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Shi Y, Zhang J, Li Y, Feng C, Shao C, Shi Y, Fang J. Engineered mesenchymal stem/stromal cells against cancer. Cell Death Dis 2025; 16:113. [PMID: 39971901 PMCID: PMC11839947 DOI: 10.1038/s41419-025-07443-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/03/2025] [Accepted: 02/11/2025] [Indexed: 02/21/2025]
Abstract
Mesenchymal stem/stromal cells (MSCs) have garnered attention for their potential in cancer therapy due to their ability to home to tumor sites. Engineered MSCs have been developed to deliver therapeutic proteins, microRNAs, prodrugs, chemotherapy drugs, and oncolytic viruses directly to the tumor microenvironment, with the goal of enhancing therapeutic efficacy while minimizing off-target effects. Despite promising results in preclinical studies and clinical trials, challenges such as variability in delivery efficiency and safety concerns persist. Ongoing research aims to optimize MSC-based cancer eradication and immunotherapy, enhancing their specificity and efficacy in cancer treatment. This review focuses on advancements in engineering MSCs for tumor-targeted therapy.
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Affiliation(s)
- Yuzhu Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Jia Zhang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
- Department of Basic Medical Sciences, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yanan Li
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Chao Feng
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
- Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200025, China.
| | - Jiankai Fang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
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Mohammadian S, Hosseni SJ, Negad Dehbashi F, Dayer D. The Insulin-Producing Cells Generated from Rat Adipose Tissue Mesenchymal Stem Cells via Pdx1 Overexpression Activate an Immune Response both in Vitro and in Vivo. IRANIAN JOURNAL OF MEDICAL SCIENCES 2025; 50:112-123. [PMID: 40026296 PMCID: PMC11870862 DOI: 10.30476/ijms.2024.101162.3378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/25/2024] [Accepted: 04/19/2024] [Indexed: 03/05/2025]
Abstract
Background The current work investigated the immunological features of insulin-producing cells (IPCs) generated from rat adipose-derived mesenchymal stem cells (ADSCs) both in vitro and in vivo. Methods The research was carried out at Ahvaz Jundishapur University of Medical Sciences in 2023. ADSCs were derived from rat adipose tissues and differentiated into IPCs. The control group included undifferentiated ADSCs. The amount of secreted insulin was measured using ELISA. The expression of major histocompatibility complex-I (MHC-I) and MHC-II, cluster of differentiation 40 (CD40), and CD80 by IPCs in vitro was assessed using Western Blot analysis. The in vivo study was performed on 10 male diabetic rats. The experimental group received 107 IPCs in the peritoneal cavity. The control group received 107 undifferentiated ADSCs. After 4 hours, the expression of CD3a and CD45 by immune cells collected from the peritoneal cavity was measured using flow cytometry. All parameters were statistically analyzed using a t test. Results The differentiated cells secreted much higher amounts of insulin than the control group (P=0.04). IPCs exhibited higher expression of MHC-I and MHC-II, CD40, and CD80 (P=0.02, P=0.008, P=0.07, and P=0.02, respectively). The experimental group showed higher levels of CD3a and CD45 expression than the control group (P=0.07, P=0.04, respectively). Conclusion Functional IPCs generated by ADSCs differentiation exhibited immunogenic activity both in vitro and in vivo. Immune-modulating strategies are required for the effective transplantation of the differentiated IPCs generated in our study.
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Affiliation(s)
- Shadab Mohammadian
- Group of Biotechnology, Institute of Persian Gulf, Persian Gulf University, Bushehr, Iran
- Department of Biological Science and Technology, Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr, Iran
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Javad Hosseni
- Group of Biotechnology, Institute of Persian Gulf, Persian Gulf University, Bushehr, Iran
- Department of Biological Science and Technology, Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr, Iran
| | - Fereshte Negad Dehbashi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Dian Dayer
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Li Y, Jin M, Guo D, Shen S, Lu K, Pan R, Sun L, Zhang H, Shao J, Pan G. Unveiling the immunogenicity of allogeneic mesenchymal stromal cells: Challenges and strategies for enhanced therapeutic efficacy. Biomed Pharmacother 2024; 180:117537. [PMID: 39405918 DOI: 10.1016/j.biopha.2024.117537] [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: 07/27/2024] [Revised: 10/01/2024] [Accepted: 10/04/2024] [Indexed: 11/14/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) exhibit significant potential in the context of cell therapy because of their capacity to perform a range of interconnected functions in damaged tissues, including immune modulation, hematopoietic support, and tissue regeneration. MSCs are hypoimmunogenic because of their diminished expression of major histocompatibility molecules, absence of costimulatory molecules, and presence of coinhibitory molecules. While autologous MSCs reduce the risk of rejection and infection, variability in cell numbers and proliferation limits their potential applications. Conversely, allogeneic MSCs (allo-MSCs) possess broad clinical applications unconstrained by donor physiology. Nonetheless, preclinical and clinical investigations highlight that transplanted allo-MSCs are subject to immune attack from recipients. These cells exhibit anti-inflammatory and proinflammatory phenotypes contingent on the microenvironment. Notably, the proinflammatory phenotype features enhanced immunogenicity and diminished immunosuppression, potentially triggering allogeneic immune reactions that impede long-term clinical efficacy. Consequently, preserving the low immunogenicity of allo-MSCs in vivo and mitigating immune rejection in diverse microenvironments represent crucial challenges for the widespread clinical application of MSCs. In this review, we elucidate the immune regulation of allo-MSCs, specifically focusing on two distinct subgroups, MSC1 and MSC2, that exhibit varying polarization states and immunogenicity. We discuss the factors and underlying mechanisms that induce MSC immunogenicity and polarization, highlighting the crucial role of major histocompatibility complex class I/II molecules in rejection post-transplantation. Additionally, we summarize the immunogenic regulatory targets and applications of allo-MSCs and outline strategies to address challenges in this promising field, aiming to enhance allo-MSC therapeutic efficacy for patients.
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Affiliation(s)
- Yuanhui Li
- Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
| | - Mengting Jin
- College of Life Sciences, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Dongyang Guo
- Hangzhou City University, School of Medicine, 50 Huzhou Street, Hangzhou, China
| | - Shuang Shen
- College of Life Sciences, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Kaining Lu
- Breast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, China
| | - Li Sun
- Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
| | - Hongchen Zhang
- Department of Gatroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, No. 261 HuanSha Road, Hangzhou, China.
| | - Jianzhong Shao
- College of Life Sciences, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang University, Hangzhou, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
| | - Gang Pan
- Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
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Bezstarosti S, Erpicum P, Maggipinto G, Dreyer GJ, Reinders MEJ, Meziyerh S, Roelen DL, De Fijter JW, Kers J, Weekers L, Beguin Y, Jouret F, Heidt S. Allogeneic mesenchymal stromal cell therapy in kidney transplantation: should repeated human leukocyte antigen mismatches be avoided? Front Genet 2024; 15:1436194. [PMID: 39399215 PMCID: PMC11466828 DOI: 10.3389/fgene.2024.1436194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 08/15/2024] [Indexed: 10/15/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) have immunomodulatory properties and are therefore considered promising tools in kidney transplantation. Although most studies have been conducted with autologous MSCs, using allogeneic MSCs as an off-the-shelf product is more feasible in clinical settings. However, allogeneic MSCs could potentially induce an immune response, which might eventually be directed towards the kidney allograft because of shared human leukocyte antigen (HLA) epitope mismatches between the kidney and MSC donor. In this study, we performed in-depth analyses of two cohorts (n = 20) that received third-party MSC therapy after kidney transplantation. While the Neptune Study from Leiden University Medical Center specifically selected MSC to avoid repeated HLA antigen mismatches between kidney and MSC donors, the study from the University of Liège did not perform specific MSC selection. The comparative analyses of amino acid mismatches between these cohorts showed that MSC selection to avoid repeated HLA mismatches at the split antigen level was not sufficient to prevent repeated mismatches at the amino acid level. However, repeated amino acid mismatches were not associated with the occurrence of donor-specific antibodies (DSAs). Thus, the clinical relevance of repeated amino acid mismatches seems to be limited with regard to the risk of DSA formation. Since DSA formation was limited (3 of 20 patients) in this study, larger studies are required to investigate the relevance of preventing repeated HLA mismatches in allogeneic MSC therapy in kidney transplantation.
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Affiliation(s)
- Suzanne Bezstarosti
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Pauline Erpicum
- Laboratory of Translational Research in Nephrology (LTRN), Interdisciplinary Cluster for Applied Genoproteomics (GIGA) - Cardiovascular Sciences, University of Liège, Liège, Belgium
- Division of Nephrology, CHU Liège, University of Liège, Liège, Belgium
| | - Gianni Maggipinto
- Division of Immuno-Hematology, CHU Liège, University of Liège, Liège, Belgium
| | - Geertje J. Dreyer
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Marlies E. J. Reinders
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Soufian Meziyerh
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Dave L. Roelen
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Johan W. De Fijter
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Jesper Kers
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
| | - Laurent Weekers
- Division of Nephrology, CHU Liège, University of Liège, Liège, Belgium
| | - Yves Beguin
- Division of Hematology, CHU Liège, University of Liège, Liège, Belgium
| | - François Jouret
- Laboratory of Translational Research in Nephrology (LTRN), Interdisciplinary Cluster for Applied Genoproteomics (GIGA) - Cardiovascular Sciences, University of Liège, Liège, Belgium
- Division of Nephrology, CHU Liège, University of Liège, Liège, Belgium
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
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Younesi FS, Hinz B. The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair? Int J Mol Sci 2024; 25:8712. [PMID: 39201399 PMCID: PMC11354465 DOI: 10.3390/ijms25168712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring-called fibrosis-that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies.
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Affiliation(s)
- Fereshteh Sadat Younesi
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
| | - Boris Hinz
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
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Jenkner S, Clark JM, Gronthos S, O’Hare Doig RL. Molars to Medicine: A Focused Review on the Pre-Clinical Investigation and Treatment of Secondary Degeneration following Spinal Cord Injury Using Dental Stem Cells. Cells 2024; 13:817. [PMID: 38786039 PMCID: PMC11119219 DOI: 10.3390/cells13100817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/01/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a potential therapy for repairing and recovering damaged cells after SCI and other CNS disorders. This focused review highlights the contributions of mesenchymal (MSCs) and dental stem cells (DSCs) in attenuating various secondary injury sequelae through paracrine and cell-to-cell communication mechanisms following SCI and other types of neurotrauma. These mechanistic events include vascular dysfunction, oxidative stress, excitotoxicity, apoptosis and cell loss, neuroinflammation, and structural deficits. The review of studies that directly compare MSC and DSC capabilities also reveals the superior capabilities of DSC in reducing the effects of secondary injury and promoting a favorable microenvironment conducive to repair and regeneration. This review concludes with a discussion of the current limitations and proposes improvements in the future assessment of stem cell therapy through the reporting of the effects of DSC viability and DSC efficacy in attenuating secondary damage after SCI.
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Affiliation(s)
- Sandra Jenkner
- School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia; (S.J.); (S.G.)
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
| | - Jillian Mary Clark
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia
| | - Stan Gronthos
- School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia; (S.J.); (S.G.)
- Mesenchymal Stem Cell Laboratory, Precision Medicine Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia
| | - Ryan Louis O’Hare Doig
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia
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7
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Wu M, Wu S, Tan S, Xu Q, Zhang D, Sun J, Yang H, Wang C, Duan T, Xu Y, Wei Z. VitroGel-loaded human MenSCs promote endometrial regeneration and fertility restoration. Front Bioeng Biotechnol 2024; 11:1310149. [PMID: 38260736 PMCID: PMC10800509 DOI: 10.3389/fbioe.2023.1310149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Introduction: Intrauterine adhesions (IUA), also known as Asherman's syndrome, is caused by trauma to the pregnant or non-pregnant uterus, which leads to damaged endometrial basal lining and partial or total occlusion of the uterine chambers, resulting in abnormal menstruation, infertility, or recurrent miscarriage. The essence of this syndrome is endometrial fibrosis. And there is no effective treatment for IUA to stimulate endometrial regeneration currently. Recently, menstrual blood-derived stem cells (MenSCs) have been proved to hold therapeutic promise in various diseases, such as myocardial infarction, stroke, diabetes, and liver cirrhosis. Methods: In this study, we examined the effects of MenSCs on the repair of uterine adhesions in a rat model, and more importantly, promoted such therapeutic effects via a xeno-free VitroGel MMP carrier. Results: This combined treatment reduced the expression of inflammatory factors, increased the expression of anti-inflammatory factors, restricted the area of endometrial fibrosis, diminished uterine adhesions, and partially restored fertility, showing stronger effectiveness than each component alone and almost resembling the sham group. Discussion: Our findings suggest a highly promising strategy for IUA treatment.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Tao Duan
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yao Xu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhiyun Wei
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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Huang X, Liu Y, Li Z, Lerman LO. Mesenchymal Stem/Stromal Cells Therapy for Metabolic Syndrome: Potential Clinical Application? Stem Cells 2023; 41:893-906. [PMID: 37407022 PMCID: PMC10560401 DOI: 10.1093/stmcls/sxad052] [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: 01/31/2023] [Accepted: 06/21/2023] [Indexed: 07/07/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs), a class of cells with proliferative, immunomodulatory, and reparative functions, have shown therapeutic potential in a variety of systemic diseases, including metabolic syndrome (MetS). The cluster of morbidities that constitute MetS might be particularly amenable for the application of MSCs, which employ an arsenal of reparative actions to target multiple pathogenic pathways simultaneously. Preclinical studies have shown that MSCs can reverse pathological changes in MetS mainly by inhibiting inflammation, improving insulin resistance, regulating glycolipid metabolism, and protecting organ function. However, several challenges remain to overcome before MSCs can be applied for treating MetS. For example, the merits of autologous versus allogeneic MSCs sources remain unclear, particularly with autologous MSCs obtained from the noxious MetS milieu. The distinct characteristics and relative efficacy of MSCs harvested from different tissue sources also require clarification. Moreover, to improve the therapeutic efficacy of MSCs, investigators have explored several approaches that improved therapeutic efficacy but may involve potential safety concerns. This review summarized the potentially useful MSCs strategy for treating MetS, as well as some hurdles that remain to be overcome. In particular, larger-scale studies are needed to determine the therapeutic efficacy and safety of MSCs for clinical application.
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Affiliation(s)
- Xiuyi Huang
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Yunchong Liu
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Zilun Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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Slovinska L, Harvanova D. The Role of Mesenchymal Stromal Cells and Their Products in the Treatment of Injured Spinal Cords. Curr Issues Mol Biol 2023; 45:5180-5197. [PMID: 37367078 DOI: 10.3390/cimb45060329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023] Open
Abstract
Spinal cord injury (SCI) is a destructive condition that results in lasting neurological damage resulting in disruption of the connection between the central nervous system and the rest of the body. Currently, there are several approaches in the treatment of a damaged spinal cord; however, none of the methods allow the patient to return to the original full-featured state of life before the injury. Cell transplantation therapies show great potential in the treatment of damaged spinal cords. The most examined type of cells used in SCI research are mesenchymal stromal cells (MSCs). These cells are at the center of interest of scientists because of their unique properties. MSCs regenerate the injured tissue in two ways: (i) they are able to differentiate into some types of cells and so can replace the cells of injured tissue and (ii) they regenerate tissue through their powerful known paracrine effect. This review presents information about SCI and the treatments usually used, aiming at cell therapy using MSCs and their products, among which active biomolecules and extracellular vesicles predominate.
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Affiliation(s)
- Lucia Slovinska
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, 040 01 Košice, Slovakia
| | - Denisa Harvanova
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
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Ma F, Zhang J, Jin X, Han P, Liu Y, Zhang T, Yan K, Kang YJ. Protocol to assess fatal embolism risks from human stem cells. STAR Protoc 2023; 4:102268. [PMID: 37133989 PMCID: PMC10176070 DOI: 10.1016/j.xpro.2023.102268] [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: 09/26/2022] [Revised: 12/15/2022] [Accepted: 04/01/2023] [Indexed: 05/04/2023] Open
Abstract
Here, we present a protocol to identify the pro-embolic sub-population of human adipose-derived multipotent stromal cells (ADSCs) and predict fatal embolism risks from ADSC infusion. We describe steps for the collection, processing, and classification of ADSC single-cell RNA-seq data. We then detail the development of a mathematical model for predicting ADSC embolic risk. This protocol allows for the development of prediction models to enhance the assessment of cell quality and advance the clinical applications of stem cells. For complete details on the use and execution of this protocol, please refer to Yan et al. (2022).1.
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Affiliation(s)
- Fei Ma
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China
| | - Jinlai Zhang
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China
| | - Xin Jin
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China
| | - Pengfei Han
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China
| | - Yuling Liu
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China
| | - Ting Zhang
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China
| | - Kaijing Yan
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China
| | - Y James Kang
- Tasly Stem Cell Biology Laboratory, Tianjin 300410, China.
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11
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Zhuo Y, Li X, He Z, Lu M. Pathological mechanisms of neuroimmune response and multitarget disease-modifying therapies of mesenchymal stem cells in Parkinson's disease. Stem Cell Res Ther 2023; 14:80. [PMID: 37041580 PMCID: PMC10091615 DOI: 10.1186/s13287-023-03280-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 03/13/2023] [Indexed: 04/13/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN); the etiology and pathological mechanism of the disease are still unclear. Recent studies have shown that the activation of a neuroimmune response plays a key role in the development of PD. Alpha-synuclein (α-Syn), the primary pathological marker of PD, can gather in the SN and trigger a neuroinflammatory response by activating microglia which can further activate the dopaminergic neuron's neuroimmune response mediated by reactive T cells through antigen presentation. It has been shown that adaptive immunity and antigen presentation processes are involved in the process of PD and further research on the neuroimmune response mechanism may open new methods for its prevention and therapy. While current therapeutic regimens are still focused on controlling clinical symptoms, applications such as immunoregulatory strategies can delay the symptoms and the process of neurodegeneration. In this review, we summarized the progression of the neuroimmune response in PD based on recent studies and focused on the use of mesenchymal stem cell (MSC) therapy and challenges as a strategy of disease-modifying therapy with multiple targets.
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Affiliation(s)
- Yi Zhuo
- Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410000, Hunan, China
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410006, Hunan, China
| | - Xuan Li
- Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410000, Hunan, China
| | - Zhengwen He
- Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410000, Hunan, China.
| | - Ming Lu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410006, Hunan, China.
- Hunan Provincial Key Laboratory of Neurorestoratology, The Second Affiliated Hospital (the 921st Hospital of PLA), Hunan Normal University, Changsha, 410003, Hunan, China.
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12
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Peshkova M, Kosheleva N, Shpichka A, Radenska-Lopovok S, Telyshev D, Lychagin A, Li F, Timashev P, Liang XJ. Targeting Inflammation and Regeneration: Scaffolds, Extracellular Vesicles, and Nanotechnologies as Cell-Free Dual-Target Therapeutic Strategies. Int J Mol Sci 2022; 23:13796. [PMID: 36430272 PMCID: PMC9694395 DOI: 10.3390/ijms232213796] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
Osteoarthritis (OA) affects over 250 million people worldwide and despite various existing treatment strategies still has no cure. It is a multifactorial disease characterized by cartilage loss and low-grade synovial inflammation. Focusing on these two targets together could be the key to developing currently missing disease-modifying OA drugs (DMOADs). This review aims to discuss the latest cell-free techniques applied in cartilage tissue regeneration, since they can provide a more controllable approach to inflammation management than the cell-based ones. Scaffolds, extracellular vesicles, and nanocarriers can be used to suppress inflammation, but they can also act as immunomodulatory agents. This is consistent with the latest tissue engineering paradigm, postulating a moderate, controllable inflammatory reaction to be beneficial for tissue remodeling and successful regeneration.
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Affiliation(s)
- Maria Peshkova
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov University, 119991 Moscow, Russia
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
- Laboratory of Clinical Smart Nanotechnologies, Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | - Nastasia Kosheleva
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
- Laboratory of Clinical Smart Nanotechnologies, Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
- FSBSI Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
| | - Anastasia Shpichka
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov University, 119991 Moscow, Russia
- Laboratory of Clinical Smart Nanotechnologies, Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Stefka Radenska-Lopovok
- Institute for Clinical Morphology and Digital Pathology, Sechenov University, 119991 Moscow, Russia
| | - Dmitry Telyshev
- Institute of Biomedical Systems, National Research University of Electronic Technology, 124498 Moscow, Russia
- Institute of Bionic Technologies and Engineering, Sechenov University, 119991 Moscow, Russia
| | - Alexey Lychagin
- Laboratory of Clinical Smart Nanotechnologies, Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
- Department of Traumatology, Orthopedics and Disaster Surgery, Sechenov University, 119991 Moscow, Russia
| | - Fangzhou Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
| | - Peter Timashev
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov University, 119991 Moscow, Russia
- Laboratory of Clinical Smart Nanotechnologies, Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Xing-Jie Liang
- Laboratory of Clinical Smart Nanotechnologies, Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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13
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Abstract
Pulmonary fibrosis (PF) is a chronic and relentlessly progressive interstitial lung disease in which the accumulation of fibroblasts and extracellular matrix (ECM) induces the destruction of normal alveolar structures, ultimately leading to respiratory failure. Patients with advanced PF are unable to perform physical labor and often have concomitant cough and dyspnea, which markedly impair their quality of life. However, there is a paucity of available pharmacological therapies, and to date, lung transplantation remains the only possible treatment for patients suffering from end-stage PF; moreover, the complexity of transplantation surgery and the paucity of donors greatly restrict the application of this treatment. Therefore, there is a pressing need for alternative therapeutic strategies for this complex disease. Due to their capacity for pluripotency and paracrine actions, stem cells are promising therapeutic agents for the treatment of interstitial lung disease, and an extensive body of literature supports the therapeutic efficacy of stem cells in lung fibrosis. Although stem cell transplantation may play an important role in the treatment of PF, some key issues, such as safety and therapeutic efficacy, remain to be resolved. In this review, we summarize recent preclinical and clinical studies on the stem cell-mediated regeneration of fibrotic lungs and present an analysis of concerning issues related to stem cell therapy to guide therapeutic development for this complex disease.
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14
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Kirkham AM, Monaghan M, Bailey AJ, Shorr R, Lalu MM, Fergusson DA, Allan DS. Mesenchymal stem/stromal cell-based therapies for COVID-19: First iteration of a living systematic review and meta-analysis: MSCs and COVID-19. Cytotherapy 2022; 24:639-649. [PMID: 35219584 PMCID: PMC8802614 DOI: 10.1016/j.jcyt.2021.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/22/2021] [Accepted: 12/09/2021] [Indexed: 01/27/2023]
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. METHODS AND FINDINGS All English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P = .02; I2 = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, -0.69; 95% CI, -1.15 to -0.22; P = .004; I2 = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. CONCLUSION Use of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.
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Affiliation(s)
- Aidan M. Kirkham
- Departments of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Madeline Monaghan
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Adrian J.M. Bailey
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Risa Shorr
- Medical Information and Learning Services, The Ottawa Hospital, Ottawa, ON, Canada
| | - Manoj M. Lalu
- Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada,Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Departments Anesthesia, The Ottawa Hospital, Ottawa, ON, Canada
| | - Dean A. Fergusson
- Medicine, University of Ottawa, Ottawa, ON, Canada,Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - David S. Allan
- Departments of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada,Medicine, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Medicine, The Ottawa Hospital, Ottawa, ON, Canada,Corresponding Author: Dr. David Allan, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704 Ottawa ON K1H 8L6, Canada, Fax +1 613-737-8861
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15
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Chan AML, Sampasivam Y, Lokanathan Y. Biodistribution of mesenchymal stem cells (MSCs) in animal models and implied role of exosomes following systemic delivery of MSCs: a systematic review. Am J Transl Res 2022; 14:2147-2161. [PMID: 35559383 PMCID: PMC9091132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/17/2022] [Indexed: 06/15/2023]
Abstract
Mesenchymal stem cells (MSC) are promising candidates to combat the growing rates of chronic degenerative diseases. These cells provide regeneration and/or differentiation into other cell types, and secrete various trophic factors that participate in migration, proliferation, and immunomodulation. However, the novelty of MSC research has noticeably declined as common barriers and unresolved challenges prevent further progress. A common issue is the low survivability and migration of systemically infused MSC towards targeted regions. Nevertheless, successful clinical treatment of various chronic diseases suggests that the MSCs may have an alternative mechanism. Recent advancements have shown labelling and imaging techniques to be a reliable source of data. These data not only illustrate the biodistribution but can be referenced to either support and/or improve the specificities of the cellular therapy construct. In this review, we compile recent studies between 2017 and 2021 to determine the homing and migration of MSCs by specific and peripherally-targeted organs. We also compare the different cell-tracking assays with the safety and efficacy of their therapeutic construct. We found that the common route of MSCs occurred in the lungs, liver, kidney and spleen. Furthermore, MSCs were also able to home and migrate towards targeted or injured organs such as the heart and lymph nodes. Although the MSCs were not detectable by the end of the study, the tested animals had significantly improved in terms of the disease symptoms and their related comorbidities. Thus, we hypothesize that the secretion of exosomes had contributed to this phenomenon.
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Affiliation(s)
- Alvin Man Lung Chan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan MalaysiaJalan Yaacob Latif, Kuala Lumpur 56000, Malaysia
| | - Yashirdisai Sampasivam
- Faculty of Science and Technology, University Kebangsaan MalaysiaBangi 43600, Selangor, Malaysia
| | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan MalaysiaJalan Yaacob Latif, Kuala Lumpur 56000, Malaysia
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16
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Fagoonee S, Shukla SP, Dhasmana A, Birbrair A, Haque S, Pellicano R. Routes of Stem Cell Administration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:63-82. [PMID: 35389198 DOI: 10.1007/5584_2022_710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Stem cells are very promising for the treatment of a plethora of human diseases. Numerous clinical studies have been conducted to assess the safety and efficacy of various stem cell types. Factors that ensure successful therapeutic outcomes in patients are cell-based parameters such as source, viability, and number, as well as frequency and timing of intervention and disease stage. Stem cell administration routes should be appropriately chosen as these can affect homing and engraftment of the cells and hence reduce therapeutic effects, or compromise safety, resulting in serious adverse events. In this chapter, we will describe the use of stem cells in organ repair and regeneration, in particular, the liver and the available routes of cell delivery in the clinic for end-stage liver diseases. Factors affecting homing and engraftment of stem cells for each administration route will be discussed.
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Affiliation(s)
- Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council (CNR), Molecular Biotechnology Center, Turin, Italy.
| | - Shiv Poojan Shukla
- Department of Dermatology & Cutaneous Biology, Sydney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA
- Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Bursa Uludağ University Faculty of Medicine, Nilüfer, Bursa, Turkey
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17
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Wang J, He W, Tan WS, Cai H. The chitosan/carboxymethyl cellulose/montmorillonite scaffolds incorporated with epigallocatechin-3-gallate-loaded chitosan microspheres for promoting osteogenesis of human umbilical cord-derived mesenchymal stem cell. BIORESOUR BIOPROCESS 2022; 9:36. [PMID: 38647806 PMCID: PMC10991275 DOI: 10.1186/s40643-022-00513-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/27/2022] [Indexed: 12/23/2022] Open
Abstract
Epigallocatechin-3-gallate (EGCG) is a plant-derived flavonoid compound with the ability to promote the differentiation of human bone marrow-derived mesenchymal stem cells (MSCs) into osteoblasts. However, the effect of EGCG on the osteogenic differentiation of the human umbilical cord-derived mesenchymal stem cells (HUMSCs) is rarely studied. Therefore, in this study, the osteogenic effects of EGCG are studied in the HUMSCs by detecting cell proliferation, alkaline phosphatase (ALP) activity, calcium deposition and the expression of relevant osteogenic markers. The results showed that EGCG can promote the proliferation and osteogenic differentiation of the HUMSCs in vitro at a concentration of 2.5-5.0 μM. Unfortunately, the EGCG is easily metabolized by cells during cell culture, which reduces its bioavailability. Therefore, in this paper, EGCG-loaded microspheres (ECM) were prepared and embedded in chitosan/carboxymethyl cellulose/montmorillonite (CS/CMC/MMT) scaffolds to form CS/CMC/MMT-ECM scaffolds for improving the bioavailability of EGCG. The HUMSCs were cultured on CS/CMC/MMT-ECM scaffolds to induce osteogenic differentiation. The results showed that the CS/CMC/MMT-ECM scaffold continuously released EGCG for up to 22 days. In addition, CS/CMC/MMT-ECM scaffolds can promote osteoblast differentiation. Taken together, the present study suggested that entrainment of ECM into CS/CMC/MMT scaffolds was a prospective scheme for promotion osteogenic differentiation of the HUMSCs.
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Affiliation(s)
- Jin Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Wubo He
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Wen-Song Tan
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Haibo Cai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
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18
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Chan AML, Ng AMH, Mohd Yunus MH, Hj Idrus RB, Law JX, Yazid MD, Chin KY, Shamsuddin SA, Mohd Yusof MR, Razali RA, Mat Afandi MA, Hassan MNF, Ng SN, Koh B, Lokanathan Y. Safety study of allogeneic mesenchymal stem cell therapy in animal model. Regen Ther 2022; 19:158-165. [PMID: 35252487 PMCID: PMC8861582 DOI: 10.1016/j.reth.2022.01.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/01/2021] [Accepted: 01/27/2022] [Indexed: 02/05/2023] Open
Abstract
Intravenous (IV) infusion of mesenchymal stem cells (MSCs) from nascent tissues like Wharton's Jelly of the umbilical cord is reported to offer therapeutic effects against chronic diseases. However, toxicological data essential for the clinical application of these cells are limited. Thus, this study aimed to determine the safety of IV infusion of Wharton's Jelly derived MSCs (WJ-MSCs) in rats. Fifteen male Sprague–Dawley rats were randomised into the control or treatment group. Each group received an equal volume of saline or WJ-MSC (10 × 106 cell/kg) respectively. The animals were evaluated for physical, biochemical and haematological changes at Week 0, 2, 4, 8 and 12 during the 12-week study. Acute toxicity was performed during Week 2 and sub-chronic toxicity during Week 12. At the end of the study, the relative weight of organs was calculated and histology was performed for lung, liver, spleen and kidney. The findings from physical, serum biochemistry and complete blood count demonstrated no statistically significant differences between groups. However, pathological evaluation reported minor inflammation in the lungs for all groups, but visible healing and resolution of inflammation were observed in the treatment group only. Additionally, the histological images of the treatment group had significantly improved pulmonary structures compared to the control group. In summary, the IV administration of WJ-MSC was safe in the rats. Further studies are needed to determine the long-term safety of the WJ-MSC in both healthy and diseased animal models.
Intravenous infusion of high-dose WJ-MSC in rats is safe. No physical, biochemical and haematological adverse side effects were observed from the treatment. WJ-MSC successfully suppressed inflammation and stimulated regeneration in histopathological analysis.
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Affiliation(s)
- Alvin Man Lung Chan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
- Ming Medical Sdn Bhd, D3-3 (2nd Floor), Block D3 Dana 1 Commercial Centre, Jalan PJU 1a/46, 47301, Petaling Jaya, Selangor, Malaysia
| | - Angela Min Hwei Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Mohd Heikal Mohd Yunus
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000, Kuala Lumpur, Malaysia
| | - Ruszymah Bt Hj Idrus
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Muhammad Dain Yazid
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000, Kuala Lumpur, Malaysia
| | - Sharen Aini Shamsuddin
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Mohd Rafizul Mohd Yusof
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000, Kuala Lumpur, Malaysia
| | - Rabiatul Adawiyah Razali
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Mohd Asyraf Mat Afandi
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Muhammad Najib Fathi Hassan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - See Nguan Ng
- Ming Medical Sdn Bhd, D3-3 (2nd Floor), Block D3 Dana 1 Commercial Centre, Jalan PJU 1a/46, 47301, Petaling Jaya, Selangor, Malaysia
| | - Benson Koh
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
- Ming Medical Sdn Bhd, D3-3 (2nd Floor), Block D3 Dana 1 Commercial Centre, Jalan PJU 1a/46, 47301, Petaling Jaya, Selangor, Malaysia
| | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
- Corresponding author.
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19
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Tamez-Mata Y, Pedroza-Montoya FE, Martínez-Rodríguez HG, García-Pérez MM, Ríos-Cantú AA, González-Flores JR, Soto-Domínguez A, Montes-de-Oca-Luna R, Simental-Mendía M, Peña-Martínez VM, Vílchez-Cavazos F. Nerve gaps repaired with acellular nerve allografts recellularized with Schwann-like cells: Preclinical trial. J Plast Reconstr Aesthet Surg 2022; 75:296-306. [PMID: 34257032 DOI: 10.1016/j.bjps.2021.05.066] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 05/03/2021] [Accepted: 05/27/2021] [Indexed: 01/26/2023]
Abstract
BACKGROUND Acellular nerve allografts (ANA) recellularized with mesenchymal stem cells (MSC) or Schwann cells (SC) are, at present, a therapeutic option for peripheral nerve injuries (PNI). This study aimed to evaluate the regenerative and functional capacity of a recellularized allograft (RA) compared with autograft nerve reconstruction in PNI. METHODS Fourteen ovines were randomly included in two groups (n=7). A peroneal nerve gap 30 mm in length was excised, and nerve repair was performed by the transplantation of either an autograft or a recellularized allograft with SC-like cells. Evaluations included a histomorphological analysis of the ANA, MSC pre differentiated into SC-like cells, at one year follow-up functional limb recovery (support and gait), and nerve regeneration using neurophysiological tests and histomorphometric analysis. All evaluations were compared with the contralateral hindlimb as the control. RESULTS The nerve allograft was successfully decellularized and more than 70% of MSC were pre differentiated into SC-like cells. Functional assessment in both treated groups improved similarly over time (p <0.05). Neurophysiological results (latency, amplitude, and conduction velocity) also improved in both treated groups at twelve months. Histological results demonstrated a less organized arrangement of nerve fibers (p <0.05) with an active remyelination process (p <0.05) in both treated groups compared with controls at twelve months. CONCLUSIONS ANA recellularized with SC-like cells proved to be a successful treatment for nerve gaps. Motor recovery and nerve regeneration were satisfactorily achieved in both graft groups compared with their contralateral nontreated nerves. This approach could be useful for the clinical therapy of PNI.
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Affiliation(s)
- Y Tamez-Mata
- Traumatology and Orthopedics, Bone and Tissue Bank Division, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - F E Pedroza-Montoya
- Biochemistry and Molecular Medicine Department, Cell Therapy Division, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - H G Martínez-Rodríguez
- Biochemistry and Molecular Medicine Department, Cell Therapy Division, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - M M García-Pérez
- Plastic Surgery Service, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - A A Ríos-Cantú
- Plastic Surgery Service, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - J R González-Flores
- Plastic Surgery Service, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - A Soto-Domínguez
- Histology Department, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - R Montes-de-Oca-Luna
- Histology Department, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - M Simental-Mendía
- Traumatology and Orthopedics, Bone and Tissue Bank Division, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - V M Peña-Martínez
- Traumatology and Orthopedics, Bone and Tissue Bank Division, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González"
| | - F Vílchez-Cavazos
- Traumatology and Orthopedics, Bone and Tissue Bank Division, Universidad Autonoma de Nuevo Leon, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González".
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20
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Norte-Muñoz M, Lucas-Ruiz F, Gallego-Ortega A, García-Bernal D, Valiente-Soriano FJ, de la Villa P, Vidal-Sanz M, Agudo-Barriuso M. Neuroprotection and Axonal Regeneration Induced by Bone Marrow Mesenchymal Stromal Cells Depend on the Type of Transplant. Front Cell Dev Biol 2021; 9:772223. [PMID: 34805178 PMCID: PMC8600074 DOI: 10.3389/fcell.2021.772223] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/18/2021] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stromal cell (MSC) therapy to treat neurodegenerative diseases has not been as successful as expected in some preclinical studies. Because preclinical research is so diverse, it is difficult to know whether the therapeutic outcome is due to the cell type, the type of transplant or the model of disease. Our aim here was to analyze the effect of the type of transplant on neuroprotection and axonal regeneration, so we tested MSCs from the same niche in the same model of neurodegeneration in the three transplantation settings: xenogeneic, syngeneic and allogeneic. For this, bone marrow mesenchymal stromal cells (BM-MSCs) isolated from healthy human volunteers or C57/BL6 mice were injected into the vitreous body of C57/BL6 mice (xenograft and syngraft) or BALB/c mice (allograft) right after optic nerve axotomy. As controls, vehicle matched groups were done. Retinal anatomy and function were analyzed in vivo by optical coherence tomography and electroretinogram, respectively. Survival of vision forming (Brn3a+) and non-vision forming (melanopsin+) retinal ganglion cells (RGCs) was assessed at 3, 5 and 90 days after the lesion. Regenerative axons were visualized by cholera toxin β anterograde transport. Our data show that grafted BM-MSCs did not integrate in the retina but formed a mesh on top of the ganglion cell layer. The xenotransplant caused retinal edema, detachment and folding, and a significant decrease of functionality compared to the murine transplants. RGC survival and axonal regeneration were significantly higher in the syngrafted retinas than in the other two groups or vehicle controls. Melanopsin+RGCs, but not Brn3a+RGCs, were also neuroprotected by the xenograft. In conclusion, the type of transplant has an impact on the therapeutic effect of BM-MSCs affecting not only neuronal survival but also the host tissue response. Our data indicate that syngrafts may be more beneficial than allografts and, interestingly, that the type of neuron that is rescued also plays a significant role in the successfulness of the cell therapy.
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Affiliation(s)
- María Norte-Muñoz
- Experimental Ophthalmology Group, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Universidad de Murcia, Murcia, Spain
| | - Fernando Lucas-Ruiz
- Experimental Ophthalmology Group, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Universidad de Murcia, Murcia, Spain
| | - Alejandro Gallego-Ortega
- Experimental Ophthalmology Group, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Universidad de Murcia, Murcia, Spain
| | - David García-Bernal
- Hematopoietic Transplant and Cellular Therapy Unit, Molecular Biology and Immunology Department, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Biochemistry, Universidad de Murcia, Murcia, Spain
| | - Francisco J Valiente-Soriano
- Experimental Ophthalmology Group, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Universidad de Murcia, Murcia, Spain
| | - Pedro de la Villa
- Systems Biology Department, Faculty of Medicine, University of Alcalá, Alcalá de Henares, Spain
| | - Manuel Vidal-Sanz
- Experimental Ophthalmology Group, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Universidad de Murcia, Murcia, Spain
| | - Marta Agudo-Barriuso
- Experimental Ophthalmology Group, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Universidad de Murcia, Murcia, Spain
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21
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Kirkham AM, Monaghan M, Bailey AJM, Shorr R, Lalu MM, Fergusson DA, Allan DS. Mesenchymal stromal cells as a therapeutic intervention for COVID-19: a living systematic review and meta-analysis protocol. Syst Rev 2021; 10:249. [PMID: 34526123 PMCID: PMC8441251 DOI: 10.1186/s13643-021-01803-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) have significant immunomodulatory and tissue repair capabilities, mediated partly by conditioned media or through secreted extracellular vesicles (MSC-EVs). Infection with SARS-CoV-2 can cause mild to life-threatening illness due to activated immune responses that may be dampened by MSCs or their secretome. Many clinical studies of MSCs have been launched since the beginning of the global pandemic, however, few have been completed and most lack power to assess efficacy. Repeated systematic searches and meta-analyses are needed to understand, in real time, the extent of potential benefit in different patient populations as the evidence emerges. METHODS This living systematic review will be maintained to provide up-to-date information as the pandemic evolves. A systematic literature search of Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases will be performed. All clinical studies (e.g., randomized, pseudorandomized and non-randomized controlled trials, uncontrolled trials, and case series) employing MSCs or their secretome as a therapeutic intervention for COVID-19 will be included. Patients must have confirmed SARS-CoV-2 infection. Study screening and data extraction will be performed in duplicate. Information concerning interventions, patient populations, methods of MSC isolation and characterization, primary and secondary clinical and/or laboratory outcomes, and adverse events will be extracted. Key clinical outcomes will be pooled through random-effects meta-analysis to determine the efficacy of MSCs and their secreted products for COVID-19. DISCUSSION Our systematic review and subsequent updates will inform the scientific, medical, and health policy communities as the pandemic evolves to guide decisions on the appropriate use of MSC-related products to treat COVID-19. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD 42021225431.
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Affiliation(s)
- Aidan M Kirkham
- Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada
| | - Madeline Monaghan
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada
| | - Adrian J M Bailey
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.,School of Medicine, University of Ottawa, Ottawa, Canada
| | - Risa Shorr
- Medical Information and Learning Services, The Ottawa Hospital, Ottawa, Canada
| | - Manoj M Lalu
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.,Regenerative Medicine, Ottawa Hospital Research Institute, 501 Smyth Rdx, Box 704, Ottawa, ON, K1H 8L6, Canada.,Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Canada
| | - Dean A Fergusson
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.,School of Public Health and Epidemiology, Faculty of Medicine, University of Ottawa, Ottawa, Canada.,Department of Medicine, The Ottawa Hospital, Ottawa, Canada
| | - David S Allan
- Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Canada. .,Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada. .,Regenerative Medicine, Ottawa Hospital Research Institute, 501 Smyth Rdx, Box 704, Ottawa, ON, K1H 8L6, Canada. .,Department of Medicine, The Ottawa Hospital, Ottawa, Canada.
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22
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Klarmann GJ, Gaston J, Ho VB. A review of strategies for development of tissue engineered meniscal implants. BIOMATERIALS AND BIOSYSTEMS 2021; 4:100026. [PMID: 36824574 PMCID: PMC9934480 DOI: 10.1016/j.bbiosy.2021.100026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/17/2021] [Accepted: 08/25/2021] [Indexed: 12/09/2022] Open
Abstract
The meniscus is a key stabilizing tissue of the knee that facilitates proper tracking and movement of the knee joint and absorbs stresses related to physical activity. This review article describes the biology, structure, and functions of the human knee meniscus, common tears and repair approaches, and current research and development approaches using modern methods to fabricate a scaffold or tissue engineered meniscal replacement. Meniscal tears are quite common, often resulting from sports or physical training, though injury can result without specific contact during normal physical activity such as bending or squatting. Meniscal injuries often require surgical intervention to repair, restore basic functionality and relieve pain, and severe damage may warrant reconstruction using allograft transplants or commercial implant devices. Ongoing research is attempting to develop alternative scaffold and tissue engineered devices using modern fabrication techniques including three-dimensional (3D) printing which can fabricate a patient-specific meniscus replacement. An ideal meniscal substitute should have mechanical properties that are close to that of natural human meniscus, and also be easily adapted for surgical procedures and fixation. A better understanding of the organization and structure of the meniscus as well as its potential points of failure will lead to improved design approaches to generate a suitable and functional replacement.
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Affiliation(s)
- George J. Klarmann
- 4D Bio³ Center, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA,The Geneva Foundation, 917 Pacific Ave., Tacoma, WA 98402, USA,Corresponding author at: USU-4D Bio³ Center, 9410 Key West Ave., Rockville, MD 20850, USA.
| | - Joel Gaston
- 4D Bio³ Center, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA,The Geneva Foundation, 917 Pacific Ave., Tacoma, WA 98402, USA
| | - Vincent B. Ho
- 4D Bio³ Center, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
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23
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Li B, Xing Y, Gan Y, He J, Hua H. Labial gland-derived mesenchymal stem cells and their exosomes ameliorate murine Sjögren's syndrome by modulating the balance of Treg and Th17 cells. Stem Cell Res Ther 2021; 12:478. [PMID: 34446113 PMCID: PMC8390194 DOI: 10.1186/s13287-021-02541-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/06/2021] [Indexed: 12/17/2022] Open
Abstract
Background Sjögren's syndrome (SS) is a chronic, systemic autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The disease severely affects the health and life of patients, and the treatment of SS has always been a clinical challenge and essentially palliative. Mesenchymal stem cells (MSCs) have been reported to exert immunomodulatory effects and as a potential novel therapeutic strategy for SS. Labial gland-derived MSCs (LGMSCs) are a population of resident stem cells in the labial gland, first isolated by our group. Exosomes released by MSCs contain a large variety of bioactive molecules and considered to function as an extension of MSCs. Methods LGMSCs were isolated from patients who were needed surgery to remove the lip mucocele and LGMSCs derived exosomes (LGMSC-Exos) were isolated by ultracentrifugation. The non-obese diabetic (NOD) mice were treated with LGMSCs or LGMSC-Exos by tail vein injection. The saliva flow rate of mice was determined and salivary glands were dissected and stained with hematoxylin and eosin. In vitro, peripheral blood mononuclear cells (PBMCs) from SS patients were cocultured with LGMSCs or LGMSC-Exos. Percentage of T helper 17 (Th17) cells and regulatory T (Treg) cells were determined by flow cytometry. The serum levels of cytokines in NOD mice and in the supernatant of the co-culture system by ELISA. Results Treatment with LGMSCs or LGMSC-Exos reduced inflammatory infiltration in the salivary glands, and restored salivary gland secretory function in NOD mice. Importantly, LGMSCs or LGMSC-Exos were demonstrated to inhibit the differentiation of Th17 cells but promote the induction of Treg cells in NOD mice and PBMCs from SS patients in vitro, accompanied by reduced interleukin 17 (IL-17), interferon gamma, and IL-6 levels and enhanced transforming growth factor beta and IL-10 secretion by T cells. Conclusions LGMSCs are potential candidates for MSCs-based therapy and LGMSC-Exos might be utilized for establishing a new cell-free therapy against SS. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02541-0.
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Affiliation(s)
- Boya Li
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China.,Central Laboratory, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yixiao Xing
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China.,Central Laboratory, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yehua Gan
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China.,Central Laboratory, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Jing He
- Department of Rheumatology and Immunology, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China.
| | - Hong Hua
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China. .,Central Laboratory, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China.
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24
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Refaie AF, Elbassiouny BL, Kloc M, Sabek OM, Khater SM, Ismail AM, Mohamed RH, Ghoneim MA. From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations. Front Immunol 2021; 12:690623. [PMID: 34248981 PMCID: PMC8262452 DOI: 10.3389/fimmu.2021.690623] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/09/2021] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy for type 1 diabetes mellitus (T1DM) has been the subject matter of many studies over the past few decades. The wide availability, negligible teratogenic risks and differentiation potential of MSCs promise a therapeutic alternative to traditional exogenous insulin injections or pancreatic transplantation. However, conflicting arguments have been reported regarding the immunological profile of MSCs. While some studies support their immune-privileged, immunomodulatory status and successful use in the treatment of several immune-mediated diseases, others maintain that allogeneic MSCs trigger immune responses, especially following differentiation or in vivo transplantation. In this review, the intricate mechanisms by which MSCs exert their immunomodulatory functions and the influencing variables are critically addressed. Furthermore, proposed avenues to enhance these effects, including cytokine pretreatment, coadministration of mTOR inhibitors, the use of Tregs and gene manipulation, are presented. As an alternative, the selection of high-benefit, low-risk donors based on HLA matching, PD-L1 expression and the absence of donor-specific antibodies (DSAs) are also discussed. Finally, the necessity for the transplantation of human MSC (hMSC)-derived insulin-producing cells (IPCs) into humanized mice is highlighted since this strategy may provide further insights into future clinical applications.
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Affiliation(s)
- Ayman F Refaie
- Nephrology Department, Urology and Nephrology Center, Mansoura, Egypt
| | | | - Malgorzata Kloc
- Department of Immunobiology, The Houston Methodist Research Institute, Houston, TX, United States.,Department of Surgery, The Houston Methodist Hospital, Houston, TX, United States.,Department of Genetics, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States
| | - Omaima M Sabek
- Department of Surgery, The Houston Methodist Hospital, Houston, TX, United States.,Department of Cell and Microbiology Biology, Weill Cornell Medical Biology, New York, NY, United States
| | - Sherry M Khater
- Pathology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Amani M Ismail
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Rania H Mohamed
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
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25
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Kamm JL, Riley CB, Parlane N, Gee EK, McIlwraith CW. Interactions Between Allogeneic Mesenchymal Stromal Cells and the Recipient Immune System: A Comparative Review With Relevance to Equine Outcomes. Front Vet Sci 2021; 7:617647. [PMID: 33521090 PMCID: PMC7838369 DOI: 10.3389/fvets.2020.617647] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/02/2020] [Indexed: 12/27/2022] Open
Abstract
Despite significant immunosuppressive activity, allogeneic mesenchymal stromal cells (MSCs) carry an inherent risk of immune rejection when transferred into a recipient. In naïve recipients, this immune response is initially driven by the innate immune system, an immediate reaction to the foreign cells, and later, the adaptive immune system, a delayed response that causes cell death due to recognition of specific alloantigens by host cells and antibodies. This review describes the actions of MSCs to both suppress and activate the different arms of the immune system. We then review the survival and effectiveness of the currently used allogeneic MSC treatments.
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Affiliation(s)
- J Lacy Kamm
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Christopher B Riley
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Natalie Parlane
- Hopkirk Laboratory, AgResearch, Palmerston North, New Zealand
| | - Erica K Gee
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - C Wayne McIlwraith
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Medical Institute, Colorado State University, Fort Collins, CO, United States
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26
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Rao P, Deo D, Marchioni M. Differentiation of Human Deceased Donor, Adipose-Derived, Mesenchymal Stem Cells into Functional Beta Cells. J Stem Cells Regen Med 2021; 16:63-72. [PMID: 33414582 DOI: 10.46582/jsrm.1602010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/14/2020] [Indexed: 12/25/2022]
Abstract
There is an emerging need for the rapid generation of functional beta cells that can be used in cell replacement therapy for the treatment of type 1 diabetes (T1D). Differentiation of stem cells into insulin-producing cells provides a promising strategy to restore pancreatic endocrine function. Stem cells can be isolated from various human tissues including adipose tissue (AT). Our study outlines a novel, non-enzymatic process to harvest mesenchymal stem cells (MSC) from research-consented, deceased donor AT. Following their expansion, MSC were characterised morphologically and phenotypically by flow cytometry to establish their use for downstream differentiation studies. MSC were induced to differentiate into insulin-producing beta cells using a step-wise differentiation medium. The differentiation was evaluated by analysing the morphology, dithizone staining, immunocytochemistry, and expression of pancreatic beta cell marker genes. We stimulated the beta cells with different concentrations of glucose and observed a dose-dependent increase in gene expression. In addition, an increase in insulin and c-Peptide secretion as a function of glucose challenge confirmed the functionality of the differentiated beta cells. The differentiation of adipose-derived MSC into beta cells has been well established. However, our data demonstrates, for the first time, that the ready availability and properties of MSC isolated from deceased donor adipose tissue render them well-suited as a source for increased production of functional beta cells. Consequently, these cells can be a promising therapeutic approach for cell replacement therapy to treat patients with T1D.
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Affiliation(s)
- Prakash Rao
- Personalized Transplant Medicine Institute at NJ Sharing Network, New Providence, NJ, USA
| | - Dayanand Deo
- Personalized Transplant Medicine Institute at NJ Sharing Network, New Providence, NJ, USA
| | - Misty Marchioni
- Personalized Transplant Medicine Institute at NJ Sharing Network, New Providence, NJ, USA
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27
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Ghoneim MA, Refaie AF, Elbassiouny BL, Gabr MM, Zakaria MM. From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Progress and Challenges. Stem Cell Rev Rep 2020; 16:1156-1172. [PMID: 32880857 PMCID: PMC7667138 DOI: 10.1007/s12015-020-10036-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted. Graphical Abstract Bone marrow MSCs are isolated from the long bone of SD rats. Then they are expanded and through directed differentiation insulin-producing cells are formed. The differentiated cells are loaded onto a collagen scaffold. If one-stage transplantation is planned, a drug delivery system must be incorporated to ensure immediate oxygenation, promote vascularization and provide some growth factors. Some mechanisms involved in the immunomodulatory function of MSCs. These are implemented either by cell to cell contact or by the release of soluble factors. Collectively, these pathways results in an increase in T-regulatory cells.
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28
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He X, Zhang J, Luo L, Shi J, Hu D. New Progress of Adipose-derived Stem Cells in the Therapy of Hypertrophic Scars. Curr Stem Cell Res Ther 2020; 15:77-85. [PMID: 31483236 DOI: 10.2174/1574888x14666190904125800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/01/2018] [Accepted: 07/10/2019] [Indexed: 12/30/2022]
Abstract
Burns are a global public health issue of great concern. The formation of scars after burns and physical dysfunction of patients remain major challenges in the treatment of scars. Regenerative medicine based on cell therapy has become a hot topic in this century. Adipose-derived stem cells (ADSCs) play an important role in cellular therapy and have become a promising source of regenerative medicine and wound repair transplantation. However, the anti-scarring mechanism of ADSCs is still unclear yet. With the widespread application of ADSCs in medical, we firmly believe that it will bring great benefits to patients with hypertrophic scars.
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Affiliation(s)
- Xiang He
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi' an, Shaanxi, China
| | - Julei Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi' an, Shaanxi, China
| | - Liang Luo
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi' an, Shaanxi, China
| | - Jihong Shi
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi' an, Shaanxi, China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi' an, Shaanxi, China
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29
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Abu-El-Rub E, Sareen N, Lester Sequiera G, Ammar HI, Yan W, ShamsEldeen AM, Rubinchik I, Moudgil M, Shokry HS, Rashed LA, Dhingra S. Hypoxia-induced increase in Sug1 leads to poor post-transplantation survival of allogeneic mesenchymal stem cells. FASEB J 2020; 34:12860-12876. [PMID: 32770803 DOI: 10.1096/fj.202000454r] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/07/2020] [Accepted: 07/17/2020] [Indexed: 11/07/2023]
Abstract
Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are immunoprivileged and have the potential to treat numerous degenerative diseases. However, recent reviews of clinical trials report poor long-term survival of transplanted cells in the recipient that turned down the enthusiasm regarding MSC therapies. Increasing evidence now confirm that though initially immunoprivileged, MSCs eventually become immunogenic after transplantation in the ischemic or hypoxic environment of diseased tissues and are rejected by the host immune system. We performed in vitro (in rat and human cells) and in vivo (in a rat model) investigations to understand the mechanisms of the immune switch in the phenotype of MSCs. The immunoprivilege of MSCs is preserved by the absence of cell surface immune antigen, major histocompatibility complex II (MHC-II) molecule. We found that the ATPase subunit of 19S proteasome "Sug1" regulates MHC-II biosynthesis in MSCs. Exposure to hypoxia upregulates Sug1 in MSCs and its binding to class II transactivator (CIITA), a coactivator of MHC-II transcription. Sug1 binding to CIITA in hypoxic MSCs promotes the acetylation and K63 ubiquitination of CIITA leading to its activation and translocation to the nucleus, and ultimately MHC-II upregulation. In both rat and human MSCs, knocking down Sug1 inactivated MHC-II and preserved immunoprivilege even following hypoxia. In a rat model of myocardial infarction, transplantation of Sug1-knockdown MSCs in ischemic heart preserved immunoprivilege and improved the survival of transplanted cells. Therefore, the current study provides novel mechanisms of post-transplantation loss of immunoprivilege of MSCs. This study may help in facilitating better planning for future clinical trials.
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Affiliation(s)
- Ejlal Abu-El-Rub
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Niketa Sareen
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Glen Lester Sequiera
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Hania I Ammar
- Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Weiang Yan
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Asmaa M ShamsEldeen
- Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Ilan Rubinchik
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Meenal Moudgil
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Heba S Shokry
- Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Laila A Rashed
- Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Sanjiv Dhingra
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
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30
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Hepatocyte growth factor (HGF) and stem cell factor (SCF) maintained the stemness of human bone marrow mesenchymal stem cells (hBMSCs) during long-term expansion by preserving mitochondrial function via the PI3K/AKT, ERK1/2, and STAT3 signaling pathways. Stem Cell Res Ther 2020; 11:329. [PMID: 32736659 PMCID: PMC7393921 DOI: 10.1186/s13287-020-01830-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/23/2020] [Accepted: 07/13/2020] [Indexed: 12/24/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have a limited self-renewal ability, impaired multi-differentiation potential, and undetermined cell senescence during in vitro series expansion. To address this concern, we investigated the effects of the microenvironment provided by stem cells from human exfoliated deciduous teeth (SHED) in maintaining the stemness of human bone marrow mesenchymal stem cells (hBMSCs) and identified the key factors and possible mechanisms responsible for maintaining the stemness of MSCs during long-term expansion in vitro. Methods The passage 3 (P3) to passage 8 (P8) hBMSCs were cultured in the conditioned medium from SHED (SHED-CM). The percentage of senescent cells was evaluated by β-galactosidase staining. In addition, the osteogenic differentiation potential was analyzed by reverse transcription quantitative PCR (RT-qPCR), Western blot, alizarin red, and alkaline phosphatase (ALP) staining. Furthermore, RT-qPCR results identified hepatocyte growth factor (HGF) and stem cell factor (SCF) as key factors. Thus, the effects of HGF and SCF on mitochondrial function were assessed by measuring the ROS and mitochondrial membrane potential levels. Finally, selected mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways were investigated to determine the effects of HGF and SCF in preserving the mitochondrial function of hBMSCs during long-term expansion. Results SHED-CM had significantly enhanced the cell proliferation, reduced the senescent cells, and maintained the osteogenesis and pro-angiogenic capacity in P8 hBMSCs during long-term expansion. In addition, hBMSCs treated with 100 ng/ml HGF and 10 ng/ml SCF had reduced ROS levels and preserved mitochondrial membrane potential compared with P8 hBMSCs during long-term expansion. Furthermore, HGF and SCF upregulated the expression of mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways, possibly contributing to the maintenance of hBMSCs stemness by preserving mitochondrial function. Conclusion Both HGF and SCF are key factors in maintaining the stemness of hBMSCs by preserving mitochondrial function through the expression of proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways. This study provides new insights into the anti-senescence capability of HGF and SCF, as well as new evidence for their potential application in optimizing the long-term culture of MSCs.
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To K, Romain K, Mak C, Kamaraj A, Henson F, Khan W. The Treatment of Cartilage Damage Using Human Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review of in vivo Studies. Front Bioeng Biotechnol 2020; 8:580. [PMID: 32596228 PMCID: PMC7300288 DOI: 10.3389/fbioe.2020.00580] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/13/2020] [Indexed: 12/21/2022] Open
Abstract
Damage to joints through injury or disease can result in cartilage loss, which if left untreated can lead to inflammation and ultimately osteoarthritis. There is currently no cure for osteoarthritis and management focusses on symptom control. End-stage osteoarthritis can be debilitating and ultimately requires joint replacement in order to maintain function. Therefore, there is growing interest in innovative therapies for cartilage repair. In this systematic literature review, we sought to explore the in vivo evidence for the use of human Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs) for treating cartilage damage. We conducted a systematic literature review in accordance with the PRISMA protocol on the evidence for the treatment of cartilage damage using human MSC-EVs. Studies examining in vivo models of cartilage damage were included. A risk of bias analysis of the studies was conducted using the SYRCLE tool. Ten case-control studies were identified in our review, including a total of 159 murine subjects. MSC-EVs were harvested from a variety of human tissues. Five studies induced osteoarthritis, including cartilage loss through surgical joint destabilization, two studies directly created osteochondral lesions and three studies used collagenase to cause cartilage loss. All studies in this review reported reduced cartilage loss following treatment with MSC-EVs, and without significant complications. We conclude that transplantation of MSC-derived EVs into damaged cartilage can effectively reduce cartilage loss in murine models of cartilage injury. Additional randomized studies in animal models that recapitulates human osteoarthritis will be necessary in order to establish findings that inform clinical safety in humans.
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Affiliation(s)
- Kendrick To
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Karl Romain
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Christopher Mak
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Achi Kamaraj
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Frances Henson
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Wasim Khan
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
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Tavakoli S, Ghaderi Jafarbeigloo HR, Shariati A, Jahangiryan A, Jadidi F, Jadidi Kouhbanani MA, Hassanzadeh A, Zamani M, Javidi K, Naimi A. Mesenchymal stromal cells; a new horizon in regenerative medicine. J Cell Physiol 2020; 235:9185-9210. [PMID: 32452052 DOI: 10.1002/jcp.29803] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/03/2020] [Accepted: 05/07/2020] [Indexed: 12/11/2022]
Abstract
In recent decades, mesenchymal stromal cells (MSCs) biomedical utilizing has attracted worldwide growing attention. After the first report of the human MSCs obtaining from the bone marrow (BM) tissue, these cells were isolated from wide types of the other tissues, ranging from adipose tissue to dental pulp. Their specific characteristics, comprising self-renewality, multipotency, and availability accompanied by their immunomodulatory properties and little ethical concern denote their importance in the context of regenerative medicine. Considering preclinical studies, MSCs can modify immune reactions during tissue repair and restoration, providing suitable milieu for tissue recovery; on the other hand, they can be differentiated into comprehensive types of the body cells, such as osteoblast, chondrocyte, hepatocyte, cardiomyocyte, fibroblast, and neural cells. Though a large number of studies have investigated MSCs capacities in regenerative medicine in varied animal models, the oncogenic capability of unregulated MSCs differentiation must be more assessed to enable their application in the clinic. In the current review, we provide a brief overview of MSCs sources, isolation, and expansion as well as immunomodulatory activities. More important, we try to collect and discuss recent preclinical and clinical research and evaluate current challenges in the context of the MSC-based cell therapy for regenerative medicine.
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Affiliation(s)
- Shirin Tavakoli
- Department of Toxicology and Pharmacology, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Shariati
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsaneh Jahangiryan
- Immunology Department, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine (IBTO), Tehran, Iran
| | - Faezeh Jadidi
- Student Research Committee, Zarand School of Nursing, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammd Amin Jadidi Kouhbanani
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hassanzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Adel Naimi
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
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Homing and Engraftment of Intravenously Administered Equine Cord Blood-Derived Multipotent Mesenchymal Stromal Cells to Surgically Created Cutaneous Wound in Horses: A Pilot Project. Cells 2020; 9:cells9051162. [PMID: 32397125 PMCID: PMC7290349 DOI: 10.3390/cells9051162] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/28/2020] [Accepted: 05/06/2020] [Indexed: 12/15/2022] Open
Abstract
Limb wounds on horses are often slow to heal and are prone to developing exuberant granulation tissue (EGT) and close primarily through epithelialization, which results in a cosmetically inferior and non-durable repair. In contrast, wounds on the body heal rapidly and primarily through contraction and rarely develop EGT. Intravenous (IV) multipotent mesenchymal stromal cells (MSCs) are promising. They home and engraft to cutaneous wounds and promote healing in laboratory animals, but this has not been demonstrated in horses. Furthermore, the clinical safety of administering >1.00 × 108 allogeneic MSCs IV to a horse has not been determined. A proof-of-principle pilot project was performed with two horses that were administered 1.02 × 108 fluorescently labeled allogeneic cord blood-derived MSCs (CB-MSCs) following wound creation on the forelimb and thorax. Wounds and contralateral non-wounded skin were sequentially biopsied on days 0, 1, 2, 7, 14, and 33 and evaluated with confocal microscopy to determine presence of homing and engraftment. Results confirmed preferential homing and engraftment to wounds with persistence of CB-MSCs at 33 days following wound creation, without clinically adverse reactions to the infusion. The absence of overt adverse reactions allows further studies to determine effects of IV CB-MSCs on equine wound healing.
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Bojanic C, To K, Zhang B, Mak C, Khan WS. Human umbilical cord derived mesenchymal stem cells in peripheral nerve regeneration. World J Stem Cells 2020; 12:288-302. [PMID: 32399137 PMCID: PMC7202926 DOI: 10.4252/wjsc.v12.i4.288] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/15/2020] [Accepted: 03/24/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Peripheral nerve injury can occur as a result of trauma or disease and carries significant morbidity including sensory and motor loss. The body has limited ability for nerve regeneration and functional recovery. Left untreated, nerve lesions can cause lifelong disability. Traditional treatment options such as neurorrhaphy and neurolysis have high failure rates. Surgical reconstruction with autograft carries donor site morbidity and often provide suboptimal results. Mesenchymal stem cells (MSCs) are known to have promising regenerative potential and have gained attention as a treatment option for nerve lesions. It is however, unclear whether it can be effectively used for nerve regeneration.
AIM To evaluate the evidence for the use of human umbilical cord derived MSCs (UCMSCs) in peripheral nerve regeneration.
METHODS We carried out a systematic literature review in accordance with the PRISMA protocol. A literature search was performed from conception to September 2019 using PubMed, EMBASE and Web of Science. The results of eligible studies were appraised. A risk of bias analysis was carried out using Cochrane’s RoB 2.0 tool.
RESULTS Fourteen studies were included in this review. A total of 279 subjects, including both human and animal were treated with UCMSCs. Four studies obtained UCMSCs from a third-party source and the remainder were harvested by the investigators. Out of the 14 studies, thirteen conducted xenogenic transplantation into nerve injury models. All studies reported significant improvement in nerve regeneration in the UCMSC treated groups compared with the various different controls and untreated groups.
CONCLUSION The evidence summarised in this PRISMA systematic review of in vivo studies supports the notion that human UCMSC transplantation is an effective treatment option for peripheral nerve injury.
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Affiliation(s)
- Christine Bojanic
- Department of Plastic and Reconstructive Surgery, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, United Kingdom
| | - Kendrick To
- Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Bridget Zhang
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Christopher Mak
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Wasim S Khan
- Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
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Weber B, Lackner I, Haffner-Luntzer M, Palmer A, Pressmar J, Scharffetter-Kochanek K, Knöll B, Schrezenemeier H, Relja B, Kalbitz M. Modeling trauma in rats: similarities to humans and potential pitfalls to consider. J Transl Med 2019; 17:305. [PMID: 31488164 PMCID: PMC6728963 DOI: 10.1186/s12967-019-2052-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 08/29/2019] [Indexed: 12/27/2022] Open
Abstract
Trauma is the leading cause of mortality in humans below the age of 40. Patients injured by accidents frequently suffer severe multiple trauma, which is life-threatening and leads to death in many cases. In multiply injured patients, thoracic trauma constitutes the third most common cause of mortality after abdominal injury and head trauma. Furthermore, 40-50% of all trauma-related deaths within the first 48 h after hospital admission result from uncontrolled hemorrhage. Physical trauma and hemorrhage are frequently associated with complex pathophysiological and immunological responses. To develop a greater understanding of the mechanisms of single and/or multiple trauma, reliable and reproducible animal models, fulfilling the ethical 3 R's criteria (Replacement, Reduction and Refinement), established by Russell and Burch in 'The Principles of Human Experimental Technique' (published 1959), are required. These should reflect both the complex pathophysiological and the immunological alterations induced by trauma, with the objective to translate the findings to the human situation, providing new clinical treatment approaches for patients affected by severe trauma. Small animal models are the most frequently used in trauma research. Rattus norvegicus was the first mammalian species domesticated for scientific research, dating back to 1830. To date, there exist numerous well-established procedures to mimic different forms of injury patterns in rats, animals that are uncomplicated in handling and housing. Nevertheless, there are some physiological and genetic differences between humans and rats, which should be carefully considered when rats are chosen as a model organism. The aim of this review is to illustrate the advantages as well as the disadvantages of rat models, which should be considered in trauma research when selecting an appropriate in vivo model. Being the most common and important models in trauma research, this review focuses on hemorrhagic shock, blunt chest trauma, bone fracture, skin and soft-tissue trauma, burns, traumatic brain injury and polytrauma.
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Affiliation(s)
- Birte Weber
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Ina Lackner
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - Annette Palmer
- Institute of Clinical and Experimental Trauma-Immunology, University of Ulm, Ulm, Germany
| | - Jochen Pressmar
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | | | - Bernd Knöll
- Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
| | - Hubert Schrezenemeier
- Institute of Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg – Hessen and University Hospital Ulm, Ulm, Germany
| | - Borna Relja
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, Frankfurt, Germany
- Department of Radiology and Nuclear Medicine, Experimental Radiology, Otto-von-Guericke University, Magdeburg, Germany
| | - Miriam Kalbitz
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
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Leberfinger AN, Dinda S, Wu Y, Koduru SV, Ozbolat V, Ravnic DJ, Ozbolat IT. Bioprinting functional tissues. Acta Biomater 2019; 95:32-49. [PMID: 30639351 PMCID: PMC6625952 DOI: 10.1016/j.actbio.2019.01.009] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 12/31/2018] [Accepted: 01/09/2019] [Indexed: 12/23/2022]
Abstract
Despite the numerous lives that have been saved since the first successful procedure in 1954, organ transplant has several shortcomings which prevent it from becoming a more comprehensive solution for medical care than it is today. There is a considerable shortage of organ donors, leading to patient death in many cases. In addition, patients require lifelong immunosuppression to prevent graft rejection postoperatively. With such issues in mind, recent research has focused on possible solutions for the lack of access to donor organs and rejections, with the possibility of using the patient's own cells and tissues for treatment showing enormous potential. Three-dimensional (3D) bioprinting is a rapidly emerging technology, which holds great promise for fabrication of functional tissues and organs. Bioprinting offers the means of utilizing a patient's cells to design and fabricate constructs for replacement of diseased tissues and organs. It enables the precise positioning of cells and biologics in an automated and high throughput manner. Several studies have shown the promise of 3D bioprinting. However, many problems must be overcome before the generation of functional tissues with biologically-relevant scale is possible. Specific focus on the functionality of bioprinted tissues is required prior to clinical translation. In this perspective, this paper discusses the challenges of functionalization of bioprinted tissue under eight dimensions: biomimicry, cell density, vascularization, innervation, heterogeneity, engraftment, mechanics, and tissue-specific function, and strives to inform the reader with directions in bioprinting complex and volumetric tissues. STATEMENT OF SIGNIFICANCE: With thousands of patients dying each year waiting for an organ transplant, bioprinted tissues and organs show the potential to eliminate this ever-increasing organ shortage crisis. However, this potential can only be realized by better understanding the functionality of the organ and developing the ability to translate this to the bioprinting methodologies. Considering the rate at which the field is currently expanding, it is reasonable to expect bioprinting to become an integral component of regenerative medicine. For this purpose, this paper discusses several factors that are critical for printing functional tissues including cell density, vascularization, innervation, heterogeneity, engraftment, mechanics, and tissue-specific function, and inform the reader with future directions in bioprinting complex and volumetric tissues.
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Affiliation(s)
- Ashley N Leberfinger
- Department of Surgery, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - Shantanab Dinda
- Department of Industrial and Manufacturing Engineering, The Pennsylvania State University, University Park, PA 16802, USA; The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Yang Wu
- The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA 16802, USA
| | - Srinivas V Koduru
- Department of Surgery, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - Veli Ozbolat
- The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Ceyhan Engineering Faculty, Cukurova University, Ceyhan, Adana 01950, Turkey
| | - Dino J Ravnic
- Department of Surgery, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - Ibrahim T Ozbolat
- The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA 16802, USA; Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
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Tong C, Li C, Xie B, Li M, Li X, Qi Z, Xia J. Generation of bioartificial hearts using decellularized scaffolds and mixed cells. Biomed Eng Online 2019; 18:71. [PMID: 31164131 PMCID: PMC6549274 DOI: 10.1186/s12938-019-0691-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 05/27/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Patients with end-stage heart failure must receive treatment to recover cardiac function, and the current primary therapy, heart transplantation, is plagued by the limited supply of donor hearts. Bioengineered artificial hearts generated by seeding of cells on decellularized scaffolds have been suggested as an alternative source for transplantation. This study aimed to develop a tissue-engineered heart with lower immunogenicity and functional similarity to a physiological heart that can be used for heart transplantation. MATERIALS AND METHODS We used sodium dodecyl sulfate (SDS) to decellularize cardiac tissue to obtain a decellularized scaffold. Mesenchymal stem cells (MSCs) were isolated from rat bone marrow and identified by flow cytometric labeling of their surface markers. At the same time, the multi-directional differentiation of MSCs was analyzed. The MSCs, endothelial cells, and cardiomyocytes were allowed to adhere to the decellularized scaffold during perfusion, and the function of tissue-engineered heart was analyzed by immunohistochemistry and electrocardiogram. RESULTS MSCs, isolated from rats differentiated into cardiomyocytes, were seeded along with primary rat cardiomyocytes and endothelial cells onto decellularized rat heart scaffolds. We first confirmed the pluripotency of the MSCs, performed immunostaining against cardiac markers expressed by MSC-derived cardiomyocytes, and completed surface antigen profiling of MSC-derived endothelial cells. After cell seeding and culture, we analyzed the performance of the bioartificial heart by electrocardiography but found that the bioartificial heart exhibited abnormal electrical activity. The results indicated that the tissue-engineered heart lacked some cells necessary for the conduction of electrical current, causing deficient conduction function compared to the normal heart. CONCLUSION Our study suggests that MSCs derived from rats may be useful in the generation of a bioartificial heart, although technical challenges remain with regard to generating a fully functional bioartificial heart.
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Affiliation(s)
- Cailing Tong
- School of Life Science, Xiamen University, Xiamen, 361102 Fujian China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361102 Fujian China
| | - Cheng Li
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361102 Fujian China
| | - Baiyi Xie
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361102 Fujian China
| | - Minghui Li
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361102 Fujian China
| | - Xianguo Li
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361102 Fujian China
| | - Zhongquan Qi
- School of Medicine, Guangxi University, Nanning, 530004 Guangxi China
| | - Junjie Xia
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361102 Fujian China
- School of Medicine, Guangxi University, Nanning, 530004 Guangxi China
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Dissecting the Pharmacodynamics and Pharmacokinetics of MSCs to Overcome Limitations in Their Clinical Translation. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 14:1-15. [PMID: 31236426 PMCID: PMC6581775 DOI: 10.1016/j.omtm.2019.05.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recently, mesenchymal stromal stem cells (MSCs) have been proposed as therapeutic agents because of their promising preclinical features and good safety profile. However, their introduction into clinical practice has been associated with a suboptimal therapeutic profile. In this review, we address the biodistribution of MSCs in preclinical studies with a focus on the current understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of MSCs as key aspects to overcome unsatisfactory clinical benefits of MSC application. Beginning with evidence of MSC biodistribution and highlighting PK and PD factors, a new PK-PD model is also proposed. According to this theory, MSCs and their released factors are key players in PK, and the efficacy biomarkers are considered relevant for PD in more predictive preclinical investigations. Accounting for the PK-PD relationship in MSC translational research and proposing new models combined with better biodistribution studies could allow realization of the promise of more robust MSC clinical translation.
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Regmi S, Pathak S, Kim JO, Yong CS, Jeong JH. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol 2019; 98:151041. [PMID: 31023504 DOI: 10.1016/j.ejcb.2019.04.002] [Citation(s) in RCA: 172] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/01/2019] [Accepted: 04/09/2019] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are promising alternative agents for the treatment of inflammatory disorders due to their immunomodulatory functions, and several clinical trials on MSC-based products are currently being conducted. In this review, we discuss recent progress made on the use of MSCs as immunomodulatory agents, developmental challenges posed by MSC-based therapy, and the strategies being used to overcome these challenges. In this context, current understanding of the mechanisms responsible for MSC interactions with the immune system and the molecular responses of MSCs to inflammatory signals are discussed. The immunosuppressive activities of MSCs are initiated by cell-to-cell contact and the release of immuno-regulatory molecules. By doing so, MSCs can inhibit the proliferation and function of T cells, natural killer cells, B cells, and dendritic cells, and can also increase the proliferation of regulatory T cells. However, various problems, such as low transplanted cell viability, poor homing and engraftment into injured tissues, MSC heterogeneity, and lack of adequate information on optimum MSC doses impede clinical applications. On the other hand, it has been shown that the immunomodulatory activities and viabilities of MSCs might be enhanced by 3D-cultured systems, genetic modifications, preconditioning, and targeted-delivery.
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Affiliation(s)
- Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
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Wang Y, Huang J, Gong L, Yu D, An C, Bunpetch V, Dai J, Huang H, Zou X, Ouyang H, Liu H. The Plasticity of Mesenchymal Stem Cells in Regulating Surface HLA-I. iScience 2019; 15:66-78. [PMID: 31030183 PMCID: PMC6487373 DOI: 10.1016/j.isci.2019.04.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/27/2019] [Accepted: 04/06/2019] [Indexed: 02/07/2023] Open
Abstract
A low surface expression level of human leukocyte antigen class I (HLA-I) ensures that the mesenchymal stem cells (MSCs) escape from the allogeneic recipients' immunological surveillance. Here, we discovered that both transcriptional and synthesis levels of HLA-I in MSCs increased continuously after interferon (IFN)-γ treatment, whereas interestingly, their surface HLA-I expression was downregulated after reaching an HLA-I surface expression peak. Microarray data indicated that the post-transcriptional process plays an important role in the downregulation of surface HLA-I. Further studies identified that IFN-γ-treated MSCs accelerated HLA-I endocytosis through a clathrin-independent dynamin-dependent endocytosis pathway. Furthermore, cells that have self-downregulated surface HLA-I expression elicit a weaker immune response than they previously could. Thus uncovering the plasticity of MSCs in the regulation of HLA-I surface expression would reveal insights into the membrane transportation events leading to the maintenance of low surface HLA-I expression, providing more evidence for selecting and optimizing low-immunogenic MSCs to improve the therapeutic efficiency.
hESC-MSCs have the plasticity of maintaining low HLA-I expression on cell surface hESC-MSCs downregulate the surface HLA-I expression through endocytosis of HLA-I hESC-MSCs with lower HLA-I surface expression induce weaker MLR and slighter DTH
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Affiliation(s)
- Yafei Wang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China
| | - Jiayun Huang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Department of Orthopedic Surgery, 2nd Affiliated Hospital, Zhejiang University, School of Medicine, Zhejiang 310009, P.R.China; Orthopaedics Research Institute of Zhejiang University, Zhejiang 310009, P.R.China
| | - Lin Gong
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China
| | - Dongsheng Yu
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, P.R.China
| | - Chenrui An
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China
| | - Varitsara Bunpetch
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China
| | - Jun Dai
- Department of Medical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finland
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang 310003, P.R.China
| | - Xiaohui Zou
- Central Laboratory, the First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R.China
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Department of Sports Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Zhejiang University-University of Edinburgh Institute & School of Basic Medicine, Zhejiang University, School of Medicine, Hangzhou 310003, P. R. China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou 310003, P.R. China
| | - Hua Liu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University, School of Medicine, Hangzhou 310058, P.R.China.
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Erpicum P, Weekers L, Detry O, Bonvoisin C, Delbouille MH, Grégoire C, Baudoux E, Briquet A, Lechanteur C, Maggipinto G, Somja J, Pottel H, Baron F, Jouret F, Beguin Y. Infusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I-II, open-label, clinical study. Kidney Int 2019; 95:693-707. [DOI: 10.1016/j.kint.2018.08.046] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 07/25/2018] [Accepted: 08/23/2018] [Indexed: 02/08/2023]
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Abu-El-Rub E, Sequiera GL, Sareen N, Yan W, Moudgil M, Sabbir MG, Dhingra S. Hypoxia-induced 26S proteasome dysfunction increases immunogenicity of mesenchymal stem cells. Cell Death Dis 2019; 10:90. [PMID: 30692516 PMCID: PMC6349874 DOI: 10.1038/s41419-019-1359-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 01/04/2019] [Accepted: 01/11/2019] [Indexed: 02/07/2023]
Abstract
Bone marrow-derived allogeneic (donor derived) mesenchymal stem cells (MSCs) are immunoprivileged and are considered to be prominent candidates for regenerative therapy for numerous degenerative diseases. Even though the outcome of initial allogeneic MSCs based clinical trials was encouraging, the overall enthusiasm, of late, has dimmed down. This is due to failure of long-term survival of transplanted cells in the recipient. In fact, recent analyses of allogeneic MSC-based studies demonstrated that cells after transplantation turned immunogenic and were subsequently rejected by host immune system. The current study reveals a novel mechanism of immune switch in MSCs. We demonstrate that hypoxia, a common denominator of ischemic tissues, induces an immune shift in MSCs from immunoprivileged to immunogenic state. The immunoprivilege of MSCs is preserved by downregulation or the absence of major histocompatibility complex class II (MHC-II) molecules. We found that 26S proteasome-mediated intracellular degradation of MHC-II helps maintain the absence of MHC-II expression on cell surface in normoxic MSCs and preserves their immunoprivilege. The exposure to hypoxia leads to dissociation of 19S and 20S subunits, and inactivation of 26S proteasome. This prevented the degradation of MHC-II and, as a result, the MSCs became immunogenic. Furthermore, we found that hypoxia-induced decrease in the levels of a chaperon protein HSP90α is responsible for inactivation of 26S proteasome. Maintaining HSP90α levels in hypoxic MSCs preserved the immunoprivilege of MSCs. Therefore, hypoxia-induced inactivation of 26S proteasome assembly instigates loss of immunoprivilege of allogeneic mesenchymal stem cells. Maintaining 26S proteasome activity in mesenchymal stem cells preserves their immunoprivilege.
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Affiliation(s)
- Ejlal Abu-El-Rub
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.,St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Glen Lester Sequiera
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.,St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Niketa Sareen
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.,St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Weiang Yan
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.,St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Meenal Moudgil
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.,St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Mohammad Golam Sabbir
- St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada.,Division of Neurodegenerative Disorders, University of Manitoba, Winnipeg, MB, Canada
| | - Sanjiv Dhingra
- Regenerative Medicine Program, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada. .,St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada.
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43
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Gharravi AM, Jafar A, Ebrahimi M, Mahmodi A, Pourhashemi E, Haseli N, Talaie N, Hajiasgarli P. Current status of stem cell therapy, scaffolds for the treatment of diabetes mellitus. Diabetes Metab Syndr 2018; 12:1133-1139. [PMID: 30168429 DOI: 10.1016/j.dsx.2018.06.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 06/25/2018] [Indexed: 12/24/2022]
Abstract
Diabetes mellitus (DM) remains the 7th leading cause of death in the world. Daily insulin injection is one component of a treatment plan for people with Diabetes mellitus type 1 (T1DM) that restores normal or near-normal blood sugar levels. However, Insulin treatment depends upon a variety of individual factors and leads to poor and drastic glycemic control. The need for an effective cell replacement strategy will be the aim of future clinical trials. Therefore, the aim of this systematic review is to outline the latest advances in scaffolding and stem cell therapy as a non-pharmacologic treatment for T1DM. It also emphasizes on some pancreas differentiation protocols and the clinical trials associated with stem cell therapy regarding T1DM in vitro and in vivo.
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Affiliation(s)
- Anneh Mohammad Gharravi
- Stem Cells and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
| | - Alireza Jafar
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mehrdad Ebrahimi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Ahmad Mahmodi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Erfan Pourhashemi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Nasrin Haseli
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Niloofar Talaie
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Parinaz Hajiasgarli
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
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44
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Saeedi P, Halabian R, Fooladi AAI. Antimicrobial effects of mesenchymal stem cells primed by modified LPS on bacterial clearance in sepsis. J Cell Physiol 2018; 234:4970-4986. [PMID: 30216449 DOI: 10.1002/jcp.27298] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 07/31/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND OBJECTIVES Mesenchymal stem cells (MSCs)-based regenerative therapy is now considered as an alternative approach to revive infectious diseases, including sepsis. Nevertheless, the efficiency of MSC application is limited by the poor survival rate of engrafted MSCs. Hence, preconditioning was established as a strategy to increase the cells' efficiency. METHODS MSCs were preconditioned with 1 μg/ml of three different lipopolysaccharides (LPSs) of Pseudomonas (Pse-LPS), Acinetobacter (Ac-LPS), and Acinetobacter inactivated lipid A by PagL (Ac-LPS-PagL). Then, preconditioned MSCs were exposed to oxidative stress and serum deprivation followed by evaluation of the antibacterial activity, survival, and apoptosis of MSCs. Then, the murine sepsis model treated with 100 μl phosphate-buffered saline (control group, sepsis group), 100 μl of 1 × 10 6 wild MSCs (MSC group), and three remained groups received 100 μl of 1 × 10 6 LPS-preconditioned MSCs (Pse-LPS-MSCs group: LPS purified from Pseudomonas, or Ac-LPS-MSCs group: LPS purified from Acinetobacter, and Ac-PagL-LPS-MSCs group: detoxified LPS Pagl). RESULTS After 4 days, LPS-preconditioned MSC transplantation modulated the immune response and reduced inflammation in septic mice. Apoptosis of Pse-LPS/Ac-LPS-preconditioned-MSCs was obviously reduced in vitro, and the survival rate of engrafted mice was evidently elevated in Pse-LPS-MSCs and Ac-LPS-MSCs groups compared with other three groups. CONCLUSION LPS preconditioning provides an innovative strategy for evolving functional and biological properties of MSCs and ameliorates the survival rate of the mouse model of sepsis after MSC transplantation, protects cells from apoptosis and organ damages, and evaluates therapeutic properties, including immunemodulatory.
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Affiliation(s)
- Pardis Saeedi
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Raheleh Halabian
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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45
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Xu X, Gao D, Wang P, Chen J, Ruan J, Xu J, Xia X. Efficient homology-directed gene editing by CRISPR/Cas9 in human stem and primary cells using tube electroporation. Sci Rep 2018; 8:11649. [PMID: 30076383 PMCID: PMC6076306 DOI: 10.1038/s41598-018-30227-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 07/20/2018] [Indexed: 12/30/2022] Open
Abstract
CRISPR/Cas9 efficiently generates gene knock-out via nonhomologous end joining (NHEJ), but the efficiency of precise homology-directed repair (HDR) is substantially lower, especially in the hard-to-transfect human stem cells and primary cells. Herein we report a tube electroporation method that can effectively transfect human stem cells and primary cells with minimal cytotoxicity. When applied to genome editing using CRISPR/Cas9 along with single stranded DNA oligonucleotide (ssODN) template in human induced pluripotent stem cells (iPSCs), up to 42.1% HDR rate was achieved, drastically higher than many reported before. We demonstrated that the high HDR efficiency can be utilized to increase the gene ablation rate in cells relevant to clinical applications, by knocking-out β2-microglobulin (B2M) in primary human mesenchymal stem cells (MSCs, 37.3% to 80.2%), and programmed death-1 (PD-1) in primary human T cells (42.6% to 58.6%). Given the generality and efficiency, we expect that the method will have immediate impacts in cell research as well as immuno- and transplantation therapies.
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Affiliation(s)
- Xiaoyun Xu
- Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, Texas, USA
| | - Dongbing Gao
- Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, Texas, USA
| | - Ping Wang
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jian Chen
- Celetrix Biotechnologies, Manassas, Virginia, USA
| | - Jinxue Ruan
- Center for Advanced Models and Translational Sciences and Therapeutics, University of Michigan Medical School, Ann Arbor, MI, 48109-2800, USA
| | - Jie Xu
- Center for Advanced Models and Translational Sciences and Therapeutics, University of Michigan Medical School, Ann Arbor, MI, 48109-2800, USA.
| | - Xiaofeng Xia
- Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, Texas, USA.
- Weill Cornell Medical College, Cornell University, New York, New York, USA.
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46
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Barrachina L, Remacha AR, Romero A, Zaragoza P, Vázquez FJ, Rodellar C. Differentiation of equine bone marrow derived mesenchymal stem cells increases the expression of immunogenic genes. Vet Immunol Immunopathol 2018; 200:1-6. [DOI: 10.1016/j.vetimm.2018.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/14/2018] [Accepted: 04/09/2018] [Indexed: 12/27/2022]
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47
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Amer MG, Embaby AS, Karam RA, Amer MG. Role of adipose tissue derived stem cells differentiated into insulin producing cells in the treatment of type I diabetes mellitus. Gene 2018; 654:87-94. [PMID: 29452233 DOI: 10.1016/j.gene.2018.02.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 01/19/2018] [Accepted: 02/01/2018] [Indexed: 02/07/2023]
Abstract
Generation of new β cells is an important approach in the treatment of type 1 diabetes mellitus (type 1 DM). Adipose tissue-derived stem cells (ADSCs) might be one of the best sources for cell replacement therapy for diabetes. Therefore, this work aimed to test the possible role of transplanted insulin-producing cells (IPCs) differentiated from ADSCs in treatment of streptozotocin (STZ) induced type I DM in rats. Type 1 DM was induced by single intra peritoneal injection with STZ (50 mg/kg BW). Half of the diabetic rats were left without treatment and the other half were injected with differentiated IPCs directly into the pancreas. ADSCs were harvested, cultured and identified by testing their phenotypes through flow cytometry. They were further subjected to differentiation into IPCs using differentiation medium. mRNA expression of pancreatic transcription factors (pdx1), insulin and glucose transporter-2 genes by real time PCR was done to detect the cellular differentiation and confirmed by stimulated insulin secretion. The pancreatic tissues from all groups were examined 2 months after IPC transplantation and were subjected to histological, Immunohistochemical and morphometric study. The differentiated IPCs showed significant expression of pancreatic β cell markers and insulin secretion in glucose dependent manner. Treatment with IPCs induced apparent regeneration, diffused proliferated islet cells and significant increase in C-peptide immune reaction. We concluded that transplantation of differentiated IPCs improved function and morphology of Islet cells in diabetic rats. Consequently, this therapy option may be a promising therapeutic approach to patient with type 1 DM if proven to be effective and safe.
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Affiliation(s)
- Mona G Amer
- Histology & Cell Biology, Faculty of Medicine, Zagazig University, Egypt; Anatomy and histology department, College of medicine, Taif University, Saudi Arabia
| | - Azza S Embaby
- Histology & Cell Biology, Faculty of Medicine, Beni-Sueif University, Egypt
| | - Rehab A Karam
- Medical Biochemistry, Faculty of Medicine, Zagazig University, Egypt.
| | - Marwa G Amer
- Clinical pathology Department, Faculty of Medicine, Zagazig University, Egypt
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48
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Dixit S, Baganizi DR, Sahu R, Dosunmu E, Chaudhari A, Vig K, Pillai SR, Singh SR, Dennis VA. Immunological challenges associated with artificial skin grafts: available solutions and stem cells in future design of synthetic skin. J Biol Eng 2017; 11:49. [PMID: 29255480 PMCID: PMC5729423 DOI: 10.1186/s13036-017-0089-9] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 11/17/2017] [Indexed: 12/29/2022] Open
Abstract
The repair or replacement of damaged skins is still an important, challenging public health problem. Immune acceptance and long-term survival of skin grafts represent the major problem to overcome in grafting given that in most situations autografts cannot be used. The emergence of artificial skin substitutes provides alternative treatment with the capacity to reduce the dependency on the increasing demand of cadaver skin grafts. Over the years, considerable research efforts have focused on strategies for skin repair or permanent skin graft transplantations. Available skin substitutes include pre- or post-transplantation treatments of donor cells, stem cell-based therapies, and skin equivalents composed of bio-engineered acellular or cellular skin substitutes. However, skin substitutes are still prone to immunological rejection, and as such, there is currently no skin substitute available to overcome this phenomenon. This review focuses on the mechanisms of skin rejection and tolerance induction and outlines in detail current available strategies and alternatives that may allow achieving full-thickness skin replacement and repair.
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Affiliation(s)
- Saurabh Dixit
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA.,Immunity, Inflammation, and Disease Laboratory, NIH/NIEHS, Durham, 27709 NC USA
| | - Dieudonné R Baganizi
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
| | - Rajnish Sahu
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
| | - Ejowke Dosunmu
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
| | - Atul Chaudhari
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
| | - Komal Vig
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
| | - Shreekumar R Pillai
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
| | - Shree R Singh
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
| | - Vida A Dennis
- Center for Nanobiotechnology Research and Department of Biological Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104 USA
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49
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Lohan P, Treacy O, Griffin MD, Ritter T, Ryan AE. Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning? Front Immunol 2017; 8:1626. [PMID: 29225601 PMCID: PMC5705547 DOI: 10.3389/fimmu.2017.01626] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/09/2017] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous) MSC may be the safer choice in terms of avoiding unwanted immune responses, factors including donor comorbidities may preclude these cells from use. In these situations, allogeneic MSC derived from genetically unrelated individuals must be used. While allogeneic MSC were initially believed to be immune-privileged, substantial evidence now exists to prove otherwise with multiple studies documenting specific cellular and humoral immune responses against donor antigens following administration of these cells. In this article, we will review recent published studies using non-manipulated, inflammatory molecule-activated (licensed) and differentiated allogeneic MSC, as well as MSC extracellular vesicles focusing on the immune responses to these cells and whether or not such responses have an impact on allogeneic MSC-mediated safety and efficacy.
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Affiliation(s)
- Paul Lohan
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Oliver Treacy
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,CURAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland
| | - Thomas Ritter
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,CURAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland
| | - Aideen E Ryan
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
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50
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Franceschetti T, De Bari C. The potential role of adult stem cells in the management of the rheumatic diseases. Ther Adv Musculoskelet Dis 2017; 9:165-179. [PMID: 28717403 PMCID: PMC5502944 DOI: 10.1177/1759720x17704639] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 02/28/2017] [Indexed: 12/27/2022] Open
Abstract
Adult stem cells are considered as appealing therapeutic candidates for inflammatory and degenerative musculoskeletal diseases. A large body of preclinical research has contributed to describing their immune-modulating properties and regenerative potential. Additionally, increasing evidence suggests that stem cell differentiation and function are disrupted in the pathogenesis of rheumatic diseases. Clinical studies have been limited, for the most part, to the application of adult stem cell-based treatments on small numbers of patients or as a 'salvage' therapy in life-threatening disease cases. Nevertheless, these preliminary studies indicate that adult stem cells are promising tools for the long-term treatment of rheumatic diseases. This review highlights recent knowledge acquired in the fields of hematopoietic and mesenchymal stem cell therapy for the management of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and osteoarthritis (OA) and the potential mechanisms mediating their function.
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Affiliation(s)
- Tiziana Franceschetti
- Arthritis & Regenerative Medicine Laboratory, Aberdeen Centre for Arthritis and Musculoskeletal Health, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - Cosimo De Bari
- Arthritis & Regenerative Medicine Laboratory, Aberdeen Centre for Arthritis and Musculoskeletal Health, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
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