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1
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Yin W, Noguchi CT. The Role of Erythropoietin in Metabolic Regulation. Cells 2025; 14:280. [PMID: 39996752 PMCID: PMC11853986 DOI: 10.3390/cells14040280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/05/2025] [Accepted: 02/12/2025] [Indexed: 02/26/2025] Open
Abstract
Erythropoietin (EPO) is a key regulator of erythrocyte production, promoting erythroid progenitor cell survival, division, and differentiation in the fetal liver and adult bone marrow. Mice lacking EPO or its receptor (EPOR) die in utero due to severe anemia. Beyond hematopoiesis, EPO influences non-hematopoietic tissues, including glucose and fat metabolism in adipose tissue, skeletal muscle, and the liver. EPO is used to treat anemia associated with chronic kidney disease clinically and plays a role in maintaining metabolic homeostasis and regulating fat mass. EPO enhances lipolysis while inhibiting lipogenic gene expression in white adipose tissue, brown adipose tissue, skeletal muscle, and the liver, acting through the EPO-EPOR-RUNX1 axis. The non-erythroid EPOR agonist ARA290 also improves diet-induced obesity and glucose tolerance providing evidence for EPO regulation of fat metabolism independent of EPO stimulated erythropoiesis. Therefore, in addition to the primary role of EPO to stimulate erythropoiesis, EPO contributes significantly to EPOR-dependent whole-body metabolic response.
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Affiliation(s)
| | - Constance T. Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA;
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2
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Zendedel E, Tayebi L, Nikbakht M, Hasanzadeh E, Asadpour S. Clinical Trials of Mesenchymal Stem Cells for the Treatment of COVID 19. Curr Stem Cell Res Ther 2024; 19:1055-1071. [PMID: 37815188 DOI: 10.2174/011574888x260032230925052240] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/14/2023] [Accepted: 07/31/2023] [Indexed: 10/11/2023]
Abstract
Mesenchymal Stem Cells (MSCs) are being investigated as a treatment for a novel viral disease owing to their immunomodulatory, anti-inflammatory, tissue repair and regeneration characteristics, however, the exact processes are unknown. MSC therapy was found to be effective in lowering immune system overactivation and increasing endogenous healing after SARS-CoV-2 infection by improving the pulmonary microenvironment. Many studies on mesenchymal stem cells have been undertaken concurrently, and we may help speed up the effectiveness of these studies by collecting and statistically analyzing data from them. Based on clinical trial information found on clinicaltrials. gov and on 16 November 2020, which includes 63 clinical trials in the field of patient treatment with COVID-19 using MSCs, according to the trend of increasing studies in this field, and with the help of meta-analysis studies, it is possible to hope that the promise of MSCs will one day be realized. The potential therapeutic applications of MSCs for COVID-19 are investigated in this study.
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Affiliation(s)
- Elham Zendedel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Lobat Tayebi
- Marquett University School of Dentistry, Milwaukee, WI, 53233, USA
| | - Mohammad Nikbakht
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Hasanzadeh
- Immunogenetics Research Center, Department of Tissue Engineering & Regenerative Medicine, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shiva Asadpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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3
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Huai Q, Zhu C, Zhang X, Dai H, Li X, Wang H. Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications. Cell Biosci 2023; 13:162. [PMID: 37670393 PMCID: PMC10478279 DOI: 10.1186/s13578-023-01122-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/30/2023] [Indexed: 09/07/2023] Open
Abstract
Liver disease is a leading cause of mortality and morbidity that is rising globally. Liver dysfunctions are classified into acute and chronic diseases. Various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Up to now, liver transplantation could be the last resort for patients with end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stromal/stem cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties can be effectively used for treating liver diseases but without the limitation that are associated with liver transplantation. In this review, we summarize and discuss recent advances in the characteristics of MSCs and the potential action mechanisms of MSCs-based cell therapies for liver diseases. We also draw attention to strategies to potentiate the therapeutic properties of MSCs through pre-treatments or gene modifications. Finally, we discuss progress toward clinical application of MSCs or their extracellular vesicles in liver diseases.
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Affiliation(s)
- Qian Huai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Cheng Zhu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Xu Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Hanren Dai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Xiaolei Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
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4
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Yu S, Yu S, Liu H, Liao N, Liu X. Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases. Stem Cell Res Ther 2023; 14:235. [PMID: 37667383 PMCID: PMC10478247 DOI: 10.1186/s13287-023-03476-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/25/2023] [Indexed: 09/06/2023] Open
Abstract
Although mesenchymal stem cell (MSC) transplantation provides an alternative strategy for end-stage liver disease (ESLD), further widespread application of MSC therapy is limited owing to low cell engraftment efficiency. Improving cell engraftment efficiency plays a critical role in enhancing MSC therapy for liver diseases. In this review, we summarize the current status and challenges of MSC transplantation for ESLD. We also outline the complicated cell-homing process and highlight how low cell engraftment efficiency is closely related to huge differences in extracellular conditions involved in MSC homing journeys ranging from constant, controlled conditions in vitro to variable and challenging conditions in vivo. Improving cell survival and homing capabilities enhances MSC engraftment efficacy. Therefore, we summarize the current strategies, including hypoxic priming, drug pretreatment, gene modification, and cytokine pretreatment, as well as splenectomy and local irradiation, used to improve MSC survival and homing capability, and enhance cell engraftment and therapeutic efficiency of MSC therapy. We hope that this review will provide new insights into enhancing the efficiency of MSC engraftment in liver diseases.
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Affiliation(s)
- Shaoxiong Yu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Saihua Yu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Haiyan Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China.
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5
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López-Seijas J, Miranda-Balbuena D, Iglesias-Fente A, Sacristán-Santos M, Carballo-Pedrares N, Arufe MC, Rey-Rico A, Fafián-Labora J. Development of new non-viral systems for genetic modification of senescent cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 32:302-317. [PMID: 37096164 PMCID: PMC10122050 DOI: 10.1016/j.omtn.2023.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 03/16/2023] [Indexed: 04/08/2023]
Abstract
Senescence is a process characterized by a prolonged irreversible cell-cycle arrest. The accumulation of senescent cells in tissues is related to aging and to the development of age-related diseases. Recently, gene therapy has emerged as a powerful tool for treating age-associated diseases by the transference of specific genes into the target cell population. However, the high sensitivity of senescent cells significantly precludes their genetic modification via classical viral and non-viral systems. Niosomes are self-assembled non-viral nanocarriers that exhibit important advantages due to their elevated cytocompatibility, versatility, and cost-efficiency, arising as a new alternative for genetic modification of senescent cells. In this work, we explore for the first time the use of niosomes for genetic modification of senescent umbilical cord-derived mesenchymal stem cells. We report that niosome composition greatly affected transfection efficiency; those formulations prepared in medium with sucrose and containing cholesterol as helper lipid being the most suitable to transfect senescent cells. Moreover, resulting niosome formulations exhibited a superior transfection efficiency with a markedly less cytotoxicity than the commercial reagent Lipofectamine. These findings highlight the potentiality of niosomes as effective vectors for genetic modification of senescent cells, providing new tools for the prevention and/or treatment of age-related diseases.
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Affiliation(s)
- Junquera López-Seijas
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Diego Miranda-Balbuena
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Alba Iglesias-Fente
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Marta Sacristán-Santos
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Natalia Carballo-Pedrares
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - María C. Arufe
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain. Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Ana Rey-Rico
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Juan Fafián-Labora
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain. Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
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6
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Advance of Mesenchymal Stem Cells in Chronic End-Stage Liver Disease Control. Stem Cells Int 2022; 2022:1526217. [PMID: 36248254 PMCID: PMC9568364 DOI: 10.1155/2022/1526217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 09/18/2022] [Accepted: 09/25/2022] [Indexed: 11/26/2022] Open
Abstract
The chronic liver diseases will slowly develop into liver fibrosis, cirrhosis, and even liver cancer if no proper control is performed with high efficiency. Up to now, the most effective treatment for end-stage liver diseases is liver transplantation. However, liver transplantation has the problems of donor deficiency, low matching rate, surgical complications, high cost, and immune rejection. These problems indicate that novel therapeutic strategies are urgently required. Mesenchymal stem cells (MSCs) are somatic stem cells with multidirectional differentiation potential and self-renewal ability. MSCs can secrete a large number of cytokines, chemokines, immunomodulatory molecules, and hepatotrophic factors, as well as produce extracellular vesicles. They alleviate liver diseases by differentiating to hepatocyte-like cells, immunomodulation, homing to the injured site, regulating cell ferroptosis, regulating cell autophagy, paracrine effects, and MSC-mitochondrial transfer. In this review, we focus on the main resources of MSCs, underlying therapeutic mechanisms, clinical applications, and efforts made to improve MSC-based cell therapy efficiency.
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Karmacharya MB, Hada B, Park SR, Kim KH, Choi BH. Granulocyte-macrophage colony-stimulating factor (GM-CSF) shows therapeutic effect on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. PLoS One 2022; 17:e0274126. [PMID: 36054162 PMCID: PMC9439244 DOI: 10.1371/journal.pone.0274126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
This study was undertaken to investigate the inhibitory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Liver fibrosis was induced in Sprague-Dawley rats by injecting DMN intraperitoneally (at 10 mg/kg of body weight) daily for three consecutive days per week for 4 weeks. To investigate the effect of GM-CSF on disease onset, GM-CSF (50 μg/kg of body weight) was co-treated with DMN for 2 consecutive days per week for 4 weeks (4-week groups). To observe the effect of GM-CSF on the progression of liver fibrosis, GM-CSF was post-treated alone at 5–8 weeks after the 4 weeks of DMN injection (8-week groups). We found that DMN administration for 4 weeks produced molecular and pathological manifestations of liver fibrosis, that is, it increased the expressions of collagen type I, alpha-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1), and decreased peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. In addition, elevated serum levels of aspartate aminotransferase (AST), total bilirubin level (TBIL), and decreased albumin level (ALB) were observed. In both the 4-week and 8-week groups, GM-CSF clearly improved the pathological liver conditions in the gross and histological observations, and significantly recovered DMN-induced increases in AST and TBIL and decreases in ALB serum levels to normal. GM-CSF also significantly decreased DMN-induced increases in collagen type I, α-SMA, and TGF-β1 and increased DMN-induced decreases in PPAR-γ expression. In the DMN groups, survival decreased continuously for 8 weeks after DMN treatment for the first 4 weeks. GM-CSF showed a survival benefit when co-treated for the first 4 weeks but a marginal effect when post-treated for 5–8 weeks. In conclusion, co-treatment of GM-CSF showed therapeutic effects on DMN-induced liver fibrosis and survival rates in rats, while post-treatment efficiently blocked liver fibrosis.
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Affiliation(s)
| | - Binika Hada
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
| | - So Ra Park
- Department of Physiology and Biophysics, Inha University College of Medicine, Incheon, South Korea
| | - Kil Hwan Kim
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, South Korea
- * E-mail: (BHC); (KHK)
| | - Byung Hyune Choi
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
- * E-mail: (BHC); (KHK)
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8
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Krishnan A, Muthusamy S, Fernandez FB, Kasoju N. Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Management of COVID19-Associated Lung Injury: A Review on Publications, Clinical Trials and Patent Landscape. Tissue Eng Regen Med 2022; 19:659-673. [PMID: 35384633 PMCID: PMC8985390 DOI: 10.1007/s13770-022-00441-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/27/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023] Open
Abstract
The unprecedented COVID-19 pandemic situation forced the scientific community to explore all the possibilities from various fields, and so far we have seen a lot of surprises, eureka moments and disappointments. One of the approaches from the cellular therapists was exploiting the immunomodulatory and regenerative potential of mesenchymal stromal cells (MSCs), more so of MSC-derived extracellular vesicles (EVs)-particularly exosomes, in order to alleviate the cytokine storm and regenerate the damaged lung tissues. Unlike MSCs, the EVs are easier to store, deliver, and are previously shown to be as effective as MSCs, yet less immunogenic. These features attracted the attention of many and thus led to a tremendous increase in publications, clinical trials and patent applications. This review presents the current landscape of the field and highlights some interesting findings on MSC-derived EVs in the context of COVID-19, including in silico, in vitro, in vivo and case reports. The data strongly suggests the potential of MSC-derived EVs as a therapeutic regime for the management of acute lung injury and associated complications in COVID-19 and beyond.
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Affiliation(s)
- Anand Krishnan
- Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, 695012, Kerala, India
| | - Senthilkumar Muthusamy
- Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, 695012, Kerala, India
| | - Francis B Fernandez
- Department of Biomaterial Science and Technology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, 695012, Kerala, India
| | - Naresh Kasoju
- Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, 695012, Kerala, India.
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9
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Li C, Wang B. Mesenchymal Stem/Stromal Cells in Progressive Fibrogenic Involvement and Anti-Fibrosis Therapeutic Properties. Front Cell Dev Biol 2022; 10:902677. [PMID: 35721482 PMCID: PMC9198494 DOI: 10.3389/fcell.2022.902677] [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: 03/24/2022] [Accepted: 05/13/2022] [Indexed: 11/22/2022] Open
Abstract
Fibrosis refers to the connective tissue deposition and stiffness usually as a result of injury. Fibrosis tissue-resident mesenchymal cells, including fibroblasts, myofibroblast, smooth muscle cells, and mesenchymal stem/stromal cells (MSCs), are major players in fibrogenic processes under certain contexts. Acknowledging differentiation potential of MSCs to the aforementioned other types of mesenchymal cell lineages is essential for better understanding of MSCs’ substantial contributions to progressive fibrogenesis. MSCs may represent a potential therapeutic option for fibrosis resolution owing to their unique pleiotropic functions and therapeutic properties. Currently, clinical trial efforts using MSCs and MSC-based products are underway but clinical data collected by the early phase trials are insufficient to offer better support for the MSC-based anti-fibrotic therapies. Given that MSCs are involved in the coagulation through releasing tissue factor, MSCs can retain procoagulant activity to be associated with fibrogenic disease development. Therefore, MSCs’ functional benefits in translational applications need to be carefully balanced with their potential risks.
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Affiliation(s)
- Chenghai Li
- Stem Cell Program of Clinical Research Center, People’s Hospital of Zhengzhou University and Henan Provincial People’s Hospital, Zhengzhou, China
- Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan University, Zhengzhou, China
- *Correspondence: Chenghai Li, ; Bin Wang,
| | - Bin Wang
- Department of Neurosurgery, People’s Hospital of Zhengzhou University and Henan Provincial People’s Hospital, Zhengzhou, China
- *Correspondence: Chenghai Li, ; Bin Wang,
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10
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Tang Y, Wu P, Li L, Xu W, Jiang J. Mesenchymal Stem Cells and Their Small Extracellular Vesicles as Crucial Immunological Efficacy for Hepatic Diseases. Front Immunol 2022; 13:880523. [PMID: 35603168 PMCID: PMC9121380 DOI: 10.3389/fimmu.2022.880523] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cell small extracellular vesicles (MSC-sEVs) are a priority for researchers because of their role in tissue regeneration. sEVs act as paracrine factors and carry various cargos, revealing the state of the parent cells and contributing to cell–cell communication during both physiological and pathological circumstances. Hepatic diseases are mainly characterized by inflammatory cell infiltration and hepatocyte necrosis and fibrosis, bringing the focus onto immune regulation and other regulatory mechanisms of MSCs/MSC-sEVs. Increasing evidence suggests that MSCs and their sEVs protect against acute and chronic liver injury by inducing macrophages (MΦ) to transform into the M2 subtype, accelerating regulatory T/B (Treg/Breg) cell activation and promoting immunosuppression. MSCs/MSC-sEVs also prevent the proliferation and differentiation of T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells. This review summarizes the potential roles for MSCs/MSC-sEVs, including immunomodulation and tissue regeneration, in various liver diseases. There is also a specific focus on the use of MSC-sEVs for targeted drug delivery to treat hepatitis.
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Affiliation(s)
- Yuting Tang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Peipei Wu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Linli Li
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Wenrong Xu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Wenrong Xu, ; Jiajia Jiang,
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Wenrong Xu, ; Jiajia Jiang,
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11
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Wang X, He Z, Zhao X. Immunoregulatory therapy strategies that target cytokine storms in patients with COVID-19 (Review). Exp Ther Med 2021; 21:319. [PMID: 33732292 PMCID: PMC7903484 DOI: 10.3892/etm.2021.9750] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
A cytokine storm is an uncontrolled, excessive immune response that contributes to the pathogenesis of coronavirus disease 2019 (COVID-19). Viral infections lead to the loss of negative feedback in immune regulation and an abnormal elevation of the levels of multiple cytokines. In COVID-19, this causes diffuse damage to alveolar functions and may culminate in multiple organ dysfunction. Immunoregulatory therapies target the cytokine storms induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and include monoclonal antibodies, recombinant granulocyte-macrophage colony stimulating factor, interferon, mesenchymal stem cell-based therapy, thymosin, immunoglobulins and blood purification therapies. These approaches may be effective in the alleviation of COVID-19 symptoms. In this review, cytokine storms caused by SARS-CoV-2 infections are evaluated and discussed, and advances in immunoregulatory therapy strategies for patients with COVID-19 are reviewed.
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Affiliation(s)
- Xianyao Wang
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China
| | - Zhixu He
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xing Zhao
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China
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Wang X, Yang Y, Wang N, Wu X, Xu J, Zhou Y, Zhao X, He Z. Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia. Int Immunopharmacol 2021; 94:107437. [PMID: 33571747 DOI: 10.1016/j.intimp.2021.107437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/21/2021] [Accepted: 01/24/2021] [Indexed: 12/12/2022]
Abstract
Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the therapeutic efficacy is modest, and most commonly manifests as relapse from remission. Thus, improving long-term AML survival is a crucial clinical challenge. In recent years, oncolytic virotherapy has provided an alternative approach for AML treatment. The use of oncolytic reoviruses has been explored in more than 30 clinical trials for safety and feasibility issues. However, like other oncolytic viruses, neutralizing antibodies (NAbs) reduce therapeutic efficacy. To tackle this problem, human umbilical cord mesenchymal stem cells (hUC-MSCs) were used to deliver reovirus using in vitro and in vivo models. Human UC-MSCs were successfully loaded with reovirus, without impairing biological function.We also observed in vitro protective effects of hUC-MSCs on reovirus in the presence of NAbs. In the immunocompromised AML mouse model, hUC-MSCs effectively carried reoviruses to tumor lesions and significantly prolonged the survival of AML xenografts in mice in the presence of a high titer anti-reovirus antibody (p = 0.001). However, reovirus-induced activation of AKT, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and NF-κB signaling led to the maintenance of intrinsic migratory properties and secretion of pro-inflammatory cytokines from hUC-MSCs, particularly CXCL10. In immuno-competent AML mice, MSCs carrying reovirus triggered immune responses, and eventually inhibited tumor growth. Therefore, these results suggest that MSCs as carriers of oncolytic reoviruses can enhance the antitumor efficacy of virotherapy.
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Affiliation(s)
- Xianyao Wang
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China
| | - Yichen Yang
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China
| | - Nianxue Wang
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China
| | - Xijun Wu
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China
| | - Jianwei Xu
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China; Department of Pharmacology, Guizhou Medical University, Guiyang 550025, China
| | - Yanhua Zhou
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China
| | - Xing Zhao
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China.
| | - Zhixu He
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China; Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China.
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13
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Zhu M, Hua T, Ouyang T, Qian H, Yu B. Applications of Mesenchymal Stem Cells in Liver Fibrosis: Novel Strategies, Mechanisms, and Clinical Practice. Stem Cells Int 2021; 2021:6546780. [PMID: 34434239 PMCID: PMC8380491 DOI: 10.1155/2021/6546780] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/07/2021] [Accepted: 07/14/2021] [Indexed: 12/14/2022] Open
Abstract
Liver fibrosis is a common result of most chronic liver diseases, and advanced fibrosis often leads to cirrhosis. Currently, there is no effective treatment for liver cirrhosis except liver transplantation. Therefore, it is important to carry out antifibrosis treatment to reverse liver damage in the early stage of liver fibrosis. Mesenchymal stem cells (MSCs) are the most widely used stem cells in the field of regenerative medicine. The preclinical and clinical research results of MSCs in the treatment of liver fibrosis and cirrhosis show that MSC administration is a promising treatment for liver fibrosis and cirrhosis. MSCs reverse liver fibrosis and increase liver function mainly through differentiation into hepatocytes, immune regulation, secretion of cytokines and other nutritional factors, reduction of hepatocyte apoptosis, and promotion of hepatocyte regeneration. Recently, many studies provided a variety of new methods and strategies to improve the effect of MSCs in the treatment of liver fibrosis. In this review, we summarized the current effective methods and strategies and their potential mechanisms of MSCs in the treatment of liver fibrosis, as well as the current research progress in clinical practice. We expect to achieve complete reversal of liver injury with MSC-based therapy in the future.
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Affiliation(s)
- Mengmei Zhu
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Tianzhen Hua
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Tao Ouyang
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Huofu Qian
- 2Department of Gastroenterology, The Second People's Hospital of Taizhou, China
| | - Bing Yu
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China
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14
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Al-Dhamin Z, Liu LD, Li DD, Zhang SY, Dong SM, Nan YM. Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies. World J Gastroenterol 2020; 26:7444-7469. [PMID: 33384547 PMCID: PMC7754546 DOI: 10.3748/wjg.v26.i47.7444] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/31/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.
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Affiliation(s)
- Zaid Al-Dhamin
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Ling-Di Liu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Dong-Dong Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Si-Yu Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Shi-Ming Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
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15
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Deng J, Zhong L, Zhou Z, Gu C, Huang X, Shen L, Cao S, Ren Z, Zuo Z, Deng J, Yu S. Autophagy: a promising therapeutic target for improving mesenchymal stem cell biological functions. Mol Cell Biochem 2020; 476:1135-1149. [PMID: 33196943 DOI: 10.1007/s11010-020-03978-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) are considered to be a promising therapeutic material due to their capacities for self-renewal, multilineage differentiation, and immunomodulation and have attracted great attention in regenerative medicine. However, MSCs may lose their biological functions because of donor age or disease and environmental pressure before and after transplantation, which hinders the application of MSC-based therapy. As a major intracellular lysosome-dependent degradative process, autophagy plays a pivotal role in maintaining cellular homeostasis and withstanding environmental pressure and may become a potential therapeutic target for improving MSC functions. Recent studies have demonstrated that the regulation of autophagy is a promising approach for improving the biological properties of MSCs. More in-depth investigations about the role of autophagy in MSC biology are required to contribute to the clinical application of MSCs. In this review, we focus on the role of autophagy regulation by various physical and chemical factors on the biological functions of MSCs in vitro and in vivo, and provide some strategies for enhancing the therapeutic efficacy of MSCs.
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Affiliation(s)
- Jiaqiang Deng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Lijun Zhong
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zihan Zhou
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Congwei Gu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Laboratory Animal Centre, Southwest Medical University, Luzhou, China
| | - Xiaoya Huang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Liuhong Shen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Suizhong Cao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhihua Ren
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhicai Zuo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Junliang Deng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shumin Yu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
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