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1
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Huang WC, Li YC, Chen PX, Ma KSK, Wang LT. Mesenchymal stem cell therapy as a game-changer in liver diseases: review of current clinical trials. Stem Cell Res Ther 2025; 16:3. [PMID: 39762946 PMCID: PMC11705688 DOI: 10.1186/s13287-024-04127-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025] Open
Abstract
Chronic liver diseases, including cirrhosis and liver failure, remain formidable challenges due to their complex progression and limited therapeutic options. Mesenchymal stem cell (MSC) therapy has emerged as a game-changing approach, leveraging its potent immunomodulatory, anti-fibrotic, and regenerative capabilities, along with the ability to transdifferentiate into hepatocytes. This review delves into the latest advances in MSC-based treatments for chronic and end-stage liver diseases, as highlighted in current clinical trials. MSCs derived from bone marrow and umbilical cord have shown remarkable promise in reversing liver damage, improving liver function, and providing hope for patients who do not respond to conventional therapies. When administered through hepatic, portal, or peripheral veins, MSCs have significantly improved liver histology, reduced fibrosis, and restored functional capacity. Furthermore, MSC-derived materials, such as extracellular vesicles and exosomes, are emerging as cutting-edge tools for treating liver failure and mitigating post-transplant complications. While autologous MSC-derived hepatocytes hold promise for non-fatal cirrhosis, allogeneic MSCs are being applied in more severe conditions, including liver failure and transplantation cases. Despite these promising early outcomes, larger trials and long-term studies are essential to fully harness MSCs as a transformative, off-the-shelf alternative to liver transplantation, heralding a new era in regenerative liver therapies.
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Affiliation(s)
- Wei-Chen Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Laboratory of Clinical Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Yuan-Chi Li
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Pin-Xuan Chen
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Kevin Sheng-Kai Ma
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Li-Tzu Wang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan.
- Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
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2
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Barbado J. Mesenchymal stem cell transplantation may be able to induce immunological tolerance in systemic lupus erythematosus. Biomed J 2024; 47:100724. [PMID: 38616015 PMCID: PMC11340565 DOI: 10.1016/j.bj.2024.100724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/24/2024] [Accepted: 04/06/2024] [Indexed: 04/16/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a common, potentially fatal autoimmune disease involving a significant inflammatory response. SLE is characterised by failure of self-tolerance and activation of autoreactive lymphocytes, leading to persistent disease. Although current treatments achieve some improvement in patients, some SLE patients are refractory and others relapse after drug withdrawal. The toxicity of current drug regimens, with recurrent infections, together with ongoing inflammation, contribute significantly to the progressive decline in organ function. Therefore, the clinical management of SLE requires more effective and less toxic treatments, ideally inducing complete remission and self-tolerance. In this context, recently developed cell therapies based on mesenchymal stem cells (MSCs) represent a promising and safe strategy in SLE. MSCs inhibit the activation of B cells, prevent the differentiation of CD4⁺ T cells into autoreactive T cells, reprogram macrophages with anti-inflammatory effects and inhibit dendritic cells (DCs), limiting their activity as antigen-presenting cells. In addition, MSCs could induce antigen-specific tolerance by enhancing anergy processes in autoreactive cells - by inhibiting the maturation of antigen-presenting DCs, blocking the T cell receptor (TcR) pathway and secreting inhibitory molecules -, increasing apoptotic activity to eliminate them, and activating regulatory T cells (Tregs) to enhance their proliferation and induction of tolerogenic DCs. Thus, induction of self-tolerance leads to immune balance, keeping inflammation under control and reducing lupus flares.
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Affiliation(s)
- Julia Barbado
- Autoimmune Diseases Unit, Internal Medicine Department, University Hospital Rio Hortega, Valladolid, Spain.
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3
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Mei R, Wan Z, Yang C, Shen X, Wang R, Zhang H, Yang R, Li J, Song Y, Su H. Advances and clinical challenges of mesenchymal stem cell therapy. Front Immunol 2024; 15:1421854. [PMID: 39100671 PMCID: PMC11294097 DOI: 10.3389/fimmu.2024.1421854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/02/2024] [Indexed: 08/06/2024] Open
Abstract
In recent years, cell therapy has provided desirable properties for promising new drugs. Mesenchymal stem cells are promising candidates for developing genetic engineering and drug delivery strategies due to their inherent properties, including immune regulation, homing ability and tumor tropism. The therapeutic potential of mesenchymal stem cells is being investigated for cancer therapy, inflammatory and fibrotic diseases, among others. Mesenchymal stem cells are attractive cellular carriers for synthetic nanoparticles for drug delivery due to their inherent homing ability. In this review, we comprehensively discuss the various genetic and non-genetic strategies of mesenchymal stem cells and their derivatives in drug delivery, tumor therapy, immune regulation, tissue regeneration and other fields. In addition, we discuss the current limitations of stem cell therapy and the challenges in clinical translation, aiming to identify important development areas and potential future directions.
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Affiliation(s)
- Ruiyan Mei
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Zhuo Wan
- Department of Hematology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Cheng Yang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Xiangjing Shen
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Ronglin Wang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Haihua Zhang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Rui Yang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Junqiang Li
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Yang Song
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Haichuan Su
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
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4
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Norte-Muñoz M, García-Bernal D, García-Ayuso D, Vidal-Sanz M, Agudo-Barriuso M. Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina. Neural Regen Res 2024; 19:542-547. [PMID: 37721282 PMCID: PMC10581591 DOI: 10.4103/1673-5374.380876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/25/2023] [Accepted: 05/11/2023] [Indexed: 09/19/2023] Open
Abstract
Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models. Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration, namely trophic factor deprivation and neuroinflammation. Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement. However, little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system. Here, we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system, focusing on recent work in the retina and the importance of the type of transplantation.
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Affiliation(s)
- María Norte-Muñoz
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - David García-Bernal
- Grupo de Investigación Trasplante Hematopoyético y Terapia celular, Departamento de Bioquímica e Inmunología. Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Diego García-Ayuso
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Manuel Vidal-Sanz
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Marta Agudo-Barriuso
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
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5
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Gao M, Guo H, Dong X, Wang Z, Yang Z, Shang Q, Wang Q. Regulation of inflammation during wound healing: the function of mesenchymal stem cells and strategies for therapeutic enhancement. Front Pharmacol 2024; 15:1345779. [PMID: 38425646 PMCID: PMC10901993 DOI: 10.3389/fphar.2024.1345779] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 03/02/2024] Open
Abstract
A wound takes a long time to heal and involves several steps. Following tissue injury, inflammation is the primary cause of tissue regeneration and repair processes. As a result, the pathophysiological processes involving skin damage, healing, and remodeling depend critically on the control of inflammation. The fact that it is a feasible target for improving the prognosis of wound healing has lately become clear. Mesenchymal stem cells (MSCs) are an innovative and effective therapeutic option for wound healing due to their immunomodulatory and paracrine properties. By controlling the inflammatory milieu of wounds through immunomodulation, transplanted MSCs have been shown to speed up the healing process. In addition to other immunomodulatory mechanisms, including handling neutrophil activity and modifying macrophage polarization, there may be modifications to the activation of T cells, natural killer (NK) cells, and dendritic cells (DCs). Furthermore, several studies have shown that pretreating MSCs improves their ability to modulate immunity. In this review, we summarize the existing knowledge about how MSCs influence local inflammation in wounds by influencing immunity to facilitate the healing process. We also provide an overview of MSCs optimizing techniques when used to treat wounds.
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Affiliation(s)
| | | | | | | | | | | | - Qiying Wang
- Department of Plastic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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6
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Barrett JG, MacDonald ES. Use of Biologics and Stem Cells in the Treatment of Other Inflammatory Diseases in the Horse. Vet Clin North Am Equine Pract 2023; 39:553-563. [PMID: 37607855 DOI: 10.1016/j.cveq.2023.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells that act via multiple mechanisms to coordinate, inhibit, and control the cells of the immune system. MSCs act as rescuers for various damaged or degenerated cells of the body via (1) cytokines, growth factors, and signaling molecules; (2) extracellular vesicle (exosome) signaling; and (3) direct donation of mitochondria. Several studies evaluating the efficacy of MSCs have used MSCs grown using xenogeneic media, which may reduce or eliminate efficacy. Although more research is needed to optimize the anti-inflammatory potential of MSCs, there is ample evidence that MSC therapeutics are worthy of further development.
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Affiliation(s)
- Jennifer G Barrett
- Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, USA.
| | - Elizabeth S MacDonald
- Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, USA
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7
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Abinti M, Favi E, Alfieri CM, Zanoni F, Armelloni S, Ferraresso M, Cantaluppi V, Castellano G. Update on current and potential application of extracellular vesicles in kidney transplantation. Am J Transplant 2023; 23:1673-1693. [PMID: 37517555 DOI: 10.1016/j.ajt.2023.07.010] [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: 05/02/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023]
Abstract
Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy.
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Affiliation(s)
- Matteo Abinti
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Evaldo Favi
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Carlo Maria Alfieri
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Francesca Zanoni
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Silvia Armelloni
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mariano Ferraresso
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplant Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), "Maggiore della Carita" University Hospital, Novara, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
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8
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Chauhan A, Agarwal S, Masih M, Gautam PK. The Multifunction Role of Tumor-Associated Mesenchymal Stem Cells and Their Interaction with Immune Cells in Breast Cancer. Immunol Invest 2023; 52:856-878. [PMID: 37615117 DOI: 10.1080/08820139.2023.2249025] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Mesenchymal stem cells (MSCs) are a heterogeneous group of progenitor cells that play a multifunctional role including tissue regeneration, self-renewal properties, and differentiate into cells of mesodermal lineage such as adipocytes, osteoblasts, and chondrocytes. MSCs come into contact with tumor microenvironment (TME) and differentiate into tumor-associated MSCs (TA-MSCs). Various substances such as chemokines, cytokines, growth factors, and others are released by tumor cells to recruit MSCs. TA-MSCs induced epithelial-mesenchymal transition (EMT) program which mediates tumor growth progression, migration, and invasion. Role of MSCs in the tumor progression, stemness, malignancy, and treatment resistance in the breast cancer TME. Immunomodulation by MSCs is mediated by a combination of cell contact-dependent mechanisms and soluble substances. Monocytes/macrophages, dendritic cells, T cells, B cells, and NK cells all show signs of MSCs' immunomodulatory capability. In a complicated interplay initiated by MSCs, anti-inflammatory monocytes/macrophages and regulatory T cells (Tregs) play a key role, as they unveil their full immunomodulatory potential. MSC- secreted cytokines are commonly blamed for the interaction between MSCs, monocytes, and Tregs. Here, we review the current knowledge of cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the role MSCs play in breast cancer progression and its TME.Abbreviation MSC: Mesenchymal Stem Cells; TME: Tumor Microenvironment; TAMS; Tumour-associated Macrophages; ECM: Extracellular matrix; CAFs: Cancer-associated Fibroblasts; CFUs: Colony-forming unit Fibroblasts; Tregs: T regulatory cells; Bregs; Regulatory B cells; IFN-γ: Interferon-gamma; TNF-α: Tumour Necrosis Factor-alpha; IL: Interleukin; TGF-β: transforming growth factorβ; PGE2: Prostaglandin E2; CXCR: Chemokine Receptor; Blimp-1; B lymphocyte-induced maturation protein-1; CCL: Chemokine motif ligand; EMT: Epithelial-mesenchymal transition.
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Affiliation(s)
- Anita Chauhan
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Sonam Agarwal
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Marilyn Masih
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Pramod Kumar Gautam
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
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9
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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10
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Reynolds L, Luo Z, Singh K. Diabetic complications and prospective immunotherapy. Front Immunol 2023; 14:1219598. [PMID: 37483613 PMCID: PMC10360133 DOI: 10.3389/fimmu.2023.1219598] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/22/2023] [Indexed: 07/25/2023] Open
Abstract
The incidence of Diabetes Mellitus is increasing globally. Individuals who have been burdened with diabetes for many years often develop complications as a result of hyperglycemia. More and more research is being conducted highlighting inflammation as an important factor in disease progression. In all kinds of diabetes, hyperglycemia leads to activation of alternative glucose metabolic pathways, resulting in problematic by-products including reactive oxygen species and advanced glycation end products. This review takes a look into the pathogenesis of three specific diabetic complications; retinopathy, nephropathy and neuropathy as well as their current treatment options. By considering recent research papers investigating the effects of immunotherapy on relevant conditions in animal models, multiple strategies are suggested for future treatment and prevention of diabetic complications with an emphasis on molecular targets associated with the inflammation.
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11
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Zuo H, Wang Y, Yuan M, Zheng W, Tian X, Pi Y, Zhang X, Song H. Small extracellular vesicles from HO-1-modified bone marrow-derived mesenchymal stem cells attenuate ischemia-reperfusion injury after steatotic liver transplantation by suppressing ferroptosis via miR-214-3p. Cell Signal 2023; 109:110793. [PMID: 37414107 DOI: 10.1016/j.cellsig.2023.110793] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/25/2023] [Accepted: 07/01/2023] [Indexed: 07/08/2023]
Abstract
Donor shortage is a major problem that limits liver transplantation availability. Steatotic donor liver presents a feasible strategy to solve this problem. However, severe ischemia-reperfusion injury (IRI) is an obstacle to the adoption of steatotic transplanted livers. Evidence from our prior studies indicated that bone marrow mesenchymal stem cells modified with heme oxygenase-1 (HMSCs) can attenuate non-steatotic liver IRI. However, the contribution of HMSCs in transplanted steatotic liver IRI is unclear. Here, HMSCs and their derived small extracellular vesicles (HM-sEVs) alleviated IRI in transplanted steatotic livers. After liver transplantation, there was significant enrichment of the differentially expressed genes in the glutathione metabolism and ferroptosis pathways, accompanied by ferroptosis marker upregulation. The HMSCs and HM-sEVs suppressed ferroptosis and attenuated IRI in the transplanted steatotic livers. MicroRNA (miRNA) microarray and validation experiments indicated that miR-214-3p, which was abundant in the HM-sEVs, suppressed ferroptosis by targeting cyclooxygenase 2 (COX2). In contrast, COX2 overexpression reversed this effect. Knockdown of miR-214-3p in the HM-sEVs diminished its ability to suppress ferroptosis and protect liver tissues/cells. The findings suggested that HM-sEVs suppressed ferroptosis to attenuate transplanted steatotic liver IRI via the miR-214-3p-COX2 axis.
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Affiliation(s)
- Huaiwen Zuo
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China
| | - Yuxin Wang
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China
| | - Mengshu Yuan
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China
| | - Weiping Zheng
- Department of Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, PR China; NHC Key Laboratory of Critical Care Medicine, Tianjin 300192, PR China
| | - Xiaorong Tian
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China
| | - Yilin Pi
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China
| | - Xinru Zhang
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China
| | - Hongli Song
- Department of Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, PR China; Tianjin Key Laboratory of Organ Transplantation, Tianjin, PR China.
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12
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Zhang Q, Wang J, Zhang J, Liu F. Potential functions and therapeutic implications of glioma-resident mesenchymal stem cells. Cell Biol Toxicol 2023; 39:853-866. [PMID: 37138122 DOI: 10.1007/s10565-023-09808-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 04/27/2023] [Indexed: 05/05/2023]
Abstract
Mesenchymal stem cells (MSCs) are emerging crucial regulators in the tumor microenvironment (TME), which contributes to tumor progression and therapeutic resistance. MSCs are considered to be the stromal components of several tumors, their ultimate contribution to tumorigenesis and their potential to drive tumor stem cells, especially in the unique microenvironment of gliomas. Glioma-resident MSCs (GR-MSCs) are non-tumorigenic stromal cells. The phenotype of GR-MSCs is similar to that of prototype bone marrow-MSCs and GR-MSCs enhance the GSCs tumorigenicity via the IL-6/gp130/STAT3 pathway. The higher percentage of GR-MSCs in TME results in the poor prognosis of glioma patients and illuminate the tumor-promoting roles for GR-MSCs by secreting specific miRNA. Furthermore, the GR-MSC subpopulations associated with CD90 expression determine their different functions in glioma progression and CD90low MSCs generate therapeutic resistance by increasing IL-6-mediated FOXS1 expression. Therefore, it is urgent to develop novel therapeutic strategies targeting GR-MSCs for GBM patients. Despite that several functions of GR-MSCs have been confirmed, their immunologic landscapes and deeper mechanisms associated with the functions are not still expounded. In this review, we summarize the progress and potential function of GR-MSCs, as well as highlight their therapeutic implications based on GR-MSCs in GBM patients.
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Affiliation(s)
- Qing Zhang
- Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Laboratory of Biomedical Materials, Beijing, China
- Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jialin Wang
- Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Laboratory of Biomedical Materials, Beijing, China
| | - Junwen Zhang
- Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Beijing Laboratory of Biomedical Materials, Beijing, China
| | - Fusheng Liu
- Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
- Beijing Laboratory of Biomedical Materials, Beijing, China.
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13
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Giacomini C, Granéli C, Hicks R, Dazzi F. The critical role of apoptosis in mesenchymal stromal cell therapeutics and implications in homeostasis and normal tissue repair. Cell Mol Immunol 2023; 20:570-582. [PMID: 37185486 DOI: 10.1038/s41423-023-01018-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/30/2023] [Indexed: 05/17/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have been extensively tested for the treatment of numerous clinical conditions and have demonstrated good safety but mixed efficacy. Although this outcome can be attributed in part to the heterogeneity of cell preparations, the lack of mechanistic understanding and tools to establish cell pharmacokinetics and pharmacodynamics, as well as the poorly defined criteria for patient stratification, have hampered the design of informative clinical trials. We and others have demonstrated that MSCs can rapidly undergo apoptosis after their infusion. Apoptotic MSCs are phagocytosed by monocytes/macrophages that are then reprogrammed to become anti-inflammatory cells. MSC apoptosis occurs when the cells are injected into patients who harbor activated cytotoxic T or NK cells. Therefore, the activation state of cytotoxic T or NK cells can be used as a biomarker to predict clinical responses to MSC treatment. Building on a large body of preexisting data, an alternative view on the mechanism of MSCs is that an inflammation-dependent MSC secretome is largely responsible for their immunomodulatory activity. We will discuss how these different mechanisms can coexist and are instructed by two different types of MSC "licensing": one that is cell-contact dependent and the second that is mediated by inflammatory cytokines. The varied and complex mechanisms by which MSCs can orchestrate inflammatory responses and how this function is specifically driven by inflammation support a physiological role for tissue stroma in tissue homeostasis, and it acts as a sensor of damage and initiator of tissue repair by reprogramming the inflammatory environment.
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Affiliation(s)
- Chiara Giacomini
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK.
| | - Cecilia Granéli
- BioPharmaceuticals R&D Cell Therapy Department, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ryan Hicks
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
- BioPharmaceuticals R&D Cell Therapy Department, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Francesco Dazzi
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK.
- BioPharmaceuticals R&D Cell Therapy Department, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
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14
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Sheikholeslami A, Fazaeli H, Kalhor N, Khoshandam M, Eshagh Hoseini SJ, Sheykhhasan M. Use of Mesenchymal Stem Cells in Crohn's Disease and Perianal Fistulas: A Narrative Review. Curr Stem Cell Res Ther 2023; 18:76-92. [PMID: 34530720 DOI: 10.2174/1574888x16666210916145717] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.
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Affiliation(s)
- Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Hoda Fazaeli
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom,Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Mohadeseh Khoshandam
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | | | - Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
- Department of Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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15
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Abdolmohammadi K, Mahmoudi T, Alimohammadi M, Tahmasebi S, Zavvar M, Hashemi SM. Mesenchymal stem cell-based therapy as a new therapeutic approach for acute inflammation. Life Sci 2023; 312:121206. [PMID: 36403645 DOI: 10.1016/j.lfs.2022.121206] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/12/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022]
Abstract
Acute inflammatory diseases such as acute colitis, kidney injury, liver failure, lung injury, myocardial infarction, pancreatitis, septic shock, and spinal cord injury are significant causes of death worldwide. Despite advances in the understanding of its pathophysiology, there are many restrictions in the treatment of these diseases, and new therapeutic approaches are required. Mesenchymal stem cell-based therapy due to immunomodulatory and regenerative properties is a promising candidate for acute inflammatory disease management. Based on preclinical results, mesenchymal stem cells and their-derived secretome improved immunological and clinical parameters. Furthermore, many clinical trials of acute kidney, liver, lung, myocardial, and spinal cord injury have yielded promising results. In this review, we try to provide a comprehensive view of mesenchymal stem cell-based therapy in acute inflammatory diseases as a new treatment approach.
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Affiliation(s)
- Kamal Abdolmohammadi
- Department of Immunology, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Tayebeh Mahmoudi
- 17 Shahrivar Hospital, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Zavvar
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanothechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Abstract
Abstract
The pathogenesis of connective tissue diseases (CTDs), represented by systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS), and idiopathic inflammatory myopathies (IIM), includes various immune cells involved in both innate and adaptive immunity. The mesenchymal stem cells (MSCs) are unique due to their regulatory effect on immunity. This makes them a promising therapeutic approach for patients with immune-mediated disorders such as CTD. The safety and clinical efficacy of MSC treatment in CTD have been tested in a growing number of preclinical and clinical studies. Administration of MSCs has consistently shown benefits with both symptomatic and histologic improvement in CTD animal models. MSC therapies in severe and drug-resistant CTD patients have shown promise in a number of the pilot studies, cohort studies, and randomized controlled trials in SLE, RA, and SSc, but some problems still need to be resolved in the transition from the bench to the bedside. The relevant studies in pSS and IIM are still in their infancy, but have displayed encouraging outcomes. Considerable efficacy variations have been observed in terms of the route of delivery, time of MSC injection, origin of the MSCs and dosage. Furthermore, the optimization of conventional drugs combined with MSC therapies and the applications of novel cell engineering approaches requires additional research. In this review, we summarize the current evidence about the immunoregulatory mechanism of MSCs, as well as the preclinical and clinical studies of MSC-based therapy for the treatment of CTDs.
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17
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Tan N, Xin W, Huang M, Mao Y. Mesenchymal stem cell therapy for ischemic stroke: Novel insight into the crosstalk with immune cells. Front Neurol 2022; 13:1048113. [PMID: 36425795 PMCID: PMC9679024 DOI: 10.3389/fneur.2022.1048113] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/17/2022] [Indexed: 09/29/2023] Open
Abstract
Stroke, a cerebrovascular accident, is prevalent and the second highest cause of death globally across patient populations; it is as a significant cause of morbidity and mortality. Mesenchymal stem cell (MSC) transplantation is emerging as a promising treatment for alleviating neurological deficits, as indicated by a great number of animal and clinical studies. The potential of regulating the immune system is currently being explored as a therapeutic target after ischemic stroke. This study will discuss recent evidence that MSCs can harness the immune system by interacting with immune cells to boost neurologic recovery effectively. Moreover, a notion will be given to MSCs participating in multiple pathological processes, such as increasing cell survival angiogenesis and suppressing cell apoptosis and autophagy in several phases of ischemic stroke, consequently promoting neurological function recovery. We will conclude the review by highlighting the clinical opportunities for MSCs by reviewing the safety, feasibility, and efficacy of MSCs therapy.
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Affiliation(s)
- Nana Tan
- Department of Health Management, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenqiang Xin
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Min Huang
- Department of Health Management, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuling Mao
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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18
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Wang Y, Fang J, Liu B, Shao C, Shi Y. Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell 2022; 29:1515-1530. [DOI: 10.1016/j.stem.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/19/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022]
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19
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Li X, Cui L, Feng G, Yu S, Shao G, He N, Li S. Collagen peptide promotes DSS-induced colitis by disturbing gut microbiota and regulation of macrophage polarization. Front Nutr 2022; 9:957391. [PMID: 36313077 PMCID: PMC9608506 DOI: 10.3389/fnut.2022.957391] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease caused by mucosal immune system disorder, which has increased steadily all over the world. Previous studies have shown that collagen peptide (CP) has various beneficial biological activities, it is not clear whether the effect of CP on UC is positive or negative. In this study, 2.5% dextran sulfate sodium (DSS) was used to establish acute colitis in mice. Our results suggested that CP supplementation (200, 400 mg/kg/day) promoted the progression of colitis, increased the expression of inflammatory factors and the infiltration of colonic lamina propria macrophages. Gut microbiota analysis showed the composition changed significantly and inflammation promoted bacteria was after CP treatment. Meanwhile, the effect of CP on macrophage polarization was further determined in Raw264.7 cell line. The results showed that CP treatment could increase the polarization of M1 macrophages and promote the expression of inflammatory factors. In conclusion, our results showed that CP treatment could disrupt the gut microbiota of host, promote macrophage activation and aggravate DSS-induced colitis. This may suggest that patients with intestinal inflammation should not take marine derived CP.
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Affiliation(s)
| | | | | | | | | | - Ningning He
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Shangyong Li
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, China
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20
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Zhou Y, Tao D, Shao Z, Wang X, Xu J, Li Y, Li K. Expression profiles of exosomal tRNA-derived fragments and their biological functions in lipomas. Front Cell Dev Biol 2022; 10:942133. [PMID: 36035989 PMCID: PMC9399354 DOI: 10.3389/fcell.2022.942133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/18/2022] [Indexed: 11/30/2022] Open
Abstract
There is evidence that exosomes derived from the lipoma tissue (Exo-LT) have a stronger capacity to promote the proliferation and migration of adipose-derived stem cells (ADSCs) than those from the adipose tissue (Exo-AT). But the Exo-LT do not have a significant effect on the adipogenic differentiation of the ADSCs. Recently, certain exosomal tRNA-derived fragments (tRFs) have been shown to play a crucial role in the pathogenesis of certain tumors. Therefore, it is necessary to identify the differently expressed tRFs in Exo-LT to further elucidate their molecular functions in lipomas. High-throughput sequencing was performed to examine the tRFs and mRNAs from the all samples belonging to the Exo-LT and Exo-AT groups. Target prediction and bioinformatics analysis were performed to explore their downstream mRNAs and biological functions. In total, 456 differently expressed tRFs and tiRNAs were identified in the Exo-LT group, 12 of which were up-regulated and 12 were down-regulated, respectively. Notably, tRF-1001 was most obviously down-regulated and tRF-3004a was most obviously up-regulated in the Exo-LT group. Moreover, among the target genes of tRF-1001 and tRF-3004a, both JAG2 and VSIG4 were significantly down-regulated in the Exo-LT group, while WNT5A, COL1A1, and PPARGC1A were highly expressed in both the Exo-LT and Exo-AT groups. The significant down-regulation of JAG2 and VSIG4 in the Exo-LT group could be due to the fact that Exo-LT had a stronger capacity to promote the proliferation and migration of ADSCs compared to the Exo-AT. The high expression of WNT5A, COL1A1, and PPARGC1A in both the Exo-LT and Exo-AT groups could be due to the similar ability of Exo-LT and Exo-AT to promote the adipogenic differentiation of ADSCs.
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Affiliation(s)
- Yuxi Zhou
- Department of Xiangya Stomatological Hospital and Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Daixi Tao
- Department of Changsha Traditional Chinese Medicine Hospital, Changsha, Hunan, China
| | - Zifei Shao
- Department of Xiangya Stomatological Hospital and Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Xiang Wang
- Department of Xiangya Stomatological Hospital and Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Jinhao Xu
- Department of Xiangya Stomatological Hospital and Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Yiyang Li
- Department of Xiangya Stomatological Hospital and Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Kun Li
- Department of Xiangya Stomatological Hospital and Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
- *Correspondence: Kun Li,
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21
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Zhang Z, Zhou X, Guo J, Zhang F, Qian Y, Wang G, Duan M, Wang Y, Zhao H, Yang Z, Liu Z, Jiang X. TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment. J Transl Med 2022; 20:320. [PMID: 35842634 PMCID: PMC9287873 DOI: 10.1186/s12967-022-03528-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
As an important component of the immunosuppressive tumor microenvironment (TME), it has been established that mesenchymal stem cells (MSCs) promote the progression of tumor cells. MSCs can directly promote the proliferation, migration, and invasion of tumor cells via cytokines and chemokines, as well as promote tumor progression by regulating the functions of anti-tumor immune and immunosuppressive cells. MSCs-derived extracellular vesicles (MSCs-EVs) contain part of the plasma membrane and signaling factors from MSCs; therefore, they display similar effects on tumors in the immunosuppressive TME. The tumor-promoting role of macrophage migration inhibitory factor (MIF) in the immunosuppressive TME has also been revealed. Interestingly, MIF exerts similar effects to those of MSCs in the immunosuppressive TME. In this review, we summarized the main effects and related mechanisms of tumor-associated MSCs (TA-MSCs), TA-MSCs-EVs, and MIF on tumors, and described their relationships. On this basis, we hypothesized that TA-MSCs-EVs, the MIF axis, and TA-MSCs form a positive feedback loop with tumor cells, influencing the occurrence and development of tumors. The functions of these three factors in the TME may undergo dynamic changes with tumor growth and continuously affect tumor development. This provides a new idea for the targeted treatment of tumors with EVs carrying MIF inhibitors.
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Affiliation(s)
- Zhenghou Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiangyu Zhou
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jinshuai Guo
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fusheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yiping Qian
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Guang Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Meiqi Duan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yutian Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Haiying Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zunpeng Liu
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
| | - Xiaofeng Jiang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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22
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Fang Y, Bouari S, Hoogduijn MJ, Ijzermans JNM, de Bruin RWF, Minnee RC. Therapeutic efficacy of extracellular vesicles to suppress allograft rejection in preclinical kidney transplantation models: A systematic review and meta-analysis. Transplant Rev (Orlando) 2022; 36:100714. [PMID: 35853384 DOI: 10.1016/j.trre.2022.100714] [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: 05/21/2022] [Revised: 07/07/2022] [Accepted: 07/10/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Kidney transplantation is the optimal treatment of end-stage renal disease. Extracellular vesicles (EVs) have tremendous therapeutic potential, but their role in modulating immune responses in kidney transplantation remains unclear. METHODS We performed a systematic review and meta-analysis to investigate the therapeutic efficacy of EVs in preclinical kidney transplant models. Outcomes for meta-analysis were graft survival and renal function. Subgroup analysis was conducted between immune cell derived EVs (immune cell-EVs) and mesenchymal stromal cell derived EVs (MSC-EVs). RESULTS Seven studies published from 2013 to 2021 were included. The overall effects showed that EVs had a positive role in prolonging allograft survival (standardized mean difference (SMD) = 2.00; 95% confidence interval (CI), 0.79 to 3.21; P < 0.01; I2 = 94%), reducing serum creatinine (SCr) (SMD = -2.19; 95%CI, -3.35 to -1.04; P < 0.01; I2 = 93%) and blood urea nitrogen (BUN) concentrations (SMD = -1.69; 95%CI, -2.98 to -0.40; P = 0.01; I2 = 94%). Subgroup analyses indicated that only immune cell-EVs significantly prolonged graft survival and improve renal function but not MSC-EVs. CONCLUSIONS EVs are promising candidates to suppress allograft rejection and improve kidney transplant outcome. Immune cell-EVs showed their superiority over MSC-EVs in prolonging graft survival and improving renal function. For interpretation of the outcomes, additional studies are needed to validate these findings.
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Affiliation(s)
- Yitian Fang
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Sarah Bouari
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Martin J Hoogduijn
- Erasmus MC Transplant Institute, Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Jan N M Ijzermans
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Ron W F de Bruin
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Robert C Minnee
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
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23
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Li J, Luo M, Li B, Lou Y, Zhu Y, Bai X, Sun B, Lu X, Luo P. Immunomodulatory Activity of Mesenchymal Stem Cells in Lupus Nephritis: Advances and Applications. Front Immunol 2022; 13:843192. [PMID: 35359961 PMCID: PMC8960601 DOI: 10.3389/fimmu.2022.843192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 02/17/2022] [Indexed: 12/29/2022] Open
Abstract
Lupus nephritis (LN) is a significant cause of various acute and chronic renal diseases, which can eventually lead to end-stage renal disease. The pathogenic mechanisms of LN are characterized by abnormal activation of the immune responses, increased cytokine production, and dysregulation of inflammatory signaling pathways. LN treatment is an important issue in the prevention and treatment of systemic lupus erythematosus. Mesenchymal stem cells (MSCs) have the advantages of immunomodulation, anti-inflammation, and anti-proliferation. These unique properties make MSCs a strong candidate for cell therapy of autoimmune diseases. MSCs can suppress the proliferation of innate and adaptive immune cells, such as natural killer cells (NKs), dendritic cells (DCs), T cells, and B cells. Furthermore, MSCs suppress the functions of various immune cells, such as the cytotoxicity of T cells and NKs, maturation and antibody secretion of B cells, maturation and antigen presentation of DCs, and inhibition of cytokine secretion, such as interleukins (ILs), tumor necrosis factor (TNF), and interferons (IFNs) by a variety of immune cells. MSCs can exert immunomodulatory effects in LN through these immune functions to suppress autoimmunity, improve renal pathology, and restore kidney function in lupus mice and LN patients. Herein, we review the role of immune cells and cytokines in the pathogenesis of LN and the mechanisms involved, as well as the progress of research on the immunomodulatory role of MSCs in LN.
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Affiliation(s)
- Jicui Li
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Manyu Luo
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Bing Li
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Yan Lou
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Yuexin Zhu
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Xue Bai
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Baichao Sun
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Xuehong Lu
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Ping Luo
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
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24
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Dihydroartemisinin Promoted Bone Marrow Mesenchymal Stem Cell Homing and Suppressed Inflammation and Oxidative Stress against Prostate Injury in Chronic Bacterial Prostatitis Mice Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:1829736. [PMID: 34956376 PMCID: PMC8694990 DOI: 10.1155/2021/1829736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/08/2021] [Indexed: 11/17/2022]
Abstract
Although bone marrow mesenchymal stem cells (BMMSCs) are effective in treating chronic bacterial prostatitis (CBP), the homing of BMMSCs seems to require ultrasound induction. Dihydroartemisinin (DHA) is an important derivative of artemisinin (ART) and has been previously reported to alleviate inflammation and autoimmune diseases. But the effect of DHA on chronic prostatitis (CP) is still unclear. This study aims to clarify the efficacy and mechanism of DHA in the treatment of CBP and its effect on the accumulation of BMMSCs. The experimental CBP was produced in C57BL/6 male mice via intraurethrally administered E. coli solution. Results showed that DHA treatment concentration-dependently promoted the accumulation of BMMSCs in prostate tissue of CBP mice. In addition, DHA and BMMSCs cotreatment significantly alleviated inflammation and improved prostate damage by decreasing the expression of proinflammatory factors such as TNF-α, IL-1β, and chemokines CXCL2, CXCL9, CXCL10, and CXCL11 in prostate tissue of CBP mice. Moreover, DHA and BMMSCs cotreatment displayed antioxidation property by increasing the production of glutathione peroxidase (GSH-Px), SOD, and decreasing malondialdehyde (MDA) expression. Mechanically, DHA and BMMSCs cotreatment significantly inhibited the expression of TGFβ-RI, TGFβ-RII, phosphor (p)-Smad2/3, and Smad4 in a dose-dependent manner while stimulated Smad7 expression in the same manner. In conclusion, our findings provided evidence that DHA effectively eliminated inflammatory and oxidative stress against prostate injury, and this effect involved the TGF-β/Smad signaling pathway in CBP.
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25
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Zhu R, Yan T, Feng Y, Liu Y, Cao H, Peng G, Yang Y, Xu Z, Liu J, Hou W, Wang X, Li Z, Deng L, Wang S, Li J, Han Q, Li H, Shan G, Cao Y, An X, Yan J, Zhang Z, Li H, Qu X, Zhu J, Zhou S, Wang J, Zhang F, Gao J, Jin R, Xu D, Ma YQ, Huang T, Peng S, Zheng Z, Stambler I, Gilson E, Lim LW, Moskalev A, Cano A, Chakrabarti S, Ulfhake B, Su H, Xu H, Xu S, Wei F, Brown-Borg HM, Min KJ, Ellison-Hughes G, Caruso C, Jin K, Zhao RC. Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms. Cell Res 2021; 31:1244-1262. [PMID: 34702946 PMCID: PMC8546390 DOI: 10.1038/s41422-021-00573-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 09/09/2021] [Indexed: 12/24/2022] Open
Abstract
The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors - CX3CR1 and L-selectin - were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.
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Affiliation(s)
- Rongjia Zhu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Tingdong Yan
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Yingmei Feng
- You'an Hospital, Capital Medical University, Beijing, China
| | - Yan Liu
- Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang, China
| | - Gongxin Peng
- Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yanlei Yang
- Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Xu
- School of Life Sciences, Shanghai University, Shanghai, China
- Versiti Blood Research Institute, Milwaukee, WI, USA
| | - Jingqi Liu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Hou
- You'an Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Wang
- Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhe Li
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Luchan Deng
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Shihua Wang
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Jing Li
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Qin Han
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Hongling Li
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Guangliang Shan
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yinghao Cao
- Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xingyan An
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Jianshe Yan
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Zhonghui Zhang
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Huafei Li
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Xuebin Qu
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Jiaqi Zhu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang, China
| | - Shumin Zhou
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Jiao Wang
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Fengchun Zhang
- Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinming Gao
- Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ronghua Jin
- You'an Hospital, Capital Medical University, Beijing, China.
| | - Dayong Xu
- Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Yan-Qing Ma
- Versiti Blood Research Institute, Milwaukee, WI, USA.
| | - Tao Huang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Shuang Peng
- Qingdao Walson Standard Biopharmaceutical Co, Ltd, Qingdao, Shangdong, China
| | - Zhi Zheng
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Ilia Stambler
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Science, Technology and Society, Bar Ilan University, Ramat Gan, Israel
| | - Eric Gilson
- International Society on Aging and Disease, Bryan, TX, USA
- Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine, Nice, France
- Department of Medical Genetics, Centre Hospitalier Universitaire (CHU), Nice, France
| | - Lee Wei Lim
- International Society on Aging and Disease, Bryan, TX, USA
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Alexey Moskalev
- International Society on Aging and Disease, Bryan, TX, USA
- Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia
- Russian Gerontological Research Clinical Center, Moscow, Russia
| | - Antonio Cano
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
| | - Sasanka Chakrabarti
- International Society on Aging and Disease, Bryan, TX, USA
- Maharishi Markandeshwar Deemed University, Mullana-Ambala, India
| | - Brun Ulfhake
- International Society on Aging and Disease, Bryan, TX, USA
- Karolinska University Hospital, Stockholm, Sweden
| | - Huanxing Su
- International Society on Aging and Disease, Bryan, TX, USA
- Institute of Chinese Medical Science, University of Macau, Taipa, Macau, China
| | - Haoying Xu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Sihuan Xu
- Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Feng Wei
- State Key Laboratory of Advanced Materials for Smart Sensing, GRINM GROUP Co, Ltd, Beijing, China
| | - Holly M Brown-Borg
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Biomedical Sciences, University of North Dakota, School of Medicine & Health Sciences, Grand Forks, ND, USA
| | - Kyung-Jin Min
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Biological Sciences, Inha University, Incheon, Republic of Korea
| | - Georgina Ellison-Hughes
- International Society on Aging and Disease, Bryan, TX, USA
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Calogero Caruso
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Kunlin Jin
- International Society on Aging and Disease, Bryan, TX, USA
- University of North Texas Health Science Center, Bryan, TX, USA
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
- School of Life Sciences, Shanghai University, Shanghai, China.
- International Society on Aging and Disease, Bryan, TX, USA.
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Li A, Guo F, Pan Q, Chen S, Chen J, Liu HF, Pan Q. Mesenchymal Stem Cell Therapy: Hope for Patients With Systemic Lupus Erythematosus. Front Immunol 2021; 12:728190. [PMID: 34659214 PMCID: PMC8516390 DOI: 10.3389/fimmu.2021.728190] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/14/2021] [Indexed: 12/26/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Although previous studies have demonstrated that SLE is related to the imbalance of cells in the immune system, including B cells, T cells, and dendritic cells, etc., the mechanisms underlying SLE pathogenesis remain unclear. Therefore, effective and low side-effect therapies for SLE are lacking. Recently, mesenchymal stem cell (MSC) therapy for autoimmune diseases, particularly SLE, has gained increasing attention. This therapy can improve the signs and symptoms of refractory SLE by promoting the proliferation of Th2 and Treg cells and inhibiting the activity of Th1, Th17, and B cells, etc. However, MSC therapy is also reported ineffective in some patients with SLE, which may be related to MSC- or patient-derived factors. Therefore, the therapeutic effects of MSCs should be further confirmed. This review summarizes the status of MSC therapy in refractory SLE treatment and potential reasons for the ineffectiveness of MSC therapy from three perspectives. We propose various MSC modification methods that may be beneficial in enhancing the immunosuppression of MSCs in SLE. However, their safety and protective effects in patients with SLE still need to be confirmed by further experimental and clinical evidence.
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Affiliation(s)
- Aifen Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fengbiao Guo
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Quanren Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuxian Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiaxuan Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hua-Feng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qingjun Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Matrix biophysical cues direct mesenchymal stromal cell functions in immunity. Acta Biomater 2021; 133:126-138. [PMID: 34365041 DOI: 10.1016/j.actbio.2021.07.075] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/14/2021] [Accepted: 07/30/2021] [Indexed: 12/25/2022]
Abstract
Hydrogels have been used to design synthetic matrices that capture salient features of matrix microenvironments to study and control cellular functions. Recent advances in understanding of both extracellular matrix biology and biomaterial design have shown that biophysical cues are powerful mediators of cell biology, especially that of mesenchymal stromal cells (MSCs). MSCs have been tested in many clinical trials because of their ability to modulate immune cells in different pathological conditions. While roles of biophysical cues in MSC biology have been studied in the context of multilineage differentiation, their significance in regulating immunomodulatory functions of MSCs is just beginning to be elucidated. This review first describes design principles behind how biophysical cues in native microenvironments influence the ability of MSCs to regulate immune cell production and functions. We will then discuss how biophysical cues can be leveraged to optimize cell isolation, priming, and delivery, which can help improve the success of MSC therapy for immunomodulation. Finally, a perspective is presented on how implementing biophysical cues in MSC potency assay can be important in predicting clinical outcomes. STATEMENT OF SIGNIFICANCE: Stromal cells of mesenchymal origin are known to direct immune cell functions in vivo by secreting paracrine mediators. This property has been leveraged in developing mesenchymal stromal cell (MSC)-based therapeutics by adoptive transfer to treat immunological rejection and tissue injuries, which have been tested in over one thousand clinical trials to date, but with mixed success. Advances in biomaterial design have enabled precise control of biophysical cues based on how stromal cells interact with the extracellular matrix in microenvironments in situ. Investigators have begun to use this approach to understand how different matrix biophysical parameters, such as fiber orientation, porosity, dimensionality, and viscoelasticity impact stromal cell-mediated immunomodulation. The insights gained from this effort can potentially be used to precisely define the microenvironmental cues for isolation, priming, and delivery of MSCs, which can be tailored based on different disease indications for optimal therapeutic outcomes.
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Liu L, Fan S, Lu Z, Chen Z, Chu C, Liu A, Xia F, Meng S, Guo F, Qiu H, Yang Y. An optimized method for the induction and purification of mouse bone marrow dendritic cells. J Immunol Methods 2021; 495:113073. [PMID: 34029621 DOI: 10.1016/j.jim.2021.113073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 05/01/2021] [Accepted: 05/13/2021] [Indexed: 11/25/2022]
Abstract
Dendritic cells (DCs) play an essential role in the initiation of adaptive immune responses, but they are rare in all organs. The traditional methods used to increase the yield and purity of DCs are the early removal of granulocyte culture medium and the isolation of high-purity DCs by magnetic-activated cell sorting (MACS). This study provides a more rapid and economical optimization method to obtain more high-purity DCs. (i) We harvested 18% more bone marrow (BM) cells by using forceps to crack the epiphysis instead of cutting it with scissors during BM cell extraction. (ii) When the cells in the culture medium that is discarded on day 3 in the traditional method were centrifuged and then added back to the petri dish, the DC yield on day 5 increased by 61%. (iii) On the third day, the addition of fresh medium and the retention of the original medium rather than discarding it increased the number of DCs harvested on the fifth day by 137%. (i-iii) The improved method cost an average of 74% less than the conventional method and yielded the same number and function of cells. (iv) The initial number of BM cells was increased by 15% in 4-week-old mice compared with 8-week-old mice. (v) The Percoll density centrifugation (PDS) method was used to purify DCs on day 6 after induction, and the purity of the DCs was greater than 90%, which showed no significant difference from the MACS method. However, the yield of the PDS method increased by 21%. In addition, the PDS method has a lower cost, with an average purification cost of 4 CNY ($0.58) compared with 648 CNY ($93.25) for MACS, reducing the cost by 99%. Therefore, high-purity and high-yield DCs can be rapidly obtained through a five-step improvement in the process of BM cell extraction, induction and purification.
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Affiliation(s)
- Ling Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Shanwen Fan
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhonghua Lu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhenxing Chen
- Department of Gastroenterology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, China
| | - Cuilin Chu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Airan Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Feiping Xia
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Shanshan Meng
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Fengmei Guo
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yi Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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Mesenchymal Stem Cells Therapies on Fibrotic Heart Diseases. Int J Mol Sci 2021; 22:ijms22147447. [PMID: 34299066 PMCID: PMC8307175 DOI: 10.3390/ijms22147447] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Stem cell therapy is a promising alternative approach to heart diseases. The most prevalent source of multipotent stem cells, usually called somatic or adult stem cells (mesenchymal stromal/stem cells, MSCs) used in clinical trials is bone marrow (BM-MSCs), adipose tissue (AT-MSCs), umbilical cord (UC-MSCs) and placenta. Therapeutic use of MSCs in cardiovascular diseases is based on the benefits in reducing cardiac fibrosis and inflammation that compose the cardiac remodeling responsible for the maintenance of normal function, something which may end up causing progressive and irreversible dysfunction. Many factors lead to cardiac fibrosis and failure, and an effective therapy is lacking to reverse or attenuate this condition. Different approaches have been shown to be promising in surpassing the poor survival of transplanted cells in cardiac tissue to provide cardioprotection and prevent cardiac remodeling. This review includes the description of pre-clinical and clinical investigation of the therapeutic potential of MSCs in improving ventricular dysfunction consequent to diverse cardiac diseases.
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Zhou L, Li H, Zhang XX, Zhao Y, Wang J, Pan LC, Du GS, He Q, Li XL. Rapamycin treated tol-dendritic cells derived from BM-MSCs reversed graft rejection in a rat liver transplantation model by inducing CD8 +CD45RC -Treg. Mol Immunol 2021; 137:11-19. [PMID: 34182227 DOI: 10.1016/j.molimm.2021.03.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To investigate the influence of tolerance dendritic cells (tolDCs), generated from Bone marrow mesenchymal stem cells (BM-MSCs) treated with rapamycin (Rapa) on liver allograft survival in a rat acute liver transplantation model. METHODS Different GM-CSF induction project was used to obtain immature DCs (imDCs), mature DCs (matDCs) or tolDCs from BM-MSCs. First, MLR was performed to analyze the activity of tolDCs on polyclonaly stimulated total T cells. Then, co-cultured imDCs, matDCs and tolDCs with CD8+T cells isolated by magnetic activated cell sorting to analyze the influence on its regulatory characteristic. Last, the established rat acute liver transplantation model were adoptive transfused with imDCs, matDCs or tolDCs isolated by anti-CD11c immunomagnetic beads. The phenotype of DC cells and level of CD8+Treg in the culture system and in vivo, the expression of CD8 and CD45RC in the tissues were analyzed by flow cytometry and immunohistochemistry, respectively. RESULTS The loGM-CSF plus IL-4 decreased the costimulatory molecules of CD80/86 and MHC class II of DCs comparison with hiGM-CSF from BM-MSCs no matter whether stimulation by LPS (P<0.05). Rapa treated not only reduced the expression of CD80/86 and MHC class II but also down-regulated the expression of CD11c after LPS stimulation which was more obviously in tolDCs by loGM-CSF project (P<0.05). Moreover, tolDCs displayed a rather higher level of IL-10 and low level of IL-12p70 than others (P<0.01), which shown a rather lower stimulative effect on the proliferation of T cells comparison with matDCs and imDCs. Co-cultured with CD8+Treg showed an improvement on induction of CD8+TCR+CD45RC-T cells (CD8+Treg) in ex vivo. The rats transfused with tolDCs has a delayed survival benefits with high level of CD8+Tregs (P<0.01) and high expression of CD45RC in liver tissue (P<0.01) and spleen when comparison with other groups. The infused tolDCs improved a mean survival time (MST) of 32 days comparison with a MTS of 9.5 days and 15.75 days displayed by rat that per-infused with matDCs and imDCs, respectively. CONCLUSION Rapa modified tolDCs derived from BM-MSCs reversed graft rejection by improve tolerance characteristics of CD8+CD45RC-Treg in acute liver rat transplantation.
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Affiliation(s)
- Lin Zhou
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, 100020, China
| | - Han Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, 100020, China
| | - Xin-Xue Zhang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yang Zhao
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jing Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, 100020, China
| | - Li-Chao Pan
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, 100853, China
| | - Guo-Sheng Du
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, 100853, China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, 100020, China.
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, 100020, China.
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Nagel S, Pommerenke C, Meyer C, Drexler HG. NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells. Int J Mol Sci 2021; 22:ijms22115902. [PMID: 34072771 PMCID: PMC8198381 DOI: 10.3390/ijms22115902] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/10/2021] [Accepted: 05/27/2021] [Indexed: 01/09/2023] Open
Abstract
Recently, we documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in human myelopoiesis including monocytes and their derived dendritic cells (DCs). Here, we enlarge this map to include normal NKL homeobox gene expressions in progenitor-derived DCs. Analysis of public gene expression profiling and RNA-seq datasets containing plasmacytoid and conventional dendritic cells (pDC and cDC) demonstrated HHEX activity in both entities while cDCs additionally expressed VENTX. The consequent aim of our study was to examine regulation and function of VENTX in DCs. We compared profiling data of VENTX-positive cDC and monocytes with VENTX-negative pDC and common myeloid progenitor entities and revealed several differentially expressed genes encoding transcription factors and pathway components, representing potential VENTX regulators. Screening of RNA-seq data for 100 leukemia/lymphoma cell lines identified prominent VENTX expression in an acute myelomonocytic leukemia cell line, MUTZ-3 containing inv(3)(q21q26) and t(12;22)(p13;q11) and representing a model for DC differentiation studies. Furthermore, extended gene analyses indicated that MUTZ-3 is associated with the subtype cDC2. In addition to analysis of public chromatin immune-precipitation data, subsequent knockdown experiments and modulations of signaling pathways in MUTZ-3 and control cell lines confirmed identified candidate transcription factors CEBPB, ETV6, EVI1, GATA2, IRF2, MN1, SPIB, and SPI1 and the CSF-, NOTCH-, and TNFa-pathways as VENTX regulators. Live-cell imaging analyses of MUTZ-3 cells treated for VENTX knockdown excluded impacts on apoptosis or induced alteration of differentiation-associated cell morphology. In contrast, target gene analysis performed by expression profiling of knockdown-treated MUTZ-3 cells revealed VENTX-mediated activation of several cDC-specific genes including CSFR1, EGR2, and MIR10A and inhibition of pDC-specific genes like RUNX2. Taken together, we added NKL homeobox gene activities for progenitor-derived DCs to the NKL-code, showing that VENTX is expressed in cDCs but not in pDCs and forms part of a cDC-specific gene regulatory network operating in DC differentiation and function.
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Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl Med 2021; 10:1288-1303. [PMID: 34008922 PMCID: PMC8380447 DOI: 10.1002/sctm.21-0021] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan, Republic of China.,Department & Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, NHRI, Zhunan, Taiwan, Republic of China
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Wang W, Lei W, Jiang L, Gao S, Hu S, Zhao ZG, Niu CY, Zhao ZA. Therapeutic mechanisms of mesenchymal stem cells in acute respiratory distress syndrome reveal potentials for Covid-19 treatment. J Transl Med 2021; 19:198. [PMID: 33971907 PMCID: PMC8107778 DOI: 10.1186/s12967-021-02862-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023] Open
Abstract
The mortality rate of critically ill patients with acute respiratory distress syndrome (ARDS) is 30.9% to 46.1%. The emergence of the coronavirus disease 2019 (Covid-19) has become a global issue with raising dire concerns. Patients with severe Covid-19 may progress toward ARDS. Mesenchymal stem cells (MSCs) can be derived from bone marrow, umbilical cord, adipose tissue and so on. The easy accessibility and low immunogenicity enable MSCs for allogeneic administration, and thus they were widely used in animal and clinical studies. Accumulating evidence suggests that mesenchymal stem cell infusion can ameliorate ARDS. However, the underlying mechanisms of MSCs need to be discussed. Recent studies showed MSCs can modulate immune/inflammatory cells, attenuate endoplasmic reticulum stress, and inhibit pulmonary fibrosis. The paracrine cytokines and exosomes may account for these beneficial effects. In this review, we summarize the therapeutic mechanisms of MSCs in ARDS, analyzed the most recent animal experiments and Covid-19 clinical trial results, discussed the adverse effects and prospects in the recent studies, and highlight the potential roles of MSC therapy for Covid-19 patients with ARDS.
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Affiliation(s)
- Wendi Wang
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China.,Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China.,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, Jiangsu, China
| | - Lina Jiang
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China
| | - Siqi Gao
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China.,Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China.,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, Jiangsu, China
| | - Zi-Gang Zhao
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China. .,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.
| | - Chun-Yu Niu
- Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China. .,Basic Medical College, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
| | - Zhen-Ao Zhao
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China. .,Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China. .,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.
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VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes. Stem Cells Int 2021; 2021:8888575. [PMID: 33927770 PMCID: PMC8053052 DOI: 10.1155/2021/8888575] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 03/02/2021] [Accepted: 03/24/2021] [Indexed: 01/19/2023] Open
Abstract
Myocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditioning of MSCs was previously demonstrated to highly improve their paracrine activity resulting in modulation of immune responses and the progression of diseases. Here, we studied the effects of bone marrow-derived preconditioned MSCs on hypertrophied induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) and also sought to identify MSC-derived antihypertrophic molecules. Phenylephrine (PE) was used to induce hypertrophy in murine iPS-CM, and markers of hypertrophy were identified by microarray analysis. Murine MSCs were treated with IFN-γ and IL-1β to enhance their paracrine activity, and transcriptional profiling was performed by microarray analysis. Hypertrophied iPS-CM were subsequently cocultured with preconditioned MSCs or MSC-conditioned medium (CM), respectively. Effects on hypertrophied iPS-CM were studied by cell area quantification, real-time PCR, and western blot. In some experiments, cells were incubated with fractions of MSC-CM obtained by ultrafiltration or by MSC-CM supplemented with inhibitory antibodies. Intracellular and extracellular levels of vascular endothelial growth factor (VEGF) were evaluated by western blot and ELISA. PE-induced hypertrophy in iPS-CM was associated with an upregulation of neuron-derived orphan receptor (Nor1) expression, activation of Akt, and inhibition of both strongly prevented hypertrophy induction in iPS-CM. VEGF secreted by preconditioned MSCs provoked hypertrophy regression in iPS-CM, and a negative correlation between Nor1 expression and hypertrophic growth could be evidenced. Our results demonstrate that Nor1 expression strongly supports hypertrophy in iPS-CM. Moreover, the secretome of preconditioned MSCs triggered regression of hypertrophy in iPS-CM in a VEGF-dependent manner. We suggest that the delivery of the MSC-derived secretome may represent a therapeutic strategy to limit cardiac hypertrophy. However, additional in vivo studies are needed to prove this hypothesis.
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Zhou JH, Lu X, Yan CL, Sheng XY, Cao HC. Mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure. World J Stem Cells 2021; 13:208-220. [PMID: 33815670 PMCID: PMC8006015 DOI: 10.4252/wjsc.v13.i3.208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/08/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI), which refers to liver damage caused by a drug or its metabolites, has emerged as an important cause of acute liver failure (ALF) in recent years. Chemically-induced ALF in animal models mimics the pathology of DILI in humans; thus, these models are used to study the mechanism of potentially effective treatment strategies. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF. Here, we summarize some of the existing research on the interaction between MSCs and immune cells, and discuss the possible mechanisms underlying the immuno-modulatory activity of MSCs in chemically-induced ALF. We conclude that MSCs can impact the phenotype and function of macrophages, as well as the differentiation and maturation of dendritic cells, and inhibit the proliferation and activation of T lymphocytes or B lymphocytes. MSCs also have immuno-modulatory effects on the production of cytokines, such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6, in animal models. Thus, MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.
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Affiliation(s)
- Jia-Hang Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xuan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Cui-Lin Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xin-Yu Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.
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Mázló A, Kovács R, Miltner N, Tóth M, Veréb Z, Szabó K, Bacskai I, Pázmándi K, Apáti Á, Bíró T, Bene K, Rajnavölgyi É, Bácsi A. MSC-like cells increase ability of monocyte-derived dendritic cells to polarize IL-17-/IL-10-producing T cells via CTLA-4. iScience 2021; 24:102312. [PMID: 33855282 PMCID: PMC8027231 DOI: 10.1016/j.isci.2021.102312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/17/2021] [Accepted: 03/11/2021] [Indexed: 11/30/2022] Open
Abstract
Mesenchymal stromal cell-like (MSCl) cells generated from human embryonic stem cells are considered to be an eligible cell line to model the immunomodulatory behavior of mesenchymal stromal cells (MSCs) in vitro. Dendritic cells (DCs) are essential players in the maintenance and restoration of the sensitive balance between tolerance and immunity. Here, the effects of MSCl cells on the in vitro differentiation of human monocytes into DCs were investigated. MSCl cells promote the differentiation of CTLA-4 expressing DCs via the production of all-trans retinoic acid (ATRA) functioning as a ligand of RARα, a key nuclear receptor in DC development. These semi-matured DCs exhibit an ability to activate allogeneic, naive T cells and polarize them into IL-10 + IL-17 + double-positive T helper cells in a CTLA-4-dependent manner. Mapping the molecular mechanisms of MSC-mediated indirect modulation of DC differentiation may help to expand MSCs' clinical application in cell-free therapies.
Mesenchymal stromal cell-like cells alter moDC differentiation via RARα activation Mesenchymal stromal cell-like cells express genes known to play role in ATRA synthesis MoDCs, differentiated in the presence of MSCl-derived factors, express CTLA-4 CTLA-4+ moDCs are able to induce polarization of IL-10- and IL-17-producing helper T cells
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Affiliation(s)
- Anett Mázló
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary.,Doctoral School of Molecular Cellular and Immune Biology, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary.,MTA-DE Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Ramóna Kovács
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary.,Doctoral School of Molecular Cellular and Immune Biology, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Noémi Miltner
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Márta Tóth
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary.,Doctoral School of Molecular Cellular and Immune Biology, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Zoltán Veréb
- Regenerative Medicine and Cellular Pharmacology Research Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Csongrád-Csanád County 6720, Hungary.,Research Institute of Translational Biomedicine, Department of Dermatology and Allergology, University of Szeged, Szeged, Csongrád-Csanád County 6720, Hungary
| | - Krisztina Szabó
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Ildikó Bacskai
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Kitti Pázmándi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Ágota Apáti
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest 1117 Hungary
| | - Tamás Bíró
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Krisztián Bene
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary.,Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Éva Rajnavölgyi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
| | - Attila Bácsi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hajdú-Bihar County 4032, Hungary
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Richard SA, Kampo S, Sackey M, Hechavarria ME, Buunaaim ADB, Kuugbee ED, Anabah TW. Elucidating the Pivotal Role of Immune Players in the Management of COVID-19: Focus on Mesenchymal Stem Cells and Inflammation. Curr Stem Cell Res Ther 2021; 16:189-198. [PMID: 32628591 DOI: 10.2174/1574888x15666200705213751] [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: 04/21/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 01/08/2023]
Abstract
The world is currently engulfed with a viral disease with no cure. Thus, far, millions of people are infected with the virus across the length and breadth of the world, with thousands losing their lives each passing day. The WHO in February 2020 classified the virus as a coronavirus and the name Coronavirus-19 (CoV-19) was offered to the virus. The disease caused by the virus was termed coronavirus disease-19 (COVID-19). The pathogenesis of COVID-19 is associated with elevation of several immune players as well as inflammatory factors which contribute to cytokine storms. Currently, the detection of CoV-19 RNA is through reverse transcriptase-polymerase chain reaction (RTPCR). Mesenchymal stem cells (MSCs) are capable of suppressing several kinds of cytokines via the paracrine secretion system. Therefore, MSCs therapy could be game changer in the treatment of the current COVID-19 pandemic. Moreover, intravenous IG may be capable of suppressing the high expression of IL-6 by the CoV-19 resulting in lessen disease burden. Anti-inflammatory medications like, corticosteroids, tocilizumab, glycyrrhetinic acid, as well as etoposide may be very advantageous in decreasing the COVID-19 burden because their mode of action targets the cytokine storms initiated by the CoV-19. It is important to indicate that, these medications do not target the virus itself. Therefore, potent CoV-19 anti-viral medications are needed to completely cure patients with COVID-19. Furthermore, a vaccine is urgently needed to stop the spread of the virus. This review, therefore, elucidates the immune players in the management of COVID-19; focusing principally on MSCs and inflammatory mediators.
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Affiliation(s)
- Seidu A Richard
- Department of Medicine, Princefield University, P. O. Box MA128, Ho, Ghana
| | - Sylvanus Kampo
- Department of Anesthesia and Critical care, School of Medicine, University of Health and Allied Sciences, Ho, Ghana
| | - Marian Sackey
- Department of Pharmacy, Ho Teaching Hospital, P.O. Box MA-374, Ho, Ghana
| | | | - Alexis D B Buunaaim
- Department of Surgery, School of Medicine and Health Science, University for Development Studies, Tamale, Ghana
| | - Eugene Dogkotenge Kuugbee
- Department of Clinical Microbiology, School of Medicine and Health Science, University for Development Studies, Tamale, Ghana
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Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Outlook for Inflammatory and Degenerative Diseases. Front Immunol 2021; 11:591065. [PMID: 33613514 PMCID: PMC7893976 DOI: 10.3389/fimmu.2020.591065] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be easily isolated from many sources such as bone marrow, umbilical cord or adipose tissue. MSCs provide support for hematopoietic stem cells and have an ability to differentiate into multiple cell lines. Moreover, they have proangiogenic, protective and immunomodulatory properties. MSCs have the capacity to modulate both innate and adaptive immune responses, which accompany many diseases, by inhibiting pro-inflammatory reactions and stimulating anti-inflammatory activity. Recent findings revealed that the positive effect of MSCs is at least partly associated with the production of extracellular vesicles (EVs). EVs are small membrane structures, containing proteins, lipids and nuclei acids, which take part in intra-cellular communication. Many studies indicate that EVs contain protective and pro-regenerative properties and can modulate an immune response that is activated in various diseases such as CNS diseases, myocardial infarction, liver injury, lung diseases, ulcerative colitis or kidney injury. Thus, EVs have similar functions as their cells of origin and since they do not carry the risk of cell transplantation, such as tumor formation or small vessel blockage, they can be considered a potential therapeutic tool for cell-free therapy.
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Affiliation(s)
- Sylwia Dabrowska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Miroslaw Janowski
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.,University of Maryland School of Medicine, Baltimore, MD, United States.,Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
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Wang F, Chen X, Li J, Wang D, Huang H, Li X, Bi Z, Peng Y, Zhang X, Li G, Wang J, Wang C, Fu Q, Liu L. Dose- and Time-Dependent Effects of Human Mesenchymal Stromal Cell Infusion on Cardiac Allograft Rejection in Mice. Stem Cells Dev 2021; 30:203-213. [PMID: 33371825 DOI: 10.1089/scd.2019.0300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Heart transplantation is the final life-saving therapeutic strategy for many end-stage heart diseases. Long-term immunosuppressive regimens are needed to prevent allograft rejection. Mesenchymal stromal cells (MSCs) have been shown as immunomodulatory therapy for organ transplantation. However, the effect of dose and timing of MSC treatment on heart transplantation has not yet been examined. In this study, we infused three doses (1 × 106, 2 × 106, or 5 × 106 cells) of human MSCs (hMSCs) to the recipient BALB/c mice before (7 days or 24 h) or after (24 h) receiving C57BL/6 cardiac transplants. We found that infusion of high dose hMSCs (5 × 106) at 24 h post-transplantation significantly prolonged the survival time of cardiac grafts. To delineate the underlying mechanism, grafts, spleens, and draining lymph nodes were harvested for analysis. Dose-dependent effect of hMSC treatment was shown in: (1) alleviation of International Society of Heart and Lung Transplantation (ISHLT) score in grafts; (2) reduction of the population of CD4+ and CD8+ T cells; (3) increase of regulatory T (Treg) cells; (4) and decrease of serum levels of inflammatory cytokines and donor-specific antibodies. Taken together, we showed timing critical and dose-dependent immunomodulatory effects of hMSC treatment against acute allograft rejection in a mouse model of heart transplantation.
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Affiliation(s)
- Feng Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Organ Transplant Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dong Wang
- Department of Clinical Laboratory, The First Affiliated Hospital, SunYat-sen University, Guangzhou, China
| | - Huiting Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xirui Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zirong Bi
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanwen Peng
- The Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoran Zhang
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Gang Li
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Jiali Wang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Changxi Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory on Organ Donation and Transplant Immunology, Guangzhou, China
| | - Qian Fu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Longshan Liu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory on Organ Donation and Transplant Immunology, Guangzhou, China
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Zhang R, Yu J, Zhang N, Li W, Wang J, Cai G, Chen Y, Yang Y, Liu Z. Bone marrow mesenchymal stem cells transfer in patients with ST-segment elevation myocardial infarction: single-blind, multicenter, randomized controlled trial. Stem Cell Res Ther 2021; 12:33. [PMID: 33413636 PMCID: PMC7791674 DOI: 10.1186/s13287-020-02096-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/10/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Our aim was to evaluate the efficacy and safety of intracoronary autologous bone marrow mesenchymal stem cell (BM-MSC) transplantation in patients with ST-segment elevation myocardial infarction (STEMI). METHODS In this randomized, single-blind, controlled trial, patients with STEMI (aged 39-76 years) were enrolled at 6 centers in Beijing (The People's Liberation Army Navy General Hospital, Beijing Armed Police General Hospital, Chinese People's Liberation Army General Hospital, Beijing Huaxin Hospital, Beijing Tongren Hospital, Beijing Chaoyang Hospital West Hospital). All patients underwent optimum medical treatment and percutaneous coronary intervention and were randomly assigned in a 1:1 ratio to BM-MSC group or control group. The primary endpoint was the change of myocardial viability at the 6th month's follow-up and left ventricular (LV) function at the 12th month's follow-up. The secondary endpoints were the incidence of cardiovascular event, total mortality, and adverse event during the 12 months' follow-up. The myocardial viability assessed by single-photon emission computed tomography (SPECT). The left ventricular ejection fraction (LVEF) was used to assess LV function. All patients underwent dynamic ECG and laboratory evaluations. This trial is registered with ClinicalTrails.gov, number NCT04421274. RESULTS Between March 2008 and July 2010, 43 patients who had underwent optimum medical treatment and successful percutaneous coronary intervention were randomly assigned to BM-MSC group (n = 21) or control group (n = 22) and followed-up for 12 months. At the 6th month's follow-up, there was no significant improvement in myocardial activity in the BM-MSC group before and after transplantation. Meanwhile, there was no statistically significant difference between the two groups in the change of myocardial perfusion defect index (p = 0.37) and myocardial metabolic defect index (p = 0.90). The LVEF increased from baseline to 12 months in the BM-MSC group and control group (mean baseline-adjusted BM-MSC treatment differences in LVEF 4.8% (SD 9.0) and mean baseline-adjusted control group treatment differences in LVEF 5.8% (SD 6.04)). However, there was no statistically significant difference between the two groups in the change of the LVEF (p = 0.23). We noticed that during the 12 months' follow-up, except for one death and one coronary microvascular embolism in the BM-MSC group, no other events occurred and alanine transaminase (ALT) and C-reactive protein (CRP) in BM-MSC group were significantly lower than that in the control group. CONCLUSIONS The present study may have many methodological limitations, and within those limitations, we did not identify that intracoronary transfer of autologous BM-MSCs could largely promote the recovery of LV function and myocardial viability after acute myocardial infarction.
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Affiliation(s)
- Runfeng Zhang
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China
| | - Jiang Yu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Ningkun Zhang
- Heart Centre, The Navy General Hospital, Beijing, 100048, China
| | - Wensong Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jisheng Wang
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China
| | - Guocai Cai
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China
| | - Yu Chen
- Heart Centre, The Navy General Hospital, Beijing, 100048, China
| | - Yong Yang
- Department of Cardiology, The General Hospital of Chinese People's Armed Police Forces, Beijing, 100039, China
| | - Zhenhong Liu
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China.
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Abstract
The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.
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Affiliation(s)
- Kamal Kant Sahu
- Department of Hematology and Oncology, Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts
| | - Ahmad Daniyal Siddiqui
- Department of Hematology and Oncology, Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts
| | - Jan Cerny
- Division of Hematology and Oncology, Department of Medicine, UMass Memorial Health Care, University of Massachusetts Medical School, Worcester, Massachusetts
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Mesenchymal Stem Cell Therapy for Osteoarthritis: Practice and Possible Promises. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1387:107-125. [DOI: 10.1007/5584_2021_695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Chakraborty S, Sinha S, Sengupta A. Emerging trends in chromatin remodeler plasticity in mesenchymal stromal cell function. FASEB J 2020; 35:e21234. [PMID: 33337557 DOI: 10.1096/fj.202002232r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/10/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022]
Abstract
Emerging evidences highlight importance of epigenetic regulation and their integration with transcriptional and cell signaling machinery in determining tissue resident adult pluripotent mesenchymal stem/stromal cell (MSC) activity, lineage commitment, and multicellular development. Histone modifying enzymes and large multi-subunit chromatin remodeling complexes and their cell type-specific plasticity remain the central defining features of gene regulation and establishment of tissue identity. Modulation of transcription factor expression gradient ex vivo and concomitant flexibility of higher order chromatin architecture in response to signaling cues are exciting approaches to regulate MSC activity and tissue rejuvenation. Being an important constituent of the adult bone marrow microenvironment/niche, pathophysiological perturbation in MSC homeostasis also causes impaired hematopoietic stem/progenitor cell function in a non-cell autonomous mechanism. In addition, pluripotent MSCs can function as immune regulatory cells, and they reside at the crossroad of innate and adaptive immune response pathways. Research in the past few years suggest that MSCs/stromal fibroblasts significantly contribute to the establishment of immunosuppressive microenvironment in shaping antitumor immunity. Therefore, it is important to understand mesenchymal stromal epigenome and transcriptional regulation to leverage its applications in regenerative medicine, epigenetic memory-guided trained immunity, immune-metabolic rewiring, and precision immune reprogramming. In this review, we highlight the latest developments and prospects in chromatin biology in determining MSC function in the context of lineage commitment and immunomodulation.
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Affiliation(s)
- Sayan Chakraborty
- Stem Cell & Leukemia Laboratory, Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,Translational Research Unit of Excellence (TRUE), Kolkata, India
| | - Sayantani Sinha
- Stem Cell & Leukemia Laboratory, Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,Translational Research Unit of Excellence (TRUE), Kolkata, India
| | - Amitava Sengupta
- Stem Cell & Leukemia Laboratory, Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,Translational Research Unit of Excellence (TRUE), Kolkata, India
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Ciccocioppo R, Comoli P, Astori G, Del Bufalo F, Prapa M, Dominici M, Locatelli F. Developing cell therapies as drug products. Br J Pharmacol 2020; 178:262-279. [PMID: 33140850 DOI: 10.1111/bph.15305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
In the last 20 years, the global regulatory frameworks for drug assessment have been managing the challenges posed by using cellular products as new therapeutic tools. Currently, they are defined as "Advanced Therapy Medicinal Products", comprising a large group of cellular types that either alone or in combination with gene and tissue engineering technology. They have the potential to change the natural course of still lethal or highly debilitating diseases, including cancers, opportunistic infections and chronic inflammatory conditions. Globally, more than 50 cell-based products have obtained market authorization. This overview describes the advantages and unsolved challenges on developing cells as innovative therapeutic vehicles. The main cell therapy players and the legal framework are discussed, starting from chimeric antigen receptor T-cells for leukaemia and solid tumours, dealing then with lymphocytes as potent anti-microbiological tools and then focusing on mesenchymal stem/stromal cells whose role covers regenerative medicine, immunology and anti-tumour therapy.
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Affiliation(s)
- Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Patrizia Comoli
- Cell Factory and Paediatric Haematology/Oncology Unit, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Giuseppe Astori
- Laboratory of Advanced Cellular Therapies, Haematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Francesca Del Bufalo
- Department of Paediatric Haematology and Oncology and Cell and Gene Therapy, I.R.C.C.S. Bambino Gesù Children's Hospital, Rome, Italy
| | - Malvina Prapa
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Franco Locatelli
- Department of Paediatric Haematology and Oncology and Cell and Gene Therapy, I.R.C.C.S. Bambino Gesù Children's Hospital, Rome, Italy.,Department of Paediatrics, Sapienza University of Rome, Rome, Italy
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45
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Li Z, Niu S, Guo B, Gao T, Wang L, Wang Y, Wang L, Tan Y, Wu J, Hao J. Stem cell therapy for COVID-19, ARDS and pulmonary fibrosis. Cell Prolif 2020; 53:e12939. [PMID: 33098357 PMCID: PMC7645923 DOI: 10.1111/cpr.12939] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 mainly causes damage to the lung, as well as other organs and systems such as the hearts, the immune system and so on. Although the pathogenesis of COVID-19 has been fully elucidated, there is no specific therapy for the disease at present, and most treatments are limited to supportive care. Stem cell therapy may be a potential treatment for refractory and unmanageable pulmonary illnesses, which has shown some promising results in preclinical studies. In this review, we systematically summarize the pathogenic progression and potential mechanisms underlying stem cell therapy in COVID-19, and registered COVID-19 clinical trials. Of all the stem cell therapies touted for COVID-19 treatment, mesenchymal stem cells (MSCs) or MSC-like derivatives have been the most promising in preclinical studies and clinical trials so far. MSCs have been suggested to ameliorate the cytokine release syndrome (CRS) and protect alveolar epithelial cells by secreting many kinds of factors, demonstrating safety and possible efficacy in COVID-19 patients with acute respiratory distress syndrome (ARDS). However, considering the consistency and uniformity of stem cell quality cannot be quantified nor guaranteed at this point, more work remains to be done in the future.
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Affiliation(s)
- Zhongwen Li
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
| | - Shuaishuai Niu
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
| | - Baojie Guo
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Tingting Gao
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Lei Wang
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
| | - Yukai Wang
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
| | - Liu Wang
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
| | - Yuanqing Tan
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
| | - Jun Wu
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
| | - Jie Hao
- Institute of ZoologyState Key Laboratory of Stem Cell and Reproductive BiologyChinese Academy of SciencesBeijingChina
- Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
- National Stem Cell Resource CenterChinese Academy of SciencesBeijingChina
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46
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Choudhery MS, Harris DT. Stem cell therapy for COVID-19: Possibilities and challenges. Cell Biol Int 2020; 44:2182-2191. [PMID: 32767687 PMCID: PMC7436138 DOI: 10.1002/cbin.11440] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 02/05/2023]
Abstract
Since its eruption in China, novel coronavirus disease (COVID-19) has been reported in most of the countries and territories (>200) of the world with ∼18 million confirmed cases (as of August 3, 2020). In most of the countries, COVID-19 upsurge is uncontrolled with a significant mortality rate. Currently, no treatment effective for COVID-19 is available in the form of vaccines or antiviral drugs and patients are currently treated symptomatically. Although the majority of the patients develop mild symptoms and recover without mechanical ventilation for respiratory management, severe respiratory illness develops in a significant portion of affected patients and may result in death. While the scientific community is working to develop vaccines and drugs against the COVID-19 pandemic, novel alternative therapies may reduce the mortality rate. Recent use of stem cells for critically ill COVID-19 patients in a small group of patients in China and subsequent Emergency Use Authorization of stem cells by Food and Drug Administration to Global Institute of Stem Cell Therapy and Research and Athersys has created excitement among the medical community. As a result, several clinical trials have been registered using stem cells for COVID-19 treatment that aim to use different cell sources, dosage, and importantly diverse targeted patient groups. In this brief review, the possibilities of stem cell use in COVID-19 patients and relevant challenges in their use have been discussed.
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Affiliation(s)
- Mahmood S. Choudhery
- Tissue Engineering and Regenerative Medicine Laboratory, Department of Biomedical SciencesKing Edward Medical UniversityLahorePakistan
| | - David T. Harris
- Department of ImmunobiologyThe University of ArizonaTucsonArizona
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Abstract
Over the past decade, the clinical application of mesenchymal stromal cells (MSCs) has generated growing enthusiasm as an innovative cell-based approach in solid organ transplantation (SOT). These expectations arise from a significant number of both transplant- and non-transplant-related experimental studies investigating the complex anti-inflammatory, immunomodulatory, and tissue-repair properties of MSCs. Promising preclinical results have prompted clinical trials using MSC-based therapy in SOT. In the present review, the general properties of MSCs are summarized, with a particular emphasis on MSC-mediated impact on the immune system and in the ischemic conditioning strategy. Next, we chronologically detail all clinical trials using MSCs in the field of SOT. Finally, we envision the challenges and perspectives of MSC-based cell therapy in SOT.
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48
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Gupta A, Kashte S, Gupta M, Rodriguez HC, Gautam SS, Kadam S. Mesenchymal stem cells and exosome therapy for COVID-19: current status and future perspective. Hum Cell 2020; 33:907-918. [PMID: 32780299 PMCID: PMC7418088 DOI: 10.1007/s13577-020-00407-w] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022]
Abstract
Acute respiratory distress syndrome (ARDS) is the main cause for the COVID-19 infection-related morbidity and mortality. Recent clinical evidences suggest increased level of cytokines and chemokines targeting lung tissue as a prominent etiological factor. The immunomodulatory effect of mesenchymal stem cells (MSCs) as the alternative therapy for the treatment of inflammatory and autoimmune diseases is well known. Several studies have also revealed that similar therapeutic impacts of parent MSCs are also exhibited by MSCs-derived extracellular vesicles (EVs) including exosomes. In this review, we explored the therapeutic potential of both MSCs and exosomes in mitigating the COVID-19 induced cytokine storm as well as promoting the regeneration of alveolar tissue, attributed to the intrinsic cytokines and growth factor present in the secretome. The preliminary studies have demonstrated the safety and efficacy of MSCs and exosomes in mitigating symptoms associated with COVID-19. Thus, they can be used on compassionate basis, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of COVID-19. However, more preclinical and clinical studies are warranted to understand their mechanism of action and further establish their safety and efficacy.
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Affiliation(s)
- Ashim Gupta
- Future Biologics, Lawrenceville, GA USA
- BioIntegrate, Lawrenceville, GA USA
- South Texas Orthopaedic Research Institute, Laredo, TX USA
- Veterans in Pain, Los Angeles, CA USA
| | - Shivaji Kashte
- Department of Stem Cell and Regenerative Medicine, Centre for Interdisciplinary Research, D. Y. Patil Education Society (Institution Deemed To Be University), Kolhapur, 416006 India
| | | | - Hugo C. Rodriguez
- Future Biologics, Lawrenceville, GA USA
- South Texas Orthopaedic Research Institute, Laredo, TX USA
- School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, TX USA
| | | | - Sachin Kadam
- Department of Stem Cell and Regenerative Medicine, Centre for Interdisciplinary Research, D. Y. Patil Education Society (Institution Deemed To Be University), Kolhapur, 416006 India
- Advancells Group, Noida, A-102, Sector 5, Noida, Uttar Pradesh 201301 India
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Shahir M, Mahmoud Hashemi S, Asadirad A, Varahram M, Kazempour‐Dizaji M, Folkerts G, Garssen J, Adcock I, Mortaz E. Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells. J Cell Physiol 2020; 235:7043-7055. [PMID: 32043593 PMCID: PMC7496360 DOI: 10.1002/jcp.29601] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022]
Abstract
Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T-cell activation via direct cell-cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) help maintain immunological tolerance through the induction of T-cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC-derived exosomes on the induction of mouse tolDCs, murine adipose-derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick-TC kits. BM-derived DCs (BMDCs) were prepared and cocultured with MSCs-derived exosomes (100 μg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS; 0.1μg/ml) at Day 8 for 24 hr. The study groups were divided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester-labeled BALB/C-derived splenocytes p. Interleukin-6 (IL-6), IL-10, and transforming growth factor-β (TGF-β) release were measured by enzyme-linked immunosorbent assay. MSC-derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC-derived exosomes decrease IL-6 release but augment IL-10 and TGF-β release (p ≤ .05). Lymphocyte proliferation was decreased (p ≤ .05) in the presence of DCs treated with MSC-derived exosomes. CMSC-derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC-induced immune responses.
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Affiliation(s)
- Mehri Shahir
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Ali Asadirad
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Mohammad Varahram
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD)Shahid Beheshti University of Medical SciencesTehranIran
| | - Mehdi Kazempour‐Dizaji
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD)Shahid Beheshti University of Medical SciencesTehranIran
| | - Gert Folkerts
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
| | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
- Immunology Platform for Specialized NutritionDanone Nutricia ResearchUtrechtThe Netherlands
| | - Ian Adcock
- Experimental Studies and Cell and Molecular Biology, Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research UnitRoyal Brompton HospitalLondonUK
- Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research InstituteUniversity of NewcastleNewcastleNew South WalesAustralia
| | - Esmaeil Mortaz
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
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50
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de Oliveira Ramos F, Malard PF, Brunel HDSS, Paludo GR, de Castro MB, da Silva PHS, da Cunha Barreto-Vianna AR. Canine atopic dermatitis attenuated by mesenchymal stem cells. J Adv Vet Anim Res 2020; 7:554-565. [PMID: 33005683 PMCID: PMC7521806 DOI: 10.5455/javar.2020.g453] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 11/23/2022] Open
Abstract
Objective: To evaluate the use of mesenchymal stem cells (MSCs) in the attenuation of canine atopic dermatitis (AD). Materials and methods: Sixteen dogs were selected and divided into three groups, mild, moderate, and severe, according to the Canine Atopic Dermatitis Extent and Severity Index (CADESI-4). They were evaluated for 82 days. The protocol recommended in this experiment was to inject 2 × 106/kg bodyweight of MSC’s in all groups by the intravenous route with intervals of applications of 21 days. The degree of pruritus was evaluated by examining the visual analog scale, the CADESI-4, the histopathology of the skin, hematological and biochemical parameters, the pyogenic effect of MSCs, and the thickness of the epidermis. Results: There was a significant difference in the reduction of epidermal thickness in the moderate and severe groups. Hematological, biochemical, and body temperature parameters remained within normal limits for the species with no side effects Conclusion: MSCs attenuated the clinical signs of AD.
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Affiliation(s)
| | | | | | - Giane Regina Paludo
- Faculty of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
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