Ahmadi F, Lotfi AS, Navaei-Nigjeh M, Kadivar M. Trimetazidine Preconditioning Potentiates the Effect of Mesenchymal Stem Cells Secretome on the Preservation of Rat Pancreatic Islet Survival and Function In Vitro. Appl Biochem Biotechnol 2023; 195:4796-4817. [PMID: 37184724 DOI: 10.1007/s12010-023-04532-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2023] [Indexed: 05/16/2023]
Abstract
Islet transplantation offers improved glycemic control in individuals with type 1 diabetes mellitus. However, in vitro islet culture is associated with islet apoptosis and eventually will lose their functionality prior to transplantation. In this study, we examined the effects of mesenchymal stem cells (MSCs) secretome preconditioned with diazoxide (DZ) and trimetazidine (TMZ) on rat islet cells during pre-transplant culture. With and without preconditioned hAD-MSCs' concentrated conditioned media (CCM) were added to the culture medium containing rat islets every 12 h for 24 and 48 h, after testing for selected cytokine concentrations (interleukin (IL)-4, IL-6, IL-13). Insulin content, glucose-stimulated insulin secretion, islet cell apoptosis, and mRNA expression of pro-apoptotic (BAX, BAK-1, and PUMA) and anti-apoptotic factors (BCL-2, BCL-xL, and XIAP) in rat islets were assessed after 24 and 48 h of culture. The protein level of IL-6 and IL-4 was significantly higher in TMZ-MSC-CM compared to MSC-non-CM. In rat isolated islets, normalized secreted insulin in the presence of 16.7 mM glucose was significantly higher in treated islet groups compared to control islets at both 24 and 48 h cultivation. Also, the percentage of apoptotic islet cells TMZ-MSC-CCM-treated islets was significantly lower compared to MSC-CM and MSC-CCM-treated islets in both 24 and 48 h cultivation. Consistent with the number of apoptotic cells, after 24 h culture, the expression of BCL-2 and BCL-xL genes in the control islets was lower than all treatment islet groups and in 48 h was lower than only TMZ-MSC-CM-treated islets. Also, the expression of the XIAP gene in control islets was significantly lower compared to the TMZ-MSC-CCM-treated islets at both at 24 and 48 h. In addition, mRNA level of the BAX gene in TMZ-MSC-CCM-treated islets was significantly lower compared to other groups at 48 h. Our findings revealed that TMZ proved to be more effective than DZ and could enhance the potential of hAD-MSCs-CM to improve the function and viability of islets prior to transplantation.
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Affiliation(s)
- Fariborz Ahmadi
- Department of Clinical Biochemistry, Tarbiat Modares University, Tehran, Iran
| | | | - Mona Navaei-Nigjeh
- Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mehdi Kadivar
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran.
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22
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Miura T, Kouno T, Takano M, Kuroda T, Yamamoto Y, Kusakawa S, Morioka MS, Sugawara T, Hirai T, Yasuda S, Sawada R, Matsuyama S, Kawaji H, Kasukawa T, Itoh M, Matsuyama A, Shin JW, Umezawa A, Kawai J, Sato Y. Single-Cell RNA-Seq Reveals LRRC75A-Expressing Cell Population Involved in VEGF Secretion of Multipotent Mesenchymal Stromal/Stem Cells Under Ischemia. Stem Cells Transl Med 2023; 12:379-390. [PMID: 37263619 PMCID: PMC10267575 DOI: 10.1093/stcltm/szad029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 04/15/2023] [Indexed: 06/03/2023] Open
Abstract
Human multipotent mesenchymal stromal/stem cells (MSCs) have been utilized in cell therapy for various diseases and their clinical applications are expected to increase in the future. However, the variation in MSC-based product quality due to the MSC heterogeneity has resulted in significant constraints in the clinical utility of MSCs. Therefore, we hypothesized that it might be important to identify and ensure/enrich suitable cell subpopulations for therapies using MSC-based products. In this study, we aimed to identify functional cell subpopulations to predict the efficacy of angiogenic therapy using bone marrow-derived MSCs (BM-MSCs). To assess its angiogenic potency, we observed various levels of vascular endothelial growth factor (VEGF) secretion among 11 donor-derived BM-MSC lines under in vitro ischemic culture conditions. Next, by clarifying the heterogeneity of BM-MSCs using single-cell RNA-sequencing analysis, we identified a functional cell subpopulation that contributed to the overall VEGF production in BM-MSC lines under ischemic conditions. We also found that leucine-rich repeat-containing 75A (LRRC75A) was more highly expressed in this cell subpopulation than in the others. Importantly, knockdown of LRRC75A using small interfering RNA resulted in significant inhibition of VEGF secretion in ischemic BM-MSCs, indicating that LRRC75A regulates VEGF secretion under ischemic conditions. Therefore, LRRC75A may be a useful biomarker to identify cell subpopulations that contribute to the angiogenic effects of BM-MSCs. Our work provides evidence that a strategy based on single-cell transcriptome profiles is effective for identifying functional cell subpopulations in heterogeneous MSC-based products.
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Affiliation(s)
- Takumi Miura
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Tsukasa Kouno
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Megumi Takano
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
| | - Takuya Kuroda
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
| | - Yumiko Yamamoto
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Shinji Kusakawa
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
| | | | - Tohru Sugawara
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan
- Biopharmaceutical and Regenerative Sciences, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
| | - Takamasa Hirai
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
| | - Satoshi Yasuda
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
| | - Rumi Sawada
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
| | - Satoko Matsuyama
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
- Center for Reverse TR, Osaka Habikino Medical Center, Osaka Prefectural Hospital Organization, Osaka, Japan
| | - Hideya Kawaji
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Research Center for Genome & Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Takeya Kasukawa
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Masayoshi Itoh
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Akifumi Matsuyama
- Center for Reverse TR, Osaka Habikino Medical Center, Osaka Prefectural Hospital Organization, Osaka, Japan
| | - Jay W Shin
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Genomic Institute of Singapore, Agency for Science, Technology and Research, Singapore
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Jun Kawai
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Life Science Technology Project, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Japan
| | - Yoji Sato
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kanagawa, Japan
- Life Science Technology Project, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Japan
- Department of Cellular and Gene Therapy Products, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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23
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Choi Y, Nam YH, Jeong S, Lee HY, Choi SY, Park S, Jung SC. Biochemical and functional characterization of skeletal muscle cells differentiated from tonsil-derived mesenchymal stem cells. Muscle Nerve 2023. [PMID: 37243484 DOI: 10.1002/mus.27847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 05/03/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023]
Abstract
INTRODUCTION/AIMS Human tonsils are a readily accessible source of stem cells for the potential treatment of skeletal muscle disorders. We reported previously that tonsil-derived mesenchymal stem cells (TMSCs) can differentiate into skeletal muscle cells (SKMCs), which renders TMSCs promising candidates for cell therapy for skeletal muscle disorders. However, the functional properties of the myocytes differentiated from mesenchymal stem cells have not been clearly evaluated. In this study we investigated whether myocytes differentiated from TMSCs (skeletal muscle cells derived from tonsil mesenchymal stem cells [TMSC-SKMCs]) exhibit the functional characteristics of SKMCs. METHODS To test the insulin reactivity of TMSC-SKMCs, the expression of glucose transporter 4 (GLUT4) and phosphatidylinositol 3-kinase/Akt was analyzed after the cells were treated for 30 minutes with 100 nmol/L insulin in normal or high-glucose medium. We also examined whether these cells formed a neuromuscular junction (NMJ) when cocultured with motor neurons, and whether they were stimulated by electrical signals using whole-cell patch clamping. RESULTS Skeletal muscle cells derived from tonsil mesenchymal stem cells expressed SKMC markers, such as MYOD, MYH3, MYH8, TNNI1, and TTN, at high levels, and exhibited a multinucleated cell morphology and a myotube-like shape. The expression of the acetylcholine receptor and GLUT4 was confirmed in TMSC-SKMCs. In addition, these cells exhibited insulin-mediated glucose uptake, NMJ formation, and transient changes in cell membrane action potential, all of which are representative functions of human SKMCs. DISCUSSION Tonsil-derived mesenchymal stem cells can be functionally differentiated into SKMCs and may have potential for clinical application for the treatment of skeletal muscle disorders.
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Affiliation(s)
- Yeonzi Choi
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul, Republic of Korea
| | - Yu Hwa Nam
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul, Republic of Korea
| | - Soyeon Jeong
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Hee-Yoon Lee
- Department of Physiology and Neuroscience, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Republic of Korea
| | - Se-Young Choi
- Department of Physiology and Neuroscience, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Republic of Korea
| | - Saeyoung Park
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Sung-Chul Jung
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul, Republic of Korea
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24
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Abuarqoub D, Adwan S, Zaza R, Wehaibi S, Aslam N, Jafar H, Qinnah N, Awidi A. Effective Generation of Functional Pancreatic β Cells from Human-Derived Dental Stem Cells of Apical Papilla and Bone-Marrow-Derived Stem Cells: A Comparative Study. Pharmaceuticals (Basel) 2023; 16:ph16050649. [PMID: 37242432 DOI: 10.3390/ph16050649] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 04/02/2023] [Accepted: 04/14/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetes Mellitus Type 1 is an autoimmune disease that occurs due to the destruction of insulin-producing cells (β cells), resulting in hyperglycemia. Therefore, diabetic patients depend on insulin treatment for the rest of their lives. Stem cells are considered a promising cellular therapy to replace the nonfunctional beta cells with functional and mature beta cells. Hence, in this study, we aimed to examine the potential of dental stem cells of apical papilla (SCAP) to differentiate into functional islet cell aggregates (ICAs), compared to the ICA generated from bone-marrow-derived stem cells (BM-MSCs). Our strategy was to induce the differentiation of SCAP and BM-MSCs into a definitive endoderm. The success of endodermal differentiation was determined by measuring the expression of definitive endodermal markers, FOXA2 and SOX-17, by flow cytometry. Next, the maturity and functionality of the differentiated cells were evaluated by measuring the amount of insulin and C-peptide secreted by the derived ICAs using ELISA. Additionally, the expression of mature beta cell markers-insulin, C-peptide, glucagon and PDX-1-was detected through confocal microscopy, while the staining of the mature islet-like clusters was detected by using diphenythiocarbazone (DTZ). Our results have shown that both SCAP and BM-MSCs were sequentially committed to a definitive pancreatic endoderm and β-cell-like cells by upregulating the expression of FOXA2 and SOX17 significantly (**** p < 0.0000 and *** p = 0.0001), respectively. Moreover, the identity of ICAs was confirmed by DTZ-positive staining, as well as by the expression of C-peptide, Pdx-1, insulin and glucagon at day 14. It was noted that at day 14, differentiated ICAs released insulin and C-peptides in a significant manner (* p < 0.01, *** p = 0.0001), respectively, exhibiting in vitro functionality. Our results demonstrated for the first time that SCAP could be differentiated into pancreatic cell lineage in a similar manner to BM-MSCs, suggesting a new unambiguous and nonconventional source of stem cells that could be used for stem cell therapy to treat diabetes.
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Affiliation(s)
- Duaa Abuarqoub
- Department of Pharmacology and Biomedical Sciences, University of Petra, Amman 11196, Jordan
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Sofia Adwan
- Department of Medical Laboratories, Faculty of Health Sciences, American University of Madaba, Madaba 11821, Jordan
| | - Rand Zaza
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Suha Wehaibi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Nazneen Aslam
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
- School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Nidal Qinnah
- Department of Pharmacology and Biomedical Sciences, University of Petra, Amman 11196, Jordan
- University of Petra Pharmaceutical Center (UPP), University of Petra, Amman 11196, Jordan
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
- School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Internal Medicine, Jordan University Hospital, Amman 11942, Jordan
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25
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Hong S, Zhu XY, Jiang Y, Zhang L, Tang H, Jordan KL, Saadiq IM, Huang W, Lerman A, Eirin A, Lerman LO. Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells. Stem Cell Rev Rep 2023; 19:700-712. [PMID: 36344721 PMCID: PMC10073252 DOI: 10.1007/s12015-022-10473-2] [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: 10/20/2022] [Indexed: 11/09/2022]
Abstract
Atherosclerotic renovascular disease (RVD) leads to hypertension, chronic kidney disease (CKD), and heart disease. Intrarenal delivery of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) attenuate renal injury and suppress release of inflammatory cytokines in porcine RVD. We hypothesized that this strategy would also be useful for cardioprotection. Pigs with renovascular hypertension and metabolic syndrome were studied 4 weeks after treatment with a single intrarenal infusion of autologous MSCs, EVs, or vehicle. Cardiac structure and function were assessed in vivo, and myocardial remodeling and expression of the pro-fibrotic factor growth factor receptor-bound protein-2 (Grb2) were measured ex-vivo. Inflammatory cytokine levels were measured in the systemic circulation and myocardial tissue. Blood pressure was elevated in all RVD groups, but serum creatinine increased in RVD and decreased in both RVD + MSCs and RVD + EVs. RVD-induced diastolic dysfunction (lower E/A ratio) was normalized in both MSCs- and EVs- treated pigs. Intrarenal delivery of MSCs and EVs also attenuated RVD-induced myocardial fibrosis, collagen deposition, and Grb2 expression, yet EVs restored capillary density and inflammation more effectively than MSCs. These observations suggest that autologous EVs attenuate cardiac injury in experimental RVD more effectively than their parent MSCs.
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Affiliation(s)
- Siting Hong
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Yamei Jiang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Lei Zhang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Kyra L Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Ishran M Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Weijun Huang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, 55905, USA
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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26
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Yan Y, Li K, Jiang J, Jiang L, Ma X, Ai F, Qiu S, Si W. Perinatal tissue-derived exosomes ameliorate colitis in mice by regulating the Foxp3 + Treg cells and gut microbiota. Stem Cell Res Ther 2023; 14:43. [PMID: 36941715 PMCID: PMC10029206 DOI: 10.1186/s13287-023-03263-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/06/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND The capacity of self-renewal and multipotent differentiation makes mesenchymal stem cells (MSC) one of the most widely investigated cell lines in preclinical studies as cell-based therapies. However, the low survival rate and poor homing efficiency of MSCs after transplantation hinder the therapeutic application. Exosomes derived from MSCs have shown promising therapeutic potential in many diseases. However, the heterogeneity of MSCs may lead to differences in the function of secreting exosomes. In this study, the therapeutic effects of hUC-Exos and hFP-Exos on the DSS-induced colitis mouse model were investigated. METHODS The colitis mouse models were randomly divided into four groups: (1) DSS administered for 7 days and euthanasia (DSS7D), (2) DSS administered for 7 days and kept for another 7 days without any treatment (DSS14D), (3) DSS administered for 7 days and followed with hUC-EVs infusion for 7 days (hUC-EVs) and (4) DSS administered for 7 days and followed with hFP-EVs infusion for 7 days (hFP-EVs). We analyzed colon length, histopathology, Treg cells, cytokines and gut microbiota composition in each group. RESULTS A large amount of IL-6, IL-17 and IFN-γ were produced along with the decrease in the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells in DSS7D group, which indicated that Th17 cells were activated and Treg cells were suppressed. We found that the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells increased in order to suppress inflammation, but the length of colon did not recover and the symotoms were worsened of the colonic tissue in DSS14D group. The subsequent infusion of either hUC-Exos or hFP-Exos mediated the transformation of Treg and Th17 cells in colitis mice to maintain immune balance. The infusion of hUC-Exos and hFP-Exos also both reduced the abundance of pro-inflammatory intestinal bacterial such as Verrucomicrobia and Akkermansia muciniphila to improve colitis. CONCLUSIONS We found that Foxp3 + Treg cells can inhibit the inflammatory response, and the over-activated Treg cells can still further damage the intestinal mucosa. hUC-Exos and hFP-Exos can control inflammation by regulating the balance between Th17 cells and Treg cells. Decreased inflammatory response improved the structure of colon wall in mice and reduced the abundance of pro-inflammatory bacteria in the intestine. The improvement of intestinal wall structure provides conditions for the reproduction of beneficial bacteria, which further contributes to the reduction of colitis.
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Affiliation(s)
- Yaping Yan
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Kaixiu Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Jiang Jiang
- Department of Obstetrics, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Lihong Jiang
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Yunnan Key Laboratory of Innovative Application of Traditional Chinese Medicine, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
| | - Xiang Ma
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Fang Ai
- Department of Obstetrics, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Shuai Qiu
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Wei Si
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
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27
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Lopes-Pacheco M, Rocco PRM. Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases. Front Pharmacol 2023; 14:1067422. [PMID: 37007034 PMCID: PMC10062457 DOI: 10.3389/fphar.2023.1067422] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.
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Affiliation(s)
- Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
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28
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Szydlak R. Mesenchymal stem cells in ischemic tissue regeneration. World J Stem Cells 2023; 15:16-30. [PMID: 36909782 PMCID: PMC9993139 DOI: 10.4252/wjsc.v15.i2.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/10/2022] [Accepted: 01/19/2023] [Indexed: 02/21/2023] Open
Abstract
Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells (MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and promote the regeneration of damaged tissues. This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases, described on the basis of data from in vitro experiments and preclinical animal studies, and also summarize the effects of using these cells in clinical trial settings. Since the obtained therapeutic benefits are not always satisfactory, approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.
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Affiliation(s)
- Renata Szydlak
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kraków 31-034, Poland
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29
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Zhang M, Zhang R, Chen H, Zhang X, Zhang Y, Liu H, Li C, Chen Y, Zeng Q, Huang G. Injectable Supramolecular Hybrid Hydrogel Delivers IL-1β-Stimulated Exosomes to Target Neuroinflammation. ACS APPLIED MATERIALS & INTERFACES 2023; 15:6486-6498. [PMID: 36716400 DOI: 10.1021/acsami.2c19997] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Long-term neuroinflammation is a major barrier to neurological recovery after cerebral ischemia-reperfusion injury (CIRI). Here, a thermosensitive injectable supramolecular hybrid hydrogel is developed to sustainably deliver exosomes derived from interleukin-1β-stimulated bone marrow stromal cells (BMSCs) (βExos) with improved exosome production and anti-inflammatory capacity for neuroinflammation inhibition and neurological recovery. The supramolecular hydrogel displays self-healing and injectable features, along with high biocompatibility and tissue-like softness. The βExos effectively reduce the lipopolysaccharide-induced inflammatory responses in the immortalized mouse microglia (BV2) cell line, and the in situ formed hydrogel improves the exosome retention in the ischemic core area. More remarkably, in the middle cerebral artery occlusion in vivo model, glial scar formation and neuronal loss are significantly reduced by regulating neuroinflammation using the released βExos. Therefore, the combination of interleukin-1β-stimulated exosomes with injectable supramolecular hydrogel provides an appealing strategy for treating central nervous system diseases.
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Affiliation(s)
- Meimei Zhang
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Runlin Zhang
- National Engineering Research Center for Tissue Restoration and Reconstruction, School of Materials Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510641, China
| | - Hui Chen
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Xiaofeng Zhang
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yilei Zhang
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
- Department of Neurorehabilitation Medicine, Xiangya Boai Rehabilitation Hospital, Changsha 410151, China
| | - Haining Liu
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Chen Li
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
- Department of Rehabilitation Medicine, Hunan Provincial People's Hospital, Hunan Normal University, Changsha 410016, China
| | - Yunhua Chen
- National Engineering Research Center for Tissue Restoration and Reconstruction, School of Materials Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510641, China
| | - Qing Zeng
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Guozhi Huang
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Rehabilitation Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
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30
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Zhang M, Xia T, Lin F, Yu J, Yang Y, Lei W, Zhang T. Vitiligo: An immune disease and its emerging mesenchymal stem cell therapy paradigm. Transpl Immunol 2023; 76:101766. [PMID: 36464219 DOI: 10.1016/j.trim.2022.101766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/31/2022] [Accepted: 11/28/2022] [Indexed: 12/02/2022]
Abstract
Melanocyte damage, innate immune response, adaptive immune response, and immune inflammatory microenvironment disorders are involved in the development of the immunological pathogenic mechanism of vitiligo. Mesenchymal stem cells are considered an ideal type of cells for the treatment of vitiligo owing to their low immunogenicity, lower rates of transplant rejection, and ability to secrete numerous growth factors, exosomes, and cytokines in vivo. The regulation of signaling pathways related to oxidative stress and immune imbalance in the immunological pathogenesis of vitiligo can improve the immune microenvironment of tissue injury sites. In addition, co-transplantation with melanocytes can reverse the progression of vitiligo. Therefore, continuous in-depth research on the immunopathogenic mechanism involved in this disease and mesenchymal stem cell-based therapy is warranted for the treatment of vitiligo in the future.
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Affiliation(s)
- Meng Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Tingting Xia
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Fengqin Lin
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Jiang Yu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China; The Clinical Stem Cell Research Institute, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Ying Yang
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Wei Lei
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China; The Clinical Stem Cell Research Institute, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China; Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
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31
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Siddiqi S, Klomjit N, Jiang K, Conley SM, Zhu X, Saadiq IM, Ferguson CM, Tang H, Lerman A, Lerman LO. Efficacy of Human Embryonic Stem Cells Compared to Adipose Tissue-Derived Human Mesenchymal Stem/Stromal Cells for Repair of Murine Post-Stenotic Kidneys. Stem Cell Rev Rep 2023; 19:491-502. [PMID: 36048327 PMCID: PMC9905277 DOI: 10.1007/s12015-022-10443-8] [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: 08/08/2022] [Indexed: 02/07/2023]
Abstract
Clinical translation of mesenchymal stem/stromal cell (MSC) therapy has been impeded by the heterogenous nature and limited replicative potential of adult-derived MSCs. Human embryonic stem cell-derived MSCs (hESC-MSCs) that differentiate from immortal cell lines are phenotypically uniform and have shown promise in-vitro and in many disease models. Similarly, adipose tissue-derived MSCs (MSC(AT)) possess potent reparative properties. How these two cell types compare in efficacy, however, remains unknown. We randomly assigned mice to six groups (n = 7-8 each) that underwent unilateral RAS or a sham procedure (3 groups each). Two weeks post-operation, each mouse was administered either vehicle, MSC(AT)s, or hESC-MSCs (5 × 105 cells) into the aorta. Mice were scanned with micro-MRI to determine renal hemodynamics two weeks later and kidneys then harvested. hESC-MSCs and MSC(AT)s were similarly effective at lowering systolic blood pressure. However, MSC(AT)s more robustly increased renal perfusion, oxygenation, and glomerular filtration rate in the post-stenotic kidney, and more effectively mitigated tubular injury, fibrosis, and vascular remodeling. These observations suggest that MSC(AT) are more effective than hESC-MSC in ameliorating kidney dysfunction and tissue injury distal to RAS. Our findings highlight the importance of tissue source in selection of MSCs for therapeutic purposes and underscore the utility of cell-based therapy for kidney disease.
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Affiliation(s)
- Sarosh Siddiqi
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
| | - Nattawat Klomjit
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN, USA
| | - Kai Jiang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
| | - Sabena M Conley
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
| | - Xianyang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
| | - Ishran M Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
| | - Christopher M Ferguson
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA.
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Ganguly A, Swaminathan G, Garcia-Marques F, Regmi S, Yarani R, Primavera R, Chetty S, Bermudez A, Pitteri SJ, Thakor AS. Integrated transcriptome-proteome analyses of human stem cells reveal source-dependent differences in their regenerative signature. Stem Cell Reports 2023; 18:190-204. [PMID: 36493779 PMCID: PMC9860079 DOI: 10.1016/j.stemcr.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are gaining increasing prominence as an effective regenerative cellular therapy. However, ensuring consistent and reliable effects across clinical populations has proved to be challenging. In part, this can be attributed to heterogeneity in the intrinsic molecular and regenerative signature of MSCs, which is dependent on their source of origin. The present work uses integrated omics-based profiling, at different functional levels, to compare the anti-inflammatory, immunomodulatory, and angiogenic properties between MSCs from neonatal (umbilical cord MSC [UC-MSC]) and adult (adipose tissue MSC [AD-MSC], and bone marrow MSC [BM-MSC]) sources. Using multi-parametric analyses, we identified that UC-MSCs promote a more robust host innate immune response; in contrast, adult-MSCs appear to facilitate remodeling of the extracellular matrix (ECM) with stronger activation of angiogenic cascades. These data should help facilitate the standardization of source-specific MSCs, such that their regenerative signatures can be confidently used to target specific disease processes.
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Affiliation(s)
- Abantika Ganguly
- Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA 94304, USA
| | - Ganesh Swaminathan
- Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA 94304, USA
| | - Fernando Garcia-Marques
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Shobha Regmi
- Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA 94304, USA
| | - Reza Yarani
- Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA 94304, USA
| | - Rosita Primavera
- Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA 94304, USA
| | - Shashank Chetty
- Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA 94304, USA
| | - Abel Bermudez
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Sharon J Pitteri
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Avnesh S Thakor
- Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA 94304, USA.
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Johnson CS, Cook LM. Osteoid cell-derived chemokines drive bone-metastatic prostate cancer. Front Oncol 2023; 13:1100585. [PMID: 37025604 PMCID: PMC10070788 DOI: 10.3389/fonc.2023.1100585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 03/07/2023] [Indexed: 04/08/2023] Open
Abstract
One of the greatest challenges in improving prostate cancer (PCa) survival is in designing new therapies to effectively target bone metastases. PCa regulation of the bone environment has been well characterized; however, bone-targeted therapies have little impact on patient survival, demonstrating a need for understanding the complexities of the tumor-bone environment. Many factors contribute to creating a favorable microenvironment for prostate tumors in bone, including cell signaling proteins produced by osteoid cells. Specifically, there has been extensive evidence from both past and recent studies that emphasize the importance of chemokine signaling in promoting PCa progression in the bone environment. Chemokine-focused strategies present promising therapeutic options for treating bone metastasis. These signaling pathways are complex, with many being produced by (and exerting effects on) a plethora of different cell types, including stromal and tumor cells of the prostate tumor-bone microenvironment. This review highlights an underappreciated molecular family that should be interrogated for treatment of bone metastatic prostate cancer (BM-PCa).
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Affiliation(s)
- Catherine S. Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
- Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, United States
| | - Leah M. Cook
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
- *Correspondence: Leah M. Cook,
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Zhang Y, Lv P, Li Y, Zhang Y, Cheng C, Hao H, Yue H. Inflammatory Cytokine Interleukin-6 (IL-6) Promotes the Proangiogenic Ability of Adipose Stem Cells from Obese Subjects via the IL-6 Signaling Pathway. Curr Stem Cell Res Ther 2023; 18:93-104. [PMID: 36883256 DOI: 10.2174/1574888x17666220429103935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/05/2022] [Accepted: 03/01/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND The prevalence of obesity, as well as obesity-induced chronic inflammatory diseases, is increasing worldwide. Chronic inflammation is related to the complex process of angiogenesis, and we found that adipose-derived stem cells from obese subjects (obADSCs) had proangiogenic features, including higher expression levels of interleukin-6 (IL-6), Notch ligands and receptors, and proangiogenic cytokines, than those from control subjects. We hypothesized that IL-6 and Notch signaling pathways are essential for regulating the proangiogenic characteristics of obADSCs. OBJECTIVE This study aimed to investigate whether the inflammatory cytokine interleukin 6 (IL-6) promotes the proangiogenic capacity of adipose stem cells in obese subjects via the IL-6 signaling pathway. METHODS We compared the phenotype analysis as well as cell doubling time, proliferation, migration, differentiation, and proangiogenic properties of ADSCs in vitro. Moreover, we used small interfering RNAs to inhibit the gene and protein expression of IL-6. RESULTS We found that ADSCs isolated from control individuals (chADSCs) and obADSCs had similar phenotypes and growth characteristics, and chADSCs had a stronger differentiation ability than obADSCs. However, obADSCs were more potent in promoting EA.hy926 cell migration and tube formation than chADSCs in vitro. We confirmed that IL-6 siRNA significantly reduced the transcriptional level of IL-6 in obADSCs, thereby reducing the expression of vascular endothelial growth factor (VEGF)- A, VEGF receptor 2, transforming growth factor β, and Notch ligands and receptors in obADSCs. CONCLUSION The finding suggests that inflammatory cytokine interleukin-6 (IL-6) promotes the proangiogenic ability of obADSCs via the IL-6 signaling pathway.
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Affiliation(s)
- Yuanyuan Zhang
- Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, 450007, China
| | - Pengju Lv
- Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, 450007, China
| | - Yalong Li
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
| | - Yonghui Zhang
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
| | - Chaofei Cheng
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
| | - Hongbo Hao
- Neuroscience Initiative, Advanced Science Research Center at the Graduate Center, City University of New York, New York, 10031, USA
| | - Han Yue
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
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Potential Therapeutic Strategies for Skeletal Muscle Atrophy. Antioxidants (Basel) 2022; 12:antiox12010044. [PMID: 36670909 PMCID: PMC9854691 DOI: 10.3390/antiox12010044] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/13/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The maintenance of muscle homeostasis is vital for life and health. Skeletal muscle atrophy not only seriously reduces people's quality of life and increases morbidity and mortality, but also causes a huge socioeconomic burden. To date, no effective treatment has been developed for skeletal muscle atrophy owing to an incomplete understanding of its molecular mechanisms. Exercise therapy is the most effective treatment for skeletal muscle atrophy. Unfortunately, it is not suitable for all patients, such as fractured patients and bedridden patients with nerve damage. Therefore, understanding the molecular mechanism of skeletal muscle atrophy is crucial for developing new therapies for skeletal muscle atrophy. In this review, PubMed was systematically screened for articles that appeared in the past 5 years about potential therapeutic strategies for skeletal muscle atrophy. Herein, we summarize the roles of inflammation, oxidative stress, ubiquitin-proteasome system, autophagic-lysosomal pathway, caspases, and calpains in skeletal muscle atrophy and systematically expound the potential drug targets and therapeutic progress against skeletal muscle atrophy. This review focuses on current treatments and strategies for skeletal muscle atrophy, including drug treatment (active substances of traditional Chinese medicine, chemical drugs, antioxidants, enzyme and enzyme inhibitors, hormone drugs, etc.), gene therapy, stem cell and exosome therapy (muscle-derived stem cells, non-myogenic stem cells, and exosomes), cytokine therapy, physical therapy (electroacupuncture, electrical stimulation, optogenetic technology, heat therapy, and low-level laser therapy), nutrition support (protein, essential amino acids, creatine, β-hydroxy-β-methylbutyrate, and vitamin D), and other therapies (biomaterial adjuvant therapy, intestinal microbial regulation, and oxygen supplementation). Considering many treatments have been developed for skeletal muscle atrophy, we propose a combination of proper treatments for individual needs, which may yield better treatment outcomes.
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36
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Niebergall-Roth E, Frank NY, Ganss C, Frank MH, Kluth MA. Skin-Derived ABCB5 + Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine. Int J Mol Sci 2022; 24:66. [PMID: 36613507 PMCID: PMC9820160 DOI: 10.3390/ijms24010066] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
The ATP-binding cassette superfamily member ABCB5 identifies a subset of skin-resident mesenchymal stem cells (MSCs) that exhibit potent immunomodulatory and wound healing-promoting capacities along with superior homing ability. The ABCB5+ MSCs can be easily accessed from discarded skin samples, expanded, and delivered as a highly homogenous medicinal product with standardized potency. A range of preclinical studies has suggested therapeutic efficacy of ABCB5+ MSCs in a variety of currently uncurable skin and non-skin inflammatory diseases, which has been substantiated thus far by distinct clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. Therefore, skin-derived ABCB5+ MSCs have the potential to provide a breakthrough at the forefront of MSC-based therapies striving to fulfill current unmet medical needs. The most recent milestones in this regard are the approval of a phase III pivotal trial of ABCB5+ MSCs for treatment of recessive dystrophic and junctional epidermolysis bullosa by the US Food and Drug Administration, and national market access of ABCB5+ MSCs (AMESANAR®) for therapy-refractory chronic venous ulcers under the national hospital exemption pathway in Germany.
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Affiliation(s)
| | - Natasha Y. Frank
- Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Christoph Ganss
- TICEBA GmbH, 69120 Heidelberg, Germany
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
| | - Markus H. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- School of Medical and Health Sciences, Edith Cowan University, Perth 6027, Australia
| | - Mark A. Kluth
- TICEBA GmbH, 69120 Heidelberg, Germany
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
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37
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MSC-EV therapy for bone/cartilage diseases. Bone Rep 2022; 17:101636. [DOI: 10.1016/j.bonr.2022.101636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022] Open
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38
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Formulation of secretome derived from mesenchymal stem cells for inflammatory skin diseases. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2022. [DOI: 10.1007/s40005-022-00599-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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39
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
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40
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Improved osteogenic differentiation by extremely low electromagnetic field exposure: possible application for bone engineering. Histochem Cell Biol 2022; 158:369-381. [PMID: 35751679 PMCID: PMC9512759 DOI: 10.1007/s00418-022-02126-9] [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] [Accepted: 06/06/2022] [Indexed: 11/21/2022]
Abstract
Human periodontal ligament mesenchymal stem cells (hPDLSCs) are a promising cell type model for regenerative medicine applications due to their anti-inflammatory, immunomodulatory and non-tumorigenic potentials. Extremely low-frequency electromagnetic fields (ELF-EMF) are reported to affect biological properties such as cell proliferation and differentiation and modulate gene expression profile. In this study, we investigated the effects of an intermittent ELF-EMF exposure (6 h/day) for the standard differentiation period (28 days) and for 10 days in hPDLSCs in the presence or not of osteogenic differentiation medium (OM). We evaluated cell proliferation, de novo calcium deposition and osteogenic differentiation marker expression in sham and ELF-EMF-exposed cells. After ELF-EMF exposure, compared with sham-exposed, an increase in cell proliferation rate (p < 0.001) and de novo calcium deposition (p < 0.001) was observed after 10 days of exposure. Real-time PCR and Western blot results showed that COL1A1 and RUNX-2 gene expression and COL1A1, RUNX-2 and OPN protein expression were upregulated respectively in the cells exposed to ELF-EMF exposure along with or without OM for 10 days. Altogether, these results suggested that the promotion of osteogenic differentiation is more efficient in ELF-EMF-exposed hPDLSCs. Moreover, our analyses indicated that there is an early induction of hPDLSC differentiation after ELF-EMF application.
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Soares MBP, Gonçalves RGJ, Vasques JF, da Silva-Junior AJ, Gubert F, Santos GC, de Santana TA, Almeida Sampaio GL, Silva DN, Dominici M, Mendez-Otero R. Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases. Front Mol Neurosci 2022; 15:883378. [PMID: 35782379 PMCID: PMC9244712 DOI: 10.3389/fnmol.2022.883378] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/19/2022] [Indexed: 11/13/2022] Open
Abstract
Neurological disorders include a wide spectrum of clinical conditions affecting the central and peripheral nervous systems. For these conditions, which affect hundreds of millions of people worldwide, generally limited or no treatments are available, and cell-based therapies have been intensively investigated in preclinical and clinical studies. Among the available cell types, mesenchymal stem/stromal cells (MSCs) have been widely studied but as yet no cell-based treatment exists for neurological disease. We review current knowledge of the therapeutic potential of MSC-based therapies for neurological diseases, as well as possible mechanisms of action that may be explored to hasten the development of new and effective treatments. We also discuss the challenges for culture conditions, quality control, and the development of potency tests, aiming to generate more efficient cell therapy products for neurological disorders.
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Affiliation(s)
- Milena B. P. Soares
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | - Renata G. J. Gonçalves
- Laboratório de Neurobiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Saúde no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Juliana F. Vasques
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Almir J. da Silva-Junior
- Laboratório de Neurobiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Nanotecnologia no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Gubert
- Programa Redes de Pesquisa em Saúde no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Girlaine Café Santos
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | - Thaís Alves de Santana
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | - Gabriela Louise Almeida Sampaio
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | | | - Massimo Dominici
- Laboratory of Cellular Therapy, Division of Oncology, University of Modena and Reggio Emilia (UNIMORE), Modena, Italy
| | - Rosalia Mendez-Otero
- Laboratório de Neurobiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Saúde no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Nanotecnologia no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
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Haghshenas MR, Erfani N, Khansalar S, Khademi B, Ashraf MJ, Razmkhah M, Ghaderi A. Proteomics Study of Mesenchymal Stem Cell-Like Cells Obtained from Tumor Microenvironment of Patients with Malignant and Benign Salivary Gland Tumors. CELL JOURNAL 2022; 24:196-203. [PMID: 35674025 PMCID: PMC9124444 DOI: 10.22074/cellj.2022.7844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/13/2021] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Salivary gland tumors (SGTs) show some aggressive and peculiar clinicopathological behaviors that might be related to the components of the tumor microenvironment, especially mesenchymal stem cells (MSCs)-associated proteins. However, the role of MSCs-related proteins in SGTs tumorigenesis is poorly understood. This study aimed to isolate and characterize MSCs from malignant and benign tumor tissues and to identify differentially expressed proteins between these two types of MSCs. MATERIALS AND METHODS In this experimental study, MSC-like cells derived from benign (pleomorphic adenoma, n=5) and malignant (mucoepidermoid carcinoma, n=5) tumor tissues were verified by fluorochrome antibodies and flow cytometric analysis. Differentially expressed proteins were identified using two-dimensional polyacrylamide gel electrophoresis (2DE) and Mass spectrometry. RESULTS Results showed that isolated cells strongly expressed characteristic MSCs markers such as CD44, CD73, CD90, CD105, and CD166, but they did not express or weakly expressed CD14, CD34, CD45 markers. Furthermore, the expression of CD24 and CD133 was absent or near absent in both isolated cells. Results also discovered overexpression of Annexin A4 (Anxa4), elongation factor 1-delta (EF1-D), FK506 binding protein 9 (FKBP9), cytosolic platelet-activating factor acetylhydrolase type IB subunit beta (PAFAH1B), type II transglutaminase (TG2), and s-formylglutathione hydrolase (FGH) in MSCs isolated from the malignant tissues. Additionally, heat shock protein 70 (Hsp70), as well as keratin, type II cytoskeletal 7 (CK-7), were found to be overexpressed in MSCs derived from the benign ones. CONCLUSION Malignant and benign SGTs probably exhibit a distinct pattern of tissue proteins that are most likely related to the metabolic pathway. However, further studies in a large number of patients are required to determine the applicability of identified proteins as new targets for cancer therapy.
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Affiliation(s)
- Mohammad Reza Haghshenas
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasrollah Erfani
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soolmaz Khansalar
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bijan Khademi
- Otolaryngology Research Center, Department of Otolaryngology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Javad Ashraf
- Department of Pathology, Khalili Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Jin W, He Y, Li T, Long F, Qin X, Yuan Y, Gao G, Shakhawat HM, Liu X, Jin G, Zhou Z. Rapid and robust derivation of mesenchymal stem cells from human pluripotent stem cells via temporal induction of neuralized ectoderm. Cell Biosci 2022; 12:31. [PMID: 35292115 PMCID: PMC8922747 DOI: 10.1186/s13578-022-00753-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/31/2022] [Indexed: 11/10/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) are emerging as the mainstay of regenerative medicine because of their ability to differentiate into multiple cell lineages. The infinite proliferative potential of human pluripotent stem cells (PSCs) grants an unlimited supply of MSCs. Despite their great potential in therapeutic applications, several drawbacks have hindered its clinical translation, including limited number of replication, compromised potential and altered function in late passages. The aim of this study is to establish an efficient method for the production of MSCs from pluripotent stem cells for potential clinical application in rare human disease Hutchinson-Gilford progeria syndrome. Results We established a robust method allowing rapid derivation of MSCs from both human iPSCs and ESCs via a temporal induction of neural ectoderm in chemically defined media. The iPSC- and ESC-derived MSCs satisfy the standard criteria of surface markers. They exhibited a high tri-lineage differentiation potential with over 90% transcriptional similarity to the primary MSCs derived from bone marrow. To evaluate the potential application of this method in disease modeling, MSCs were generated from iPSCs derived from a patient with Hutchinson-Gilford progeria syndrome (HGPS-MSCs) and from mutation-rectified HGPS-iPSCs (cHGPS-MSCs). HGPS-MSCs manifested accelerated senescence whereas mutation rectification rescued cellular senescence in HGPS-MSCs. Conclusions The robust method of MSC derivation from ESCs and iPSCs provides an efficient approach to rapidly generate sufficient MSCs for in vitro disease modeling and clinical applications. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00753-2.
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Affiliation(s)
- Wei Jin
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,Chinese Academy of Sciences Regenerative Medicine of Hong Kong, Hong Kong, China
| | - Yi He
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tuo Li
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,Department of Endocrinology, Chang Zheng Hospital, Shanghai, 200003, China
| | - Fei Long
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xin Qin
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuan Yuan
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute for Aging Research, Guangdong Medical University, Dongguan, China
| | - Ge Gao
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hosen Md Shakhawat
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xinguang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute for Aging Research, Guangdong Medical University, Dongguan, China
| | - Guoxiang Jin
- Medical Research Center, Guangdong Provincial People's Hospital, Guangzhou, China.
| | - Zhongjun Zhou
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. .,Shenzhen Hospital, The University of Hong Kong, Shenzhen, China.
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Mesenchymal Stromal Cells (MSCs) Isolated from Various Tissues of the Human Arthritic Knee Joint Possess Similar Multipotent Differentiation Potential. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12042239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
(1) Background: The mesenchymal stromal cells (MSCs) of different tissue origins are applied in cell-based chondrogenic regeneration. However, there is a lack of comparability determining the most suitable cell source for the tissue engineering (TE) of cartilage. The purpose of this study was to compare the in vitro chondrogenic potential of MSC-like cells from different tissue sources (bone marrow, meniscus, anterior cruciate ligament, synovial membrane, and the infrapatellar fat pad removed during total knee arthroplasty (TKA)) and define which cell source is best suited for cartilage regeneration. (2) Methods: MSC-like cells were isolated from five donors and expanded using adherent monolayer cultures. Differentiation was induced by culture media containing specific growth factors. Transforming growth factor (TGF)-ß1 was used as the growth factor for chondrogenic differentiation. Osteogenesis and adipogenesis were induced in monolayer cultures for 27 days, while pellet cell cultures were used for chondrogenesis for 21 days. Control cultures were maintained under the same conditions. After, the differentiation period samples were analyzed, using histological and immunohistochemical staining, as well as molecularbiological analysis by RT-PCR, to assess the expression of specific marker genes. (3) Results: Plastic-adherent growth and in vitro trilineage differentiation capacity of all isolated cells were proven. Flow cytometry revealed the clear co-expression of surface markers CD44, CD73, CD90, and CD105 on all isolated cells. Adipogenesis was validated through the formation of lipid droplets, while osteogenesis was proven by the formation of calcium deposits within differentiated cell cultures. The formation of proteoglycans was observed during chondrogenesis in pellet cultures, with immunohistochemical staining revealing an increased relative gene expression of collagen type II. RT-PCR proved an elevated expression of specific marker genes after successful differentiation, with no significant differences regarding different cell source of native tissue. (4) Conclusions: Irrespective of the cell source of native tissue, all MSC-like cells showed multipotent differentiation potential in vitro. The multipotent differentiation capacity did not differ significantly, and chondrogenic differentiation was proven in all pellet cultures. Therefore, cell suitability for cell-based cartilage therapies and tissue engineering is given for various tissue origins that are routinely removed during total knee arthroplasty (TKA). This study might provide essential information for the clinical tool of cell harvesting, leading to more flexibility in cell availability.
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Al-Obaide M, Ishmakej A, Brown C, Mazzella M, Agosta P, Perez-Cruet M, Chaudhry GR. The potential role of integrin alpha 6 in human mesenchymal stem cells. Front Genet 2022; 13:968228. [PMID: 36212156 PMCID: PMC9535380 DOI: 10.3389/fgene.2022.968228] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Human mesenchymal stem cells (MSCs) are isolated from various adult and perinatal tissues. Although mesenchymal stem cells from multiple sources exhibit similar morphology and cell surface markers, they differ in their properties. In this study, we determined that the expression of integrin alpha 6 (ITGA6) and ITGA6 antisense RNA (ITGA6-AS1) correlates with the proliferation, cell size, and differentiation potential. The expression of ITGA6 was inversely correlated with ITGA6-AS1 in MSCs. The expression of ITGA6 was higher, but ITGA6-AS1 was lower in MSCs from cord placenta junction, cord tissue, and Wharton's jelly. In contrast, ITGA6 expression was lower, while ITGA6-AS1 was higher in MSCs from the placenta. The bioinformatic analysis showed that ITGA6 genomic DNA transcribes ITGA6-AS1 from the reverse strand, overlapping ITGA6 exon-2. Additionally, we identify several putative promoters (P1-P10) of ITGA6. ITGA6-P10 is CG rich and contains CGI. EMBOSS Cpgplot software revealed a CGI length of 180 bp that extends from nucleotide 125 to 304 of the P10 sequence. We suggest that the post-transcriptional regulation of the ITGA6 in mesenchymal stem cells is controlled by the ITGA6-AS1, which could be a critical factor responsible for the heterogeneity in function and cell fate of human MSCs. These results may provide further impetus for investigations to unravel the mechanisms of ITGA6 regulation that could help maintain or improve the properties of mesenchymal stem cells.
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Affiliation(s)
- Mohammed Al-Obaide
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Albi Ishmakej
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Christina Brown
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Matteo Mazzella
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Patrina Agosta
- Ascension Providence Hospital, Southfield, MI, United States
| | - Mick Perez-Cruet
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States.,Department of Neurosurgery, Beaumont Health, Royal Oak, MI, United States
| | - G Rasul Chaudhry
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
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Soltanyzadeh M, Khorsand B, Baneh AA, Houri H. Clarifying differences in gene expression profile of umbilical cord vein and bone marrow-derived mesenchymal stem cells; a comparative in silico study. INFORMATICS IN MEDICINE UNLOCKED 2022. [DOI: 10.1016/j.imu.2022.101072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
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47
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Hu X, Xia Z, Cai K. Recent advances of 3D hydrogel culture systems for mesenchymal stem cell-based therapy and cell behavior regulation. J Mater Chem B 2022; 10:1486-1507. [DOI: 10.1039/d1tb02537f] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Mesenchymal stem cells (MSCs) have been increasingly recognized as resources for disease treatments and regenerative medicine. Meanwhile, the unique chemical and physical properties of hydrogels provide innate advantages to achieve...
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Chen JM, Huang QY, Zhao YX, Chen WH, Lin S, Shi QY. The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous. Front Immunol 2021; 12:785717. [PMID: 34868069 PMCID: PMC8634714 DOI: 10.3389/fimmu.2021.785717] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs.
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Affiliation(s)
- Jia-Ming Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Qiao-Yi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yun-Xia Zhao
- Department of Gynaecology and Obstetrics, Shenzhen Hospital of University of Hong Kong, Shenzhen, China
| | - Wei-Hong Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.,Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Qi-Yang Shi
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Alshareef GH, Mohammed AE, Abumaree M, Basmaeil YS. Phenotypic and Functional Responses of Human Decidua Basalis Mesenchymal Stem/Stromal Cells to Lipopolysaccharide of Gram-Negative Bacteria. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2021; 14:51-69. [PMID: 34754198 PMCID: PMC8572118 DOI: 10.2147/sccaa.s332952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/11/2021] [Indexed: 12/24/2022]
Abstract
Introduction Human decidua basalis mesenchymal stem cells (DBMSCs) are potential therapeutics for the medication to cure inflammatory diseases, like atherosclerosis. The current study investigates the capacity of DBMSCs to stay alive and function in a harmful inflammatory environment induced by high levels of lipopolysaccharide (LPS). Methods DBMSCs were exposed to different levels of LPS, and their viability and functional responses (proliferation, adhesion, and migration) were examined. Furthermore, DBMSCs’ expression of 84 genes associated with their functional activities in the presence of LPS was investigated. Results Results indicated that LPS had no significant effect on DBMSCs’ adhesion, migration, and proliferation (24 h and 72 h) (p > 0.05). However, DBMSCs’ proliferation was significantly reduced at 10 µg/mL of LPS at 48 h (p < 0.05). In addition, inflammatory cytokines and receptors related to adhesion, proliferation, migration, and differentiation were significantly overexpressed when DBMSCs were treated with 10 µg/mL of LPS (p < 0.05). Conclusion These results indicated that DBMSCs maintained their functional activities (proliferation, adhesion, and migration) in the presence of LPS as there was no variation between the treated DBMSCs and the control group. This study will lay the foundation for future preclinical and clinical studies to confirm the appropriateness of DBMSCs as a potential medication to cure inflammatory diseases, like atherosclerosis.
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Affiliation(s)
- Ghofran Hasan Alshareef
- Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, 84428, Saudi Arabia
| | - Afrah E Mohammed
- Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, 84428, Saudi Arabia
| | - Mohammed Abumaree
- Stem Cell & Regenerative Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.,College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, 11481, Saudi Arabia
| | - Yasser S Basmaeil
- Stem Cell & Regenerative Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
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Cell Therapy of Stroke: Do the Intra-Arterially Transplanted Mesenchymal Stem Cells Cross the Blood-Brain Barrier? Cells 2021; 10:cells10112997. [PMID: 34831220 PMCID: PMC8616541 DOI: 10.3390/cells10112997] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/31/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023] Open
Abstract
Animal model studies and first clinical trials have demonstrated the safety and efficacy of the mesenchymal stem cells' (MSCs) transplantation in stroke. Intra-arterial (IA) administration looks especially promising, since it provides targeted cell delivery to the ischemic brain, is highly effective, and can be safe as long as the infusion is conducted appropriately. However, wider clinical application of the IA MSCs transplantation will only be possible after a better understanding of the mechanism of their therapeutic action is achieved. On the way to achieve this goal, the study of transplanted cells' fate and their interactions with the blood-brain barrier (BBB) structures could be one of the key factors. In this review, we analyze the available data concerning one of the most important aspects of the transplanted MSCs' action-the ability of cells to cross the blood-brain barrier (BBB) in vitro and in vivo after IA administration into animals with experimental stroke. The collected data show that some of the transplanted MSCs temporarily attach to the walls of the cerebral vessels and then return to the bloodstream or penetrate the BBB and either undergo homing in the perivascular space or penetrate deeper into the parenchyma. Transmigration across the BBB is not necessary for the induction of therapeutic effects, which can be incited through a paracrine mechanism even by cells located inside the blood vessels.
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