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Zhang L, Deng Y, Bai X, Wei X, Ren Y, Chen S, Deng H. Cell therapy for end-stage liver disease: Current state and clinical challenge. Chin Med J (Engl) 2024; 137:2808-2820. [PMID: 39602326 DOI: 10.1097/cm9.0000000000003332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Indexed: 11/29/2024] Open
Abstract
ABSTRACT Liver disease involves a complex interplay of pathological processes, including inflammation, hepatocyte necrosis, and fibrosis. End-stage liver disease (ESLD), such as liver failure and decompensated cirrhosis, has a high mortality rate, and liver transplantation is the only effective treatment. However, to overcome problems such as the shortage of donor livers and complications related to immunosuppression, there is an urgent need for new treatment strategies that need to be developed for patients with ESLD. For instance, hepatocytes derived from donor livers or stem cells can be engrafted and multiplied in the liver, substituting the host hepatocytes and rebuilding the liver parenchyma. Stem cell therapy, especially mesenchymal stem cell therapy, has been widely proved to restore liver function and alleviate liver injury in patients with severe liver disease, which has contributed to the clinical application of cell therapy. In this review, we discussed the types of cells used to treat ESLD and their therapeutic mechanisms. We also summarized the progress of clinical trials around the world and provided a perspective on cell therapy.
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Affiliation(s)
- Lin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Yang W, Jin M, Gu Y, Zhao X, Zhu L, He S, Wang H, Ding X, Wang B, Jiang T, Xiao Y, Zhou G, Huang J, Zhang Y. Intracellular osteopontin potentiates the immunosuppressive activity of mesenchymal stromal cells. Stem Cell Res Ther 2024; 15:366. [PMID: 39407354 PMCID: PMC11475537 DOI: 10.1186/s13287-024-03979-8] [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: 06/12/2024] [Accepted: 10/05/2024] [Indexed: 10/19/2024] Open
Abstract
INTRODUCTION Mesenchymal stromal cell (MSC)-based cell therapy is a promising approach for various inflammatory disorders based on their immunosuppressive capacity. Osteopontin (OPN) regulates several cellular functions including tissue repair, bone metabolism and immune reaction. However, the biological function of OPN in regulating the immunosuppressive capacity of MSCs remains elusive. OBJECTIVES This study aims to highlight the underlying mechanism of the proinflammatory cytokines affect the therapeutic ability of MSCs through OPN. METHODS MSCs in response to the proinflammatory cytokines were collected to determine the expression profile of OPN. In vitro T-cell proliferation assays and gene editing were performed to check the role and mechanisms of OPN in regulating the immunosuppressive capacity of MSCs. Inflammatory disease mouse models were established to evaluate the effect of OPN on improving MSC-based immunotherapy. RESULTS We observed that OPN, including its two isoforms iOPN and sOPN, was downregulated in MSCs upon proinflammatory cytokine stimulation. Interestingly, iOPN, but not sOPN, greatly enhanced the immunosuppressive activity of MSCs on T-cell proliferation and thus alleviated the inflammatory pathologies of hepatitis and colitis. Mechanistically, iOPN interacted with STAT1 and mediated its deubiquitination, thereby inducing the master immunosuppressive mediator inducible nitric oxide synthase (iNOS) in MSCs. In addition, iOPN expression was directly downregulated by activated STAT1, which formed a negative feedback loop to restrain MSC immunosuppressive capacity. CONCLUSION Our findings demonstrated that iOPN expression modulation in MSCs is a novel strategy to improve MSC-based immunotherapy.
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Affiliation(s)
- Wanlin Yang
- Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Jin
- Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuting Gu
- Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaonan Zhao
- Children's Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Lingqiao Zhu
- Children's Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Shan He
- Children's Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Hui Wang
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinyuan Ding
- Gusu College, Nanjing Medical University, Nanjing, China
| | - Bei Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Tingwang Jiang
- Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Guoqiang Zhou
- Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China.
- Gusu College, Nanjing Medical University, Nanjing, China.
| | - Jiefang Huang
- Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China.
- Gusu College, Nanjing Medical University, Nanjing, China.
| | - Yanyun Zhang
- Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China.
- Children's Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Soochow University, Suzhou, China.
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
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Pharoun J, Berro J, Sobh J, Abou-Younes MM, Nasr L, Majed A, Khalil A, Joseph, Stephan, Faour WH. Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications. Eur J Pharmacol 2024; 977:176719. [PMID: 38849038 DOI: 10.1016/j.ejphar.2024.176719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 06/09/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. METHODS Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. RESULTS The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. CONCLUSION Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.
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Affiliation(s)
- Jana Pharoun
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jana Berro
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jeanine Sobh
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | | | - Leah Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Ali Majed
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Joseph
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Stephan
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36.
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Chen C, Feng D, Wang Y, Yao T, Mackowiak B, Gao B. Necrotic Liver Lesion Resolution: Another Mode of Liver Regeneration. Semin Liver Dis 2024; 44:333-342. [PMID: 38955211 DOI: 10.1055/a-2358-9505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2024]
Abstract
The liver has the great ability to regenerate after partial resection or injury, and the mechanisms underlying liver regeneration have been extensively investigated. Interestingly, acute liver injuries triggered by various etiologies are associated with the formation of necrotic lesions, and such necrotic lesions are also rapidly resolved. However, how necrotic liver lesions are repaired has not been carefully investigated until recently. In this review, we briefly summarize the spatiotemporal process of necrotic liver lesion resolution in several liver injury models including immune-mediated liver injury and drug-induced liver injury. The roles of liver nonparenchymal cells and infiltrating immune cells in controlling necrotic liver lesion resolution are discussed, which may help identify potential therapies for acute liver injury and failure.
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Affiliation(s)
- Cheng Chen
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yang Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Tiantian Yao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Feng L, Wang Y, Fu Y, Li T, He G. Stem Cell-Based Strategies: The Future Direction of Bioartificial Liver Development. Stem Cell Rev Rep 2024; 20:601-616. [PMID: 38170319 DOI: 10.1007/s12015-023-10672-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2023] [Indexed: 01/05/2024]
Abstract
Acute liver failure (ALF) results from severe liver damage or end-stage liver disease. It is extremely fatal and causes serious health and economic burdens worldwide. Once ALF occurs, liver transplantation (LT) is the only definitive and recommended treatment; however, LT is limited by the scarcity of liver grafts. Consequently, the clinical use of bioartificial liver (BAL) has been proposed as a treatment strategy for ALF. Human primary hepatocytes are an ideal cell source for these methods. However, their high demand and superior viability prevent their widespread use. Hence, finding alternatives that meet the seed cell quality and quantity requirements is imperative. Stem cells with self-renewing, immunogenic, and differentiative capacities are potential cell sources. MSCs and its secretomes encompass a spectrum of beneficial properties, such as anti-inflammatory, immunomodulatory, anti-ROS (reactive oxygen species), anti-apoptotic, pro-metabolomic, anti-fibrogenesis, and pro-regenerative attributes. This review focused on the recent status and future directions of stem cell-based strategies in BAL for ALF. Additionally, we discussed the opportunities and challenges associated with promoting such strategies for clinical applications.
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Affiliation(s)
- Lei Feng
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550000, Guizhou, China.
| | - Yi Wang
- Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, Shanxi, China
| | - Yu Fu
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Ting Li
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510140, Guangdong, China.
| | - Guolin He
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
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Lee HJ, Chae CW, Han HJ. Enhancing the therapeutic efficacy of mesenchymal stem cell transplantation in diabetes: Amelioration of mitochondrial dysfunction-induced senescence. Biomed Pharmacother 2023; 168:115759. [PMID: 37865993 DOI: 10.1016/j.biopha.2023.115759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/09/2023] [Accepted: 10/17/2023] [Indexed: 10/24/2023] Open
Abstract
Mesenchymal stem cell (MSC) transplantation offers significant potential for the treatment of diabetes mellitus (DM) and its complications. However, hyperglycemic conditions can induce senescence and dysfunction in both transplanted and resident MSCs, thereby limiting their therapeutic potential. Mitochondrial dysfunction and oxidative stress are key contributors to this process in MSCs exposed to hyperglycemia. As such, strategies aimed at mitigating mitochondrial dysfunction could enhance the therapeutic efficacy of MSC transplantation in DM. In this review, we provide an updated overview of how mitochondrial dysfunction mediates MSC senescence. We present experimental evidence for the molecular mechanisms behind high glucose-induced mitochondrial dysfunction in MSCs, which include impairment of mitochondrial biogenesis, mitochondrial calcium regulation, the mitochondrial antioxidant system, mitochondrial fusion-fission dynamics, mitophagy, and intercellular mitochondrial transfer. Furthermore, we propose potential pharmacological candidates that could improve the efficacy of MSC transplantation by enhancing mitochondrial function in patients with DM and related complications.
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Affiliation(s)
- Hyun Jik Lee
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of South Korea; Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju 28644, Republic of South Korea
| | - Chang Woo Chae
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul 08826, Republic of Korea
| | - Ho Jae Han
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul 08826, Republic of Korea.
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8
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Lan T, Li S, Yu H, Kostallari E, Gao J. Editorial: Community series in hepatic immune response underlying liver cirrhosis and portal hypertension, volume II. Front Immunol 2023; 14:1305666. [PMID: 37901235 PMCID: PMC10600445 DOI: 10.3389/fimmu.2023.1305666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/31/2023] Open
Affiliation(s)
- Tian Lan
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Haopeng Yu
- West China Biomedical Big Data Center, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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Wang YH, Chen EQ. Mesenchymal Stem Cell Therapy in Acute Liver Failure. Gut Liver 2023; 17:674-683. [PMID: 36843422 PMCID: PMC10502502 DOI: 10.5009/gnl220417] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 02/28/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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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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Tao H, Liu Q, Zeng A, Song L. Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging. Int Immunopharmacol 2023; 121:110497. [PMID: 37329808 DOI: 10.1016/j.intimp.2023.110497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/30/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023]
Abstract
Liver fibrosis is a chronic liver disease characterized by extracellular matrix protein accumulation, potentially leading to cirrhosis or hepatocellular carcinoma. Liver cell damage, inflammatory responses, and apoptosis due to various reasons induce liver fibrosis. Although several treatments, such as antiviral drugs and immunosuppressive therapies, are available for liver fibrosis, they only provide limited efficacy. Mesenchymal stem cells (MSCs) have become a promising therapeutic option for liver fibrosis, because they can modulate the immune response, promote liver regeneration, and inhibit the activation of hepatic stellate cells that contribute to disease development. Recent studies have suggested that the mechanisms through which MSCs gain their antifibrotic properties involve autophagy and senescence. Autophagy, a vital cellular self-degradation process, is critical for maintaining homeostasis and protecting against nutritional, metabolic, and infection-mediated stress. The therapeutic effects of MSCs depend on appropriate autophagy levels, which can improve the fibrotic process. Nonetheless, aging-related autophagic damage is associated with a decline in MSC number and function, which play a crucial role in liver fibrosis development. This review summarizes the recent advancements in the understanding of autophagy and senescence in MSC-based liver fibrosis treatment, presenting the key findings from relevant studies.
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Affiliation(s)
- Hongxia Tao
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Qianglin Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, PR China.
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China.
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Chen J, Cao Y, Jia O, Wang X, Luo Y, Cheuk YC, Zhu T, Zhu D, Zhang Y, Wang J. Monomethyl fumarate prevents alloimmune rejection in mouse heart transplantation by inducing tolerogenic dendritic cells. Acta Biochim Biophys Sin (Shanghai) 2023. [PMID: 37184280 DOI: 10.3724/abbs.2023088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023] Open
Abstract
Dendritic cells (DCs) are important targets for eliciting allograft rejection after transplantation. Previous studies have demonstrated that metabolic reprogramming of DCs can transform their immune functions and induce their differentiation into tolerogenic DCs. In this study, we aim to investigate the protective effects and mechanisms of monomethyl fumarate (MMF), a bioactive metabolite of fumaric acid esters, in a mouse model of allogeneic heart transplantation. Bone marrow-derived DCs are harvested and treated with MMF to determine the impact of MMF on the phenotype and immunosuppressive function of DCs by flow cytometry and T-cell proliferation assays. RNA sequencing and Seahorse analyses are performed for mature DCs and MMF-treated DCs (MMF-DCs) to investigate the underlying mechanism. Our results show that MMF prolongs the survival time of heart grafts and inhibits the activation of DCs in vivo. MMF-DCs exhibit a tolerogenic phenotype and function in vitro. RNA sequencing and Seahorse analyses reveal that MMF activates the Nrf2 pathway and mediates metabolic reprogramming. Additionally, MMF-DC infusion prolongs cardiac allograft survival, induces regulatory T cells, and inhibits T-cell activation. MMF prevents allograft rejection in mouse heart transplantation by inducing tolerogenic DCs.
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Affiliation(s)
- Juntao Chen
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yirui Cao
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Ouyang Jia
- Nursing Department of Huashan Hospital Affiliated to Fudan University, Shanghai 200031, China
| | - Xuanchuan Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yongsheng Luo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Tongyu Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Dong Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
- Department of Urology, Zhongshan Hospital, Fudan University (Xiamen branch), Xiamen 361015, China
| | - Yi Zhang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
- Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jina Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
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13
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Zeng CW. Multipotent Mesenchymal Stem Cell-Based Therapies for Spinal Cord Injury: Current Progress and Future Prospects. BIOLOGY 2023; 12:biology12050653. [PMID: 37237467 DOI: 10.3390/biology12050653] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023]
Abstract
Spinal cord injury (SCI) represents a significant medical challenge, often resulting in permanent disability and severely impacting the quality of life for affected individuals. Traditional treatment options remain limited, underscoring the need for novel therapeutic approaches. In recent years, multipotent mesenchymal stem cells (MSCs) have emerged as a promising candidate for SCI treatment due to their multifaceted regenerative capabilities. This comprehensive review synthesizes the current understanding of the molecular mechanisms underlying MSC-mediated tissue repair in SCI. Key mechanisms discussed include neuroprotection through the secretion of growth factors and cytokines, promotion of neuronal regeneration via MSC differentiation into neural cell types, angiogenesis through the release of pro-angiogenic factors, immunomodulation by modulating immune cell activity, axonal regeneration driven by neurotrophic factors, and glial scar reduction via modulation of extracellular matrix components. Additionally, the review examines the various clinical applications of MSCs in SCI treatment, such as direct cell transplantation into the injured spinal cord, tissue engineering using biomaterial scaffolds that support MSC survival and integration, and innovative cell-based therapies like MSC-derived exosomes, which possess regenerative and neuroprotective properties. As the field progresses, it is crucial to address the challenges associated with MSC-based therapies, including determining optimal sources, intervention timing, and delivery methods, as well as developing standardized protocols for MSC isolation, expansion, and characterization. Overcoming these challenges will facilitate the translation of preclinical findings into clinical practice, providing new hope and improved treatment options for individuals living with the devastating consequences of SCI.
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Affiliation(s)
- Chih-Wei Zeng
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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14
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The Role of COX-2 and PGE2 in the Regulation of Immunomodulation and Other Functions of Mesenchymal Stromal Cells. Biomedicines 2023; 11:biomedicines11020445. [PMID: 36830980 PMCID: PMC9952951 DOI: 10.3390/biomedicines11020445] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 01/27/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the key mediators in the immunomodulatory effect of MSCs. Due to the pleiotropic effect of this molecule, determining its role in particular intercellular interactions and aspects of cell functioning is very difficult. In this article, the authors attempt to summarize the previous observations regarding the role of PGE2 and COX-2 in the immunomodulatory properties and other vital functions of MSCs. So far, the most consistent results relate to the inhibitory effect of MSC-derived PGE2 on the early maturation of dendritic cells, suppressive effect on the proliferation of activated lymphocytes, and stimulatory effect on the differentiation of macrophages into M2 phenotype. Additionally, COX-2/PGE2 plays an important role in maintaining the basic life functions of MSCs, such as the ability to proliferate, migrate and differentiate, and it also positively affects the formation of niches that are conducive to both hematopoiesis and carcinogenesis.
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15
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Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury. Antioxidants (Basel) 2023; 12:antiox12010158. [PMID: 36671020 PMCID: PMC9854665 DOI: 10.3390/antiox12010158] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/31/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.
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16
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Mechanisms of Action of Mesenchymal Stem Cells in Metabolic-Associated Fatty Liver Disease. Stem Cells Int 2023; 2023:3919002. [PMID: 36644008 PMCID: PMC9839417 DOI: 10.1155/2023/3919002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 11/15/2022] [Accepted: 12/09/2022] [Indexed: 01/09/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is currently the most common chronic liver disease worldwide. However, its pathophysiological mechanism is complicated, and currently, it has no FDA-approved pharmacological therapies. In recent years, mesenchymal stem cell (MSC) therapy has attracted increasing attention in the treatment of hepatic diseases. MSCs are multipotent stromal cells that originated from mesoderm mesenchyme, which have self-renewal and multipotent differentiation capability. Recent experiments and studies have found that MSCs have the latent capacity to be used for MAFLD treatment. MSCs have the potential to differentiate into hepatocytes, which could be induced into hepatocyte-like cells (HLCs) with liver-specific morphology and function under appropriate conditions to promote liver tissue regeneration. They can also reduce liver tissue injury and reverse the development of MAFLD by regulating immune response, antifibrotic activities, and lipid metabolism. Moreover, several advantages are attributed to MSC-derived exosomes (MSC-exosomes), such as targeted delivery, reliable reparability, and poor immunogenicity. After entering the target cells, MSC-exosomes help regulate cell function and signal transduction; thus, it is expected to become an emerging treatment for MAFLD. In this review, we comprehensively discussed the roles of MSCs in MAFLD, main signaling pathways of MSCs that affect MAFLD, and mechanisms of MSC-exosomes on MAFLD.
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17
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Liu P, Qian Y, Liu X, Zhu X, Zhang X, Lv Y, Xiang J. Immunomodulatory role of mesenchymal stem cell therapy in liver fibrosis. Front Immunol 2023; 13:1096402. [PMID: 36685534 PMCID: PMC9848585 DOI: 10.3389/fimmu.2022.1096402] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/15/2022] [Indexed: 01/06/2023] Open
Abstract
Liver fibrosis is a fibrogenic and inflammatory process that results from hepatocyte injury and is characterized by hepatic architectural distortion and resultant loss of liver function. There is no effective treatment for advanced fibrosis other than liver transplantation, but it is limited by expensive costs, immune rejection, and postoperative complications. With the development of regenerative medicine in recent years, mesenchymal stem cell (MSCs) transplantation has become the most promising treatment for liver fibrosis. The underlying mechanisms of MSC anti-fibrotic effects include hepatocyte differentiation, paracrine, and immunomodulation, with immunomodulation playing a central role. This review discusses the immune cells involved in liver fibrosis, the immunomodulatory properties of MSCs, and the immunomodulation mechanisms of MSC-based strategies to attenuate liver fibrosis. Meanwhile, we discuss the current challenges and future directions as well.
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Affiliation(s)
- Peng Liu
- Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yerong Qian
- Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xin Liu
- Department of Radiotherapy, Xi’an Medical University, Xi’an, Shaanxi, China
| | - Xulong Zhu
- Department of Surgical Oncology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Xufeng Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yi Lv
- Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,*Correspondence: Junxi Xiang, ; Yi Lv,
| | - Junxi Xiang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,*Correspondence: Junxi Xiang, ; Yi Lv,
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18
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Chen Q, Jin M, Wang S, Wang K, Chen L, Zhu X, Zhang Y, Wang Y, Li Y, Li S, Zeng Y, Feng L, Yang W, Gao Y, Zhou S, Peng Q. Establishing an hTERT-driven immortalized umbilical cord-derived mesenchymal stem cell line and its therapeutic application in mice with liver failure. J Tissue Eng 2023; 14:20417314231200328. [PMID: 37736245 PMCID: PMC10510347 DOI: 10.1177/20417314231200328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/25/2023] [Indexed: 09/23/2023] Open
Abstract
Acute liver failure (ALF) is characterized by rapid liver cell destruction. It is a multi-etiological and fulminant complication with a clinical mortality of over 80%. Therapy using mesenchymal stem cells (MSCs) or MSCs-derived exosomes can alleviate acute liver injury, which has been demonstrated in animal experiments and clinical application. However, similar to other stem cells, different cell sources, poor stability, cell senescence and other factors limit the clinical application of MSCs. To achieve mass production and quality control on stem cells and their exosomes, transfecting umbilical cord mesenchymal stem cell (UCMSC) with lentivirus overexpressing human telomerase reverse transcriptase (hTERT) gene, the hTERT-UCMSC was constructed as an immortalized MSC cell line. Compared with the primary UCMSC (P3) and immortalized cell line hTERT-UCMSC at early passage (P10), the hTERT-UCMSC retained the key morphological and physiological characteristics of UCMSC at the 35th passage (P35), and showed no signs of carcinogenicity and toxic effect in mice. There was no difference in either exosome production or characteristics of exosomes among cultures from P3 primary cells, P10 and P35 immortalized hTERT-UCMSCs. Inoculation of either hTERT-UCMSC (P35) or its exosomes improved the survival rate and liver function of ALF mice induced by thioacetamide (TAA). Our findings suggest that this immortalized cell line can maintain its characteristics in long-term culture. Inoculation of hTERT-UCMSC and its exosomes could potentially be used in clinics for the treatment of liver failure in the future.
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Affiliation(s)
- Qi Chen
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Meixian Jin
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Simin Wang
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Kexin Wang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Liqin Chen
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaojuan Zhu
- Department of Anesthesiology, The First People’ s Hospital of Kashi, Kashgar, Xinjiang, China
| | - Ying Zhang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Wang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yang Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shao Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Youmin Zeng
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Feng
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Wanren Yang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shuqin Zhou
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qing Peng
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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19
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USP9x promotes CD8 + T-cell dysfunction in association with autophagy inhibition in septic liver injury. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1-10. [PMID: 36514222 PMCID: PMC10157537 DOI: 10.3724/abbs.2022174] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Sepsis is a life-threatening condition manifested by concurrent inflammation and immunosuppression. Ubiquitin-specific peptidase 9, X-linked (USP9x), is a USP domain-containing deubiquitinase which is required in T-cell development. In the present study, we investigate whether USP9x plays a role in hepatic CD8 + T-cell dysfunction in septic mice. We find that CD8 + T cells are decreased in the blood of septic patients with liver injury compared with those without liver injury, the CD4/CD8 ratio is increased, and the levels of cytolytic factors, granzyme B and perforin are downregulated. The number of hepatic CD8 + T cells and USP9x expression are both increased 24 h after cecal ligation and puncture-induced sepsis in a mouse model, a pattern similar to liver injury. The mechanism involves promotion of CD8 + T-cell dysfunction by USP9x associated with suppression of cell cytolytic activity via autophagy inhibition, which is reversed by the USP9x inhibitor WP1130. In the in vivo studies, autophagy is significantly increased in hepatic CD8 + T cells of septic mice with conditional knockout of mammalian target of rapamycin. This study shows that USP9x has the potential to be used as a therapeutic target in septic liver injury.
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20
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Gao S, Zhang Y, Liang K, Bi R, Du Y. Mesenchymal Stem Cells (MSCs): A Novel Therapy for Type 2 Diabetes. Stem Cells Int 2022; 2022:8637493. [PMID: 36045953 PMCID: PMC9424025 DOI: 10.1155/2022/8637493] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/15/2022] [Accepted: 07/05/2022] [Indexed: 11/25/2022] Open
Abstract
Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.
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Affiliation(s)
- Shuang Gao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yuanyuan Zhang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ran Bi
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
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21
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Harrell CR, Pavlovic D, Djonov V, Volarevic V. Therapeutic potential of mesenchymal stem cells in the treatment of acute liver failure. World J Gastroenterol 2022; 28:3627-3636. [PMID: 36161038 PMCID: PMC9372816 DOI: 10.3748/wjg.v28.i28.3627] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/08/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
Acute liver failure (ALF) is a severe and life-threatening condition in which rapid deterioration of liver function develops in a patient who has no preexisting liver disease. Mesenchymal stem cells (MSCs) are immunoregulatory stem cells which are able to modulate phenotype and function of all immune cells that play pathogenic role in the development and progression of ALF. MSCs in juxtacrine and paracrine manner attenuate antigen-presenting properties of dendritic cells and macrophages, reduce production of inflammatory cytokines in T lymphocytes, suppress hepatotoxicity of natural killer T (NKT) cells and promote generation and expansion of immunosuppressive T, B and NKT regulatory cells in acutely inflamed liver. Due to their nano-sized dimension and lipid envelope, intravenously injected MSC-derived exosomes (MSC-Exos) may by-pass all biological barriers to deliver MSC-sourced immunoregulatoy factors directly into the liver-infiltrated immune cells and injured hepatocytes. Results obtained by us and others revealed that intravenous administration of MSCs and MSC-Exos efficiently attenuated detrimental immune response and acute inflammation in the liver, suggesting that MSCs and MSC-Exos could be considered as potentially new remedies in the immunotherapy of ALF. In this review, we emphasize the current knowledge about molecular and cellular mechanisms which are responsible for MSC-based modulation of liver-infiltrated immune cells and we discuss different insights regarding the therapeutic potential of MSCs in liver regeneration.
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Affiliation(s)
| | - Dragica Pavlovic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Bern 3012, Switzerland
| | - Vladislav Volarevic
- Department of Medical Genetics and Microbiology and Immunology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
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22
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Yang Y, Zhao RC, Zhang F. Potential mesenchymal stem cell therapeutics for treating primary biliary cholangitis: advances, challenges, and perspectives. Front Cell Dev Biol 2022; 10:933565. [PMID: 35923849 PMCID: PMC9339990 DOI: 10.3389/fcell.2022.933565] [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: 05/01/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by the gradual destruction of small intrahepatic bile ducts that eventually leads to liver cirrhosis, failure, and even carcinoma. The treatment options for PBC are limited, and the main treatment choices are the US Food and Drug Administration–approved ursodeoxycholic acid and obeticholic acid. However, many patients fail to respond adequately to these drugs and the adverse effects frequently lead to low life quality. For patients with end-stage PBC, liver transplantation remains the only effective treatment. Given their low immunogenicity, prominent immunomodulation property, differentiation potential, and tissue maintenance capacity, mesenchymal stem cells (MSCs) are emerging as new options for treating liver diseases, including PBC. Accumulating evidence from basic research to clinical studies supports the positive effects of MSC-based therapy for treating PBC. In this review, we characterized the underlying roles and mechanisms of MSCs for treating liver diseases and highlight recent basic and clinical advances in MSC-based therapy for treating PBC. Finally, the current challenges and perspectives for MSC-based therapy in clinical application are discussed, which could help accelerate the application of MSCs in clinical practice, especially for refractory diseases such as PBC.
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Affiliation(s)
- Yanlei Yang
- Clinical Biobank, National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Medical Science Research Centre, Medical Science Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- The Ministry of Education Key Laboratory, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Robert Chunhua Zhao
- Beijing Key Laboratory, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Beijing, China
- School of Life Sciences, Shanghai University, Shanghai, China
- *Correspondence: Fengchun Zhang, ; Robert Chunhua Zhao,
| | - Fengchun Zhang
- The Ministry of Education Key Laboratory, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Fengchun Zhang, ; Robert Chunhua Zhao,
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23
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Yao L, Hu X, Dai K, Yuan M, Liu P, Zhang Q, Jiang Y. Mesenchymal stromal cells: promising treatment for liver cirrhosis. Stem Cell Res Ther 2022; 13:308. [PMID: 35841079 PMCID: PMC9284869 DOI: 10.1186/s13287-022-03001-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/13/2022] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
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24
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Hazrati A, Malekpour K, Soudi S, Hashemi SM. Mesenchymal Stromal/Stem Cells and Their Extracellular Vesicles Application in Acute and Chronic Inflammatory Liver Diseases: Emphasizing on the Anti-Fibrotic and Immunomodulatory Mechanisms. Front Immunol 2022; 13:865888. [PMID: 35464407 PMCID: PMC9021384 DOI: 10.3389/fimmu.2022.865888] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
Abstract
Various factors, including viral and bacterial infections, autoimmune responses, diabetes, drugs, alcohol abuse, and fat deposition, can damage liver tissue and impair its function. These factors affect the liver tissue and lead to acute and chronic liver damage, and if left untreated, can eventually lead to cirrhosis, fibrosis, and liver carcinoma. The main treatment for these disorders is liver transplantation. Still, given the few tissue donors, problems with tissue rejection, immunosuppression caused by medications taken while receiving tissue, and the high cost of transplantation, liver transplantation have been limited. Therefore, finding alternative treatments that do not have the mentioned problems is significant. Cell therapy is one of the treatments that has received a lot of attention today. Hepatocytes and mesenchymal stromal/stem cells (MSCs) are used in many patients to treat liver-related diseases. In the meantime, the use of mesenchymal stem cells has been studied more than other cells due to their favourable characteristics and has reduced the need for liver transplantation. These cells increase the regeneration and repair of liver tissue through various mechanisms, including migration to the site of liver injury, differentiation into liver cells, production of extracellular vesicles (EVs), secretion of various growth factors, and regulation of the immune system. Notably, cell therapy is not entirely excellent and has problems such as cell rejection, undesirable differentiation, accumulation in unwanted locations, and potential tumorigenesis. Therefore, the application of MSCs derived EVs, including exosomes, can help treat liver disease and prevent its progression. Exosomes can prevent apoptosis and induce proliferation by transferring different cargos to the target cell. In addition, these vesicles have been shown to transport hepatocyte growth factor (HGF) and can promote the hepatocytes'(one of the most important cells in the liver parenchyma) growths.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, Hua D, Shao C, Shi Y. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther 2022; 7:92. [PMID: 35314676 PMCID: PMC8935608 DOI: 10.1038/s41392-022-00932-0] [Citation(s) in RCA: 287] [Impact Index Per Article: 95.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 11/18/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
AbstractMesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.
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GPR120 induces regulatory dendritic cells by inhibiting HK2-dependent glycolysis to alleviate fulminant hepatic failure. Cell Death Dis 2021; 13:1. [PMID: 34911928 PMCID: PMC8674251 DOI: 10.1038/s41419-021-04394-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 10/24/2021] [Accepted: 11/09/2021] [Indexed: 01/12/2023]
Abstract
Fulminant hepatic failure (FHF) is a potentially fatal liver disease that is associated with intrahepatic infiltration of inflammatory cells. As the receptor of polyunsaturated long chain fatty acids, GPR120 can regulate cell differentiation, proliferation, metabolism, and immune response. However, whether GPR120 is involved in FHF remains unknown. Using Propionibacterium acnes (P. acnes)-primed, LPS-induced FHF in mice, we found that interference with GPR120 activity using pharmacological agonist attenuated the severity of the liver injury and mortality of FHF in mice, while a lack of GPR120 exacerbated the disease. GPR120 activation potently alleviated FHF and led to decreased T helper (Th) 1 cell response and expansion of regulatory T cells (Tregs). Interestingly, GPR120 agonist didn't directly target T cells, but dramatically induced a distinct population of CD11c+MHC IIlowCD80lowCD86low regulatory DCs in the livers of FHF mice. GPR120 was found to restrict HIF-1α-dependent glycolysis. The augmented HIF-1α stabilization caused by GPR120 antagonism or deletion could be attenuated by the inhibition of ERK or by the activation of AMPK. Through the analysis of the clinical FHF, we further confirmed the activation of GPR120 was negatively associated with the severity in patients. Our findings indicated that GPR120 activation has therapeutic potential in FHF. Strategies to target GPR120 using agonists or free fatty acids (FFAs) may represent a novel approach to FHF treatment.
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Shi M, Li YY, Xu RN, Meng FP, Yu SJ, Fu JL, Hu JH, Li JX, Wang LF, Jin L, Wang FS. Mesenchymal stem cell therapy in decompensated liver cirrhosis: a long-term follow-up analysis of the randomized controlled clinical trial. Hepatol Int 2021; 15:1431-1441. [PMID: 34843069 PMCID: PMC8651584 DOI: 10.1007/s12072-021-10199-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/24/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Mesenchymal stem cell (MSC) infusion was reported to improve liver function in patients with decompensated liver cirrhosis (DLC); however, whether the medication can improve outcome of these patients is poorly understood. METHODS This prospective, open-labeled, randomized controlled study enrolled 219 patients with HBV-related DLC who were divided into control group (n = 111) and umbilical cord-derived MSC (UC-MSC)-treated group (n = 108), then all of them received a follow-up check from October 2010 to October 2017. The treated patients received three times of UC-MSC infusions at 4-week intervals plus conventional treatment that was only used for control group. The overall survival rate and HCC-free survival rate were calculated as primary endpoints and the liver function and adverse events associated with the medication were also evaluated. RESULTS During the follow-up check period from 13 to 75th months, there was a significantly higher overall survival rate in the treated group than the control group, while the difference of the hepatocellular carcinoma event-free survival rate between the treated and control groups was not observed during the 75-month follow-up. UC-MSC treatment markedly improved liver function, as indicated by the levels of serum albumin, prothrombin activity, cholinesterase, and total bilirubin during 48 weeks of follow-up. No significant side effects or treatment-related complications were observed in the UC-MSC group. CONCLUSIONS Therapy of UC-MSC is not only well tolerated, but also significantly improves long-term survival rate, as well as the liver function in patients with HBV-related DLC. UC-MSC medication, therefore, might present a novel therapeutic approach for the disease.
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Affiliation(s)
- Ming Shi
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Yuan-Yuan Li
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Ruo-Nan Xu
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Fan-Ping Meng
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Shuang-Jie Yu
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Jun-Liang Fu
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Jin-Hua Hu
- Medical Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Jing-Xin Li
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009 Jiangsu China
| | - Li-Feng Wang
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Lei Jin
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
| | - Fu-Sheng Wang
- Medical Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039 China
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Han L, Ma C, Peng H, Wu Z, Xu H, Wu J, Zhang N, Jiang Q, Ma C, Huang R, Li H, Pan G. Define Mesenchymal Stem Cell from Its Fate: Biodisposition of Human Mesenchymal Stem Cells in Normal and Concanavalin A-Induced Liver Injury Mice. J Pharmacol Exp Ther 2021; 379:125-133. [PMID: 34373354 DOI: 10.1124/jpet.121.000607] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 08/02/2021] [Indexed: 11/22/2022] Open
Abstract
The pharmaceutical industry and clinical trials have been revolutionized mesenchymal stem cell-based therapeutics. However, the pharmacokinetics of transplanted cells has been little characterized in their target tissues under healthy or disease condition. A quantitative polymerase chain reaction analytical method with matrix effect was developed to track the biodistribution of human mesenchymal stem cells in normal mice and those with Concanavalin A (Con A)-induced liver injury. Mesenchymal stem/stromal cell (MSC) disposition in blood and different organs were compared, and relevant pharmacokinetic parameters were calculated. Human MSCs (hMSCs) and mouse MSCs (mMSCs) displayed a very similar pharmacokinetic profile in all tested doses: about 95% of the detected hMSCs accumulated in the lung and 3% in the liver, and almost negligible cells were detected in other tissues. A significant double peak of hMSC concentration emerged in the lung within 1-2 hours after intravenous injection, as with mMSCs. Prazosin, a vasodilator, could eliminate the second peak in the lung and increase its Cmax and area under the concentration-time curve (AUC) by 10% in the first 2 hours. The injury caused by Con A was significantly reduced by hMSCs, and the Cmax and AUC0-8 (AUC from time 0 to 8 hours) of cells in the injured liver decreased by 54 and 50%, respectively. The Cmax and AUC would be improved with the alleviation of congestion through the administration of heparin. The study provides a novel insight into the pharmacokinetics of exogenous MSCs in normal and Con A-induced liver injury mice, which provides a framework for optimizing cell transplantation. SIGNIFICANCE STATEMENT: Mesenchymal stem/stromal cells (MSCs) are known for their potential as regenerative therapies in treating several diseases, but an insufficient understanding of the pharmacokinetics of MSCs restricts their future application. The current study was the first to elucidate the pharmacokinetics and possible factors, including dosage, species, and derived sources, in a systematic way. The study further revealed that Concanavalin A-induced liver injury significantly prevented cells from entering the injury site, which could be reversed by the diminished congestion achieved by heparin.
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Affiliation(s)
- Li Han
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Chenhui Ma
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Huige Peng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Zhitao Wu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Huiming Xu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Jiajun Wu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Ning Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Qinghui Jiang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Chen Ma
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Ruimin Huang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Hai Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
| | - Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., C.M., H.P., Z.W., J.W., N.Z., Q.J., C.M., R.H., G.P.); University of Chinese Academy of Sciences, Beijing, China (L.H., C.M., J.W., Q.J., C.M., R.H., G.P.); State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center (H.X.) and Department of Gastroenterology (H.L.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Nanjing University of Chinese Medicine, Nanjing, China (Z.W.)
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Zhu CH, Zhang DH, Zhu CW, Xu J, Guo CL, Wu XG, Cao QL, Di GH. Adult stem cell transplantation combined with conventional therapy for the treatment of end-stage liver disease: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:558. [PMID: 34717737 PMCID: PMC8557537 DOI: 10.1186/s13287-021-02625-x] [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: 06/14/2021] [Accepted: 10/11/2021] [Indexed: 01/11/2023] Open
Abstract
End-stage liver disease (ESLD) is characterized by the deterioration of liver function and a subsequent high mortality rate. Studies have investigated the use of adult stem cells to treat ESLD. Here, a systematic review and meta-analysis was conducted to determine the efficacy of a combination therapy with adult stem cell transplantation and traditional medicine for treating ESLD. Four databases-including PubMed, Web of Science, Embase, and Cochrane Library-were investigated for studies published before January 31, 2021. The main outcome indicators were liver function index, model for end-stage liver disease (MELD) scores, and Child‒Turcotte‒Pugh (CTP) scores. Altogether, 1604 articles were retrieved, of which eight met the eligibility criteria; these studies included data for 579 patients with ESLD. Combination of adult stem cell transplantation with conventional medicine significantly improved its efficacy with respect to liver function index, CTP and MELD scores, but this effect gradually decreased over time. Moreover, a single injection of stem cells was more effective than two injections with respect to MELD and CTP scores and total bilirubin (TBIL) and albumin (ALB) levels, with no significant difference in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. With respect to the TBIL levels, patients receiving mononuclear cells (MNCs) experienced a significantly greater therapeutic effect-starting from twenty-four weeks after the treatment-whereas with respect to ALB levels, CD34+ autologous peripheral blood stem cells (CD34+ APBSCs) and MNCs had similar therapeutic effects. Severe complications associated with adult stem cell treatment were not observed. Although the benefits of combination therapy with respect to improving liver function were slightly better than those of the traditional treatment alone, they gradually decreased over time.Systematic review registration: PROSPERO registration number: CRD42021238576.
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Affiliation(s)
- Chen-Hui Zhu
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Dian-Han Zhang
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Chen-Wei Zhu
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Jing Xu
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Chuan-Long Guo
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China
| | - Xiang-Gen Wu
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China
| | - Qi-Long Cao
- Qingdao Haier Biotech Co. Ltd, Qingdao, China
| | - Guo-Hu Di
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China.
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de Carvalho LRP, Abreu SC, de Castro LL, Andrade da Silva LH, Silva PM, Vieira JB, Santos RT, Cabral MR, Khoury M, Weiss DJ, Lopes-Pacheco M, Silva PL, Cruz FF, Rocco PRM. Mitochondria-Rich Fraction Isolated From Mesenchymal Stromal Cells Reduces Lung and Distal Organ Injury in Experimental Sepsis. Crit Care Med 2021; 49:e880-e890. [PMID: 33870913 DOI: 10.1097/ccm.0000000000005056] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES To ascertain whether systemic administration of mitochondria-rich fraction isolated from mesenchymal stromal cells would reduce lung, kidney, and liver injury in experimental sepsis. DESIGN Animal study. SETTING Laboratory investigation. SUBJECTS Sixty C57BL/6 male mice. INTERVENTIONS Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. At 24 hours after surgery, cecal ligation and puncture and Sham animals were further randomized to receive saline or mitochondria-rich fraction isolated from mesenchymal stromal cells (3 × 106) IV. At 48 hours, survival, peritoneal bacterial load, lung, kidney, and liver injury were analyzed. Furthermore, the effects of mitochondria on oxygen consumption rate and reactive oxygen species production of lung epithelial and endothelial cells were evaluated in vitro. MEASUREMENTS AND MAIN RESULTS In vitro exposure of lung epithelial and endothelial cells from cecal ligation and puncture animals to mitochondria-rich fraction isolated from mesenchymal stromal cells restored oxygen consumption rate and reduced total reactive oxygen species production. Infusion of exogenous mitochondria-rich fraction from mesenchymal stromal cells (mitotherapy) reduced peritoneal bacterial load, improved lung mechanics and histology, and decreased the expression of interleukin-1β, keratinocyte chemoattractant, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in lung tissue, while increasing keratinocyte growth factor expression and survival rate in cecal ligation and puncture-induced sepsis. Mitotherapy also reduced kidney and liver injury, plasma creatinine levels, and messenger RNA expressions of interleukin-18 in kidney, interleukin-6, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in liver, while increasing nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 in kidney and interleukin-10 in liver. CONCLUSIONS Mitotherapy decreased lung, liver, and kidney injury and increased survival rate in cecal ligation and puncture-induced sepsis.
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Affiliation(s)
- Luiza Rachel Pinheiro de Carvalho
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Soraia Carvalho Abreu
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Ligia Lins de Castro
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luísa Helena Andrade da Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paula Matos Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Juliana Borges Vieira
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Renata Trabach Santos
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marianna Ribeiro Cabral
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maroun Khoury
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Cells for Cells and Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Daniel J Weiss
- Department of Medicine, University of Vermont, Burlington, VT
| | - Miquéias Lopes-Pacheco
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
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Zheng Y, Zhu S, Zheng X, Xu W, Li X, Li J, Gao Z, Xie C, Peng L. Serum from Acute-on-chronic Liver Failure Patients May Affect Mesenchymal Stem Cells Transplantation by Impairing the Immunosuppressive Function of Cells. J Clin Transl Hepatol 2021; 9:503-513. [PMID: 34447679 PMCID: PMC8369013 DOI: 10.14218/jcth.2021.00014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/22/2021] [Accepted: 03/11/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS The safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of acute-on-chronic liver failure (ACLF) have been validated. However, the impact of the pathological ACLF microenvironment on MSCs is less well understood. This study was designed to explore the changes in the functional properties of MSCs exposed to ACLF serum. METHODS MSCs were cultured in the presence of 10%, 30% and 50% serum concentrations from ACLF patients and healthy volunteers. Then, the cell morphology, phenotype, apoptosis and proliferation of MSCs were evaluated, including the immunosuppressive effects. Subsequently, mRNA sequencing analysis was used to identify the molecules and pathways involved in MSC functional changes in the context of ACLF. RESULTS In the presence of ACLF serum, MSC morphology significantly changed but phenotype did not. Besides, MSC proliferation activity was weakened, while the apoptosis rate was lightly increased. Most importantly, the immunosuppressive function of MSCs was enhanced in a low-concentration serum environment but transformed into a proinflammatory response in a high-concentration serum environment. RNA sequencing indicated that 10% serum concentration from ACLF patients mediated the PI3K-Akt pathway to enhance the anti-inflammatory effect of MSCs, while the 50% serum concentration from ACLF patients promoted the conversion of MSCs into a proinflammatory function by affecting the cell cycle. CONCLUSIONS The 50% ACLF serum concentration is more similar to the environment in the human body, which means that direct peripheral blood intravenous infusion of MSCs may reduce the effect of transplantation. Combining treatments of plasma exchange to reduce harmful substances in serum may promote MSCs to exert a stronger anti-inflammatory effect.
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Affiliation(s)
- Yongyuan Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shu Zhu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xingrong Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenxiong Xu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xuejun Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianguo Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhiliang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chan Xie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Corresponding Authors: Liang Peng, 600 Tianhe Road, Tianhe district, Guangzhou, Guangdong 510530, China. ORCID: https://orcid.org/0000-0001-6184-5750. Tel/Fax: +86-20-8525-2372, E-mail: ; Chan Xie, 600 Tianhe Road, Tianhe district, Guangzhou, Guangdong 510530, China. ORCID: https://orcid.org/0000-0002-0225-5483. Tel/Fax: +86-20-8525-2372, E-mail:
| | - Liang Peng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Corresponding Authors: Liang Peng, 600 Tianhe Road, Tianhe district, Guangzhou, Guangdong 510530, China. ORCID: https://orcid.org/0000-0001-6184-5750. Tel/Fax: +86-20-8525-2372, E-mail: ; Chan Xie, 600 Tianhe Road, Tianhe district, Guangzhou, Guangdong 510530, China. ORCID: https://orcid.org/0000-0002-0225-5483. Tel/Fax: +86-20-8525-2372, E-mail:
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Mesenchymal stem cells enhance Treg immunosuppressive function at the fetal-maternal interface. J Reprod Immunol 2021; 148:103366. [PMID: 34492568 DOI: 10.1016/j.jri.2021.103366] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/01/2021] [Accepted: 08/20/2021] [Indexed: 12/29/2022]
Abstract
Well-regulated maternal-fetal immune tolerance is a prerequisite for normal pregnancy. Hyperactivated immune cells and overwhelming inflammatory responses trigger adverse gestation outcome, such as recurrent spontaneous abortion (RSA). Local exacerbation of immunomodulatory cells in maternal decidua is a critical event, tightly linked with fetus acceptance. Owning to the notable immunoregulatory potentials, mesenchymal stromal cells (MSCs) and regulatory T cells (Tregs) have been separately reported as promising therapeutic approaches for refractory RSA attributable to certain immune disorders. However, the cross-talk between MSCs and Tregs at the fetal-maternal interface remains poorly understood. Here we revealed, for the first time, that umbilical MSCs could induce expansion of decidual Foxp3+CD4+ T cells with upregulated production of IL-10 and TGF-β. Meanwhile, MSCs reinforced the immune suppressive functions of decidual Tregs (dTregs). More important, MSCs-instructed dTregs gained enhanced capacity to suppress Th1 and Th17 related inflammatory responses. In vivo data demonstrated that adoptive transfer of MSCs obviously promoted accumulation of Foxp3+ dTregs in lipopolysaccharide (LPS)-induced mice abortion model and spontaneous abortion model (DBA/2-mated female CBA/J mice). Furthermore, MSCs treatment effectively ameliorated absorption rate in both models. This study may offer a new insight for the application of MSCs and Tregs in clinical recurrent miscarriage.
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LIU L, YANG F. Application of Modified Mesenchymal Stem Cells Transplantation in the Treatment of Liver Injury. Physiol Res 2021. [DOI: 10.33549/physiolres.934623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Acute and chronic hepatitis, cirrhosis, and other liver diseases pose a serious threat to human health; however, liver transplantation is the only reliable treatment for the terminal stage of liver diseases. Previous researchers have shown that mesenchymal stem cells (MSCs) are characterized by differentiation and paracrine effects, as well as anti-oxidative stress and immune regulation functions. When MSCs are transplanted into animals, they migrate to the injured liver tissue along with the circulation, to protect the liver and alleviate the injury through the paracrine, immune regulation and other characteristics, making mesenchymal stem cell transplantation a promising alternative therapy for liver diseases. Although the efficacy of MSCs transplantation has been confirmed in various animal models of liver injury, many researchers have also proposed various pretreatment methods to improve the efficacy of mesenchymal stem cell transplantation, but there is still lack a set of scientific methods system aimed at improving the efficacy of transplantation therapy in scientific research and clinical practice. In this review, we summarize the possible mechanisms of MSCs therapy and compare the existing methods of MSCs modification corresponding to the treatment mechanism, hoping to provide as a reference to help future researchers explore a safe and simple transplantation strategy.
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Affiliation(s)
- L LIU
- School of Basic Medicine, Yangtze University Health Science Center, Jingzhou, China
| | - F YANG
- School of Basic Medicine, Yangtze University Health Science Center, Jingzhou, China
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Zhang J, Huang J, Gu Y, Xue M, Qian F, Wang B, Yang W, Yu H, Wang Q, Guo X, Ding X, Wang J, Jin M, Zhang Y. Inflammation-induced inhibition of chaperone-mediated autophagy maintains the immunosuppressive function of murine mesenchymal stromal cells. Cell Mol Immunol 2021; 18:1476-1488. [PMID: 31900460 PMCID: PMC8167126 DOI: 10.1038/s41423-019-0345-7] [Citation(s) in RCA: 17] [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: 06/05/2019] [Accepted: 12/04/2019] [Indexed: 12/13/2022] Open
Abstract
Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells (MSCs). However, the biological function of chaperone-mediated autophagy (CMA) in MSCs remains elusive. Here, we found that CMA was inhibited in MSCs in response to the proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). In addition, suppression of CMA by knocking down the CMA-related lysosomal receptor lysosomal-associated membrane protein 2 (LAMP-2A) in MSCs significantly enhanced the immunosuppressive effect of MSCs on T cell proliferation, and as expected, LAMP-2A overexpression in MSCs exerted the opposite effect on T cell proliferation. This effect of CMA on the immunosuppressive function of MSCs was attributed to its negative regulation of the expression of chemokine C-X-C motif ligand 10 (CXCL10), which recruits inflammatory cells, especially T cells, to MSCs, and inducible nitric oxide synthase (iNOS), which leads to the subsequent inhibition of T cell proliferation via nitric oxide (NO). Mechanistically, CMA inhibition dramatically promoted IFN-γ plus TNF-α-induced activation of NF-κB and STAT1, leading to the enhanced expression of CXCL10 and iNOS in MSCs. Furthermore, we found that IFN-γ plus TNF-α-induced AKT activation contributed to CMA inhibition in MSCs. More interestingly, CMA-deficient MSCs exhibited improved therapeutic efficacy in inflammatory liver injury. Taken together, our findings established CMA inhibition as a critical contributor to the immunosuppressive function of MSCs induced by inflammatory cytokines and highlighted a previously unknown function of CMA.
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Affiliation(s)
- Jie Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jiefang Huang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yuting Gu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Mingxing Xue
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Fengtao Qian
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Bei Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wanlin Yang
- Pediatric Institute of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Hongshuang Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qiwei Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin Guo
- Pediatric Institute of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Xinyuan Ding
- Pediatric Institute of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Jina Wang
- Department of Urology and Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Min Jin
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Yanyun Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
- Pediatric Institute of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Luan Y, Kong X, Feng Y. Mesenchymal stem cells therapy for acute liver failure: Recent advances and future perspectives. LIVER RESEARCH 2021; 5:53-61. [PMID: 39959343 PMCID: PMC11791815 DOI: 10.1016/j.livres.2021.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/16/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
Acute liver failure (ALF) is a life-threatening disease characterized by the rapid development of hepatocyte death and a systemic inflammatory response, which leads to high mortality. Despite the prevention of ALF complications, therapeutic effectiveness remains limited because of the rapid disease progression. Thus, there is a need to explore various therapeutic approaches. Currently, the only effective treatment is liver transplantation; However, the lack of donors, surgical complications, immunosuppression, and high medical costs limit its clinical application. Recently, mesenchymal stem cells (MSCs) have been found to exert hepatoprotective effects in ALF through suppression of inflammation, immunoregulation, promotion of mitosis, anti-apoptosis effects, and alleviation of the metabolic and oxidative stress imbalance. In this review, we summarize the advantages and disadvantages of MSCs from different sources and their molecular mechanisms in ALF treatment, along with future perspectives that may provide guidance to improve the current status of MSCs therapy for ALF.
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Affiliation(s)
- Yuling Luan
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Feng
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Yang Y, Zhao Y, Zhang L, Zhang F, Li L. The Application of Mesenchymal Stem Cells in the Treatment of Liver Diseases: Mechanism, Efficacy, and Safety Issues. Front Med (Lausanne) 2021; 8:655268. [PMID: 34136500 PMCID: PMC8200416 DOI: 10.3389/fmed.2021.655268] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is a novel treatment for liver diseases due to the roles of MSCs in regeneration, fibrosis inhibition and immune regulation. However, the mechanisms are still not completely understood. Despite the significant efficacy of MSC therapy in animal models and preliminary clinical trials, issues remain. The efficacy and safety of MSC-based therapy in the treatment of liver diseases remains a challenging issue that requires more investigation. This article reviews recent studies on the mechanisms of MSCs in liver diseases and the associated challenges and suggests potential future applications.
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Affiliation(s)
- Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Guo H, Zhang H, Sheng N, Wang J, Chen J, Dai J. Perfluorooctanoic acid (PFOA) exposure induces splenic atrophy via overactivation of macrophages in male mice. JOURNAL OF HAZARDOUS MATERIALS 2021; 407:124862. [PMID: 33360190 DOI: 10.1016/j.jhazmat.2020.124862] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/27/2020] [Accepted: 12/12/2020] [Indexed: 06/12/2023]
Abstract
Perfluorooctanoic acid (PFOA), a synthetic and widely used chemical, has aroused wide public concern due to its persistence, bioaccumulation, and potential toxicity. To investigate splenic atrophy induced by PFOA, male mice were exposed to 0, 0.4, 2, or 10 mg/kg/d PFOA for 28 d. Results demonstrated that spleen weight and relative spleen weight (RSW) decreased in the 2 and 10 mg/kg/d PFOA exposure groups. Iron levels in the spleen and serum were also reduced in all PFOA exposure groups. Weighted gene co-expression network analysis (WGCNA) of 7 043 genes highlighted enrichment in cell cycle, autoimmunity, and anemia in the spleen. In addition, changes in the levels of hemoglobin, platelets, bilirubin, and heme oxygenase-1 were consistent with anemia. The ratio of total macrophages to M1 macrophages in the spleen, phagocytic ability of macrophages, and levels of cytokines such as TNF-α, IL-1β, and IL-6 all increased, thus suggesting the occurrence of autoimmune disorder. Therefore, we concluded that overactivation of macrophages may be an important reason for splenic atrophy induced by PFOA exposure.
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Affiliation(s)
- Hua Guo
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongxia Zhang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Nan Sheng
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jinghua Wang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiamiao Chen
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiayin Dai
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
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Najafi-Ghalehlou N, Roudkenar MH, Langerodi HZ, Roushandeh AM. Taming of Covid-19: potential and emerging application of mesenchymal stem cells. Cytotechnology 2021; 73:253-298. [PMID: 33776206 PMCID: PMC7982879 DOI: 10.1007/s10616-021-00461-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 02/17/2021] [Indexed: 12/24/2022] Open
Abstract
Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has turned out to cause a pandemic, with a sky scraping mortality. The virus is thought to cause tissue injury by affecting the renin-angiotensin system. Also, the role of the over-activated immune system is noteworthy, leading to severe tissue injury via the cytokine storms. Thus it would be feasible to modulate the immune system response in order to attenuate the disease severity, as well as treating the patients. Today different medicines are being administered to the patients, but regardless of the efficacy of these treatments, adverse effects are pretty probable. Meanwhile, mesenchymal stem cells (MSCs) prove to be an effective candidate for treating the patients suffering from COVID-19 pneumonia, owing to their immunomodulatory and tissue-regenerative potentials. So far, several experiments have been conducted; transplanting MSCs and results are satisfying with no adverse effects being reported. This paper aims to review the recent findings regarding the novel coronavirus and the conducted experiments to treat patients suffering from COVID-19 pneumonia utilizing MSCs.
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Affiliation(s)
- Nima Najafi-Ghalehlou
- Department of Medical Laboratory Sciences, Faculty of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehryar Habibi Roudkenar
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Medical Biotechnology Department, Paramedicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
| | - Habib Zayeni Langerodi
- Guilan Rheumatology Research Center (GRRC), Guilan University of Medical Sciences, Rasht, Iran
| | - Amaneh Mohammadi Roushandeh
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Anatomical Sciences Department, Medicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
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He C, Yang Y, Zheng K, Chen Y, Liu S, Li Y, Han Q, Zhao RC, Wang L, Zhang F. Mesenchymal stem cell-based treatment in autoimmune liver diseases: underlying roles, advantages and challenges. Ther Adv Chronic Dis 2021; 12:2040622321993442. [PMID: 33633826 PMCID: PMC7887681 DOI: 10.1177/2040622321993442] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/18/2021] [Indexed: 12/20/2022] Open
Abstract
Autoimmune liver disease (AILD) is a series of chronic liver diseases with abnormal immune responses, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The treatment options for AILD remain limited, and the adverse side effects of the drugs that are typically used for treatment frequently lead to a low quality of life for AILD patients. Moreover, AILD patients may have a poor prognosis, especially those with an incomplete response to first-line treatment. Mesenchymal stem cells (MSCs) are pluripotent stem cells with low immunogenicity and can be conveniently harvested. MSC-based therapy is emerging as a promising approach for treating liver diseases based on their advantageous characteristics of immunomodulation, anti-fibrosis effects, and differentiation to hepatocytes, and accumulating evidence has revealed the positive effects of MSC therapy in AILD. In this review, we first summarize the mechanisms, safety, and efficacy of MSC treatment for AILD based on work in animal and clinical studies. We also discuss the challenges of MSC therapy in clinical applications. In summary, although promising data from preclinical studies are now available, MSC therapy is currently far for being applied in clinical practice, thus developing MSC therapy in AILD is still challenging and warrants further research.
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Affiliation(s)
- Chengmei He
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yanlei Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kunyu Zheng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yiran Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Suying Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science and 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, Peking Union Medical College Hospital, Beijing, China
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
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Mahmood A, Seetharaman R, Kshatriya P, Patel D, Srivastava AS. Stem Cell Transplant for Advanced Stage Liver Disorders: Current Scenario and Future Prospects. Curr Med Chem 2021; 27:6276-6293. [PMID: 31584360 DOI: 10.2174/0929867326666191004161802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 09/11/2019] [Accepted: 09/22/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Chronic Liver Disorders (CLD), caused by the lifestyle patterns like alcoholism or by non-alcoholic fatty liver disease or because of virus-mediated hepatitis, affect a large population fraction across the world. CLD progresses into end-stage diseases with a high mortality rate. Liver transplant is the only approved treatment available for such end-stage disease patients. However, the number of liver transplants is limited due to the limited availability of suitable donors and the extremely high cost of performing the procedure. Under such circumstances, Stem Cell (SC) mediated liver regeneration has emerged as a potential therapeutic alternative approach. OBJECTIVE This review aims to critically analyze the current status and future prospects of stem cellbased interventions for end-stage liver diseases. The clinical studies undertaken, the mechanism underlying therapeutic effects and future directions have been examined. METHOD The clinical trial databases were searched at https://clinicaltrials.gov.in and http://www.isrctn.com to identify randomized, non-randomized and controlled studies undertaken with keywords such as "liver disorder and Mesenchymal Stem Cells (MSCs)", "liver cirrhosis and MSCs" and "liver disorder and SCs". Furthermore, https://www.ncbi.nlm.nih.gov/pubmed/ database was also explored with similar keywords for finding the available reports and their critical analyses. RESULTS The search results yielded a significant number of studies that used bone marrow-derived stem cells, MSCs and hepatocytes. The studies clearly indicated that SCs play a key role in the hepatoprotection process by some mechanisms involving anti-inflammation, auto-immune-suppression, angiogenesis and anti-apoptosis. Further, studies indicated that SCs derived paracrine factors promote angiogenesis, reduce inflammation and inhibit hepatocyte apoptosis. CONCLUSION The SC-based interventions provide a significant improvement in patients with CLD; however, there is a need for randomized, controlled studies with the analysis of a long-term follow-up.
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Affiliation(s)
| | | | | | | | - Anand S Srivastava
- Global Institute of Stem Cell Therapy and Research, 4660 La Jolla Village Drive, San Diego, CA 92122, United States
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Mo C, Xie S, Liu B, Zhong W, Zeng T, Huang S, Lai Y, Deng G, Zhou C, Yan W, Chen Y, Huang S, Gao L, Lv Z. Indoleamine 2,3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis. Cell Death Dis 2021; 12:16. [PMID: 33414436 PMCID: PMC7791029 DOI: 10.1038/s41419-020-03277-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 11/18/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a course of chronic liver dysfunction, can develop into cirrhosis and hepatocellular carcinoma. Inflammatory insult owing to pathogenic factors plays a crucial role in the pathogenesis of liver fibrosis. Indoleamine 2,3-dioxygenase 1 (IDO1) can affect the infiltration of immune cells in many pathology processes of diseases, but its role in liver fibrosis has not been elucidated completely. Here, the markedly elevated protein IDO1 in livers was identified, and dendritic cells (DCs) immune-phenotypes were significantly altered after BDL challenge. A distinct hepatic population of CD11c+DCs was decreased and presented an immature immune-phenotype, reflected by lower expression levels of co-stimulatory molecules (CD40, MHCII). Frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+MHCII+, and CD11c+CD40+ cells in splenic leukocytes were reduced significantly. Notably, IDO1 overexpression inhibited hepatic, splenic CD11c+DCs maturation, mature DCs-mediated T-cell proliferation and worsened liver fibrosis, whereas above pathological phenomena were reversed in IDO1-/- mice. Our data demonstrate that IDO1 affects the process of immune cells recruitment via inhibiting DCs maturation and subsequent T cells proliferation, resulting in the promotion of hepatic fibrosis. Thus, amelioration of immune responses in hepatic and splenic microenvironment by targeting IDO1 might be essential for the therapeutic effects on liver fibrosis.
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Affiliation(s)
- Chan Mo
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Shuwen Xie
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Bin Liu
- Department of Emergency, Guangzhou Red Cross Hospital, Medical College, Jinan University, 510220, Guangzhou, China
| | - Weichao Zhong
- Shenzhen Traditional Chinese Medicine Hospital, No.1, Fuhua Road, Futian District, 518033, Shenzhen, Guangdong, People's Republic of China
| | - Ting Zeng
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Sha Huang
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Yuqi Lai
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Guanghui Deng
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Chuying Zhou
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Weixin Yan
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Yuyao Chen
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Shaohui Huang
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, 510515, Guangzhou, People's Republic of China.
| | - Zhiping Lv
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
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Miyamoto H, Takemura S, Minamiyama Y, Tsukioka T, Toda M, Nishiyama N, Shibata T. Acute exacerbation of idiopathic pulmonary fibrosis model by small amount of lipopolysaccharide in rats. J Clin Biochem Nutr 2021; 70:129-139. [PMID: 35400816 PMCID: PMC8921716 DOI: 10.3164/jcbn.21-7] [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: 01/12/2021] [Accepted: 06/02/2021] [Indexed: 11/22/2022] Open
Abstract
Idiopathic pulmonary fibrosis, a chronic and progressive lung disease with poor prognosis, presents with acute exacerbation. Pathophysiology and treatments for this acute exacerbation, and an appropriate animal model to perform such examinations, have not established yet. We presented a rat model for assessing acute exacerbation in cases of idiopathic pulmonary fibrosis. Wistar rats were intratracheally administered bleomycin (3 mg/kg) to induce pulmonary fibrosis. After 7 days, lipopolysaccharide (0, 0.05, or 0.15 mg/kg) was administered. In the bleomycin or lipopolysaccharide group, there were almost no change in the oxygen partial pressure, arterial blood gas (PaO2), plasma nitrite/nitrate, nitric oxide synthase, and lung nitrotyrosine levels. In the bleomycin (+)/lipopolysaccharide (+) groups, these three indicators deteriorated significantly. The plasma nitrite/nitrate and PaO2 levels were significantly correlated in the bleomycin (+) groups (r = 0.758). Although lung fibrosis was not different with or without lipopolysaccharide in the bleomycin (+) groups, macrophage infiltration was marked in the bleomycin (+)/lipopolysaccharide (+) group. There were many NOS2-positive macrophages, and the PaO2 levels decrease may be induced by the nitric oxide production of macrophages in the lung. This model may mimic the pathophysiological changes in cases of acute exacerbation during idiopathic pulmonary fibrosis in humans.
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Affiliation(s)
- Hikaru Miyamoto
- Department of Thoracic Surgery, Graduate School of Medicine, Osaka City University
| | - Shigekazu Takemura
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka City University
| | - Yukiko Minamiyama
- Food Hygiene and Environmental Health Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
| | - Takuma Tsukioka
- Department of Thoracic Surgery, Graduate School of Medicine, Osaka City University
| | - Michihito Toda
- Department of Thoracic Surgery, Graduate School of Medicine, Osaka City University
| | - Noritoshi Nishiyama
- Department of Thoracic Surgery, Graduate School of Medicine, Osaka City University
| | - Toshihiko Shibata
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka City University
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Wang Y, Wang Q, Wang B, Gu Y, Yu H, Yang W, Ren X, Qian F, Zhao X, Xiao Y, Zhang Y, Jin M, Zhu M. Inhibition of EZH2 ameliorates bacteria-induced liver injury by repressing RUNX1 in dendritic cells. Cell Death Dis 2020; 11:1024. [PMID: 33262329 PMCID: PMC7708645 DOI: 10.1038/s41419-020-03219-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 01/31/2023]
Abstract
Fulminant hepatic failure (FHF) is a clinical syndrome characterized by a sudden and severe impairment in liver function. However, the precise mechanism of immune dysregulation that is significant to FHF pathogenesis remains unclear. Enhancer of zeste homolog 2 (EZH2) has been implicated in inflammation as a regulator of immune cell function. In this study, we investigated the role of EZH2 in an animal model of human FHF induced by Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS). We demonstrated that EZH2 depletion in dendritic cells (DCs) and pharmacological inhibition of EZH2 using GSK126 both significantly ameliorated liver injury and improved the survival rates of mice with P. acnes plus LPS-induced FHF, which could be attributed to the decreased infiltration and activation of CD4+ T cells in the liver, inhibition of T helper 1 cells and induction of regulatory T cells. The expression of EZH2 in DCs was increased after P. acnes administration, and EZH2 deficiency in DCs suppressed DC maturation and prevented DCs from efficiently stimulating CD4+ T-cell proliferation. Further mechanistic analyses indicated that EZH2 deficiency directly increased the expression of the transcription factor RUNX1 and thereby suppressed the immune functions of DCs. The functional dependence of EZH2 on RUNX1 was further illustrated in DC-specific Ezh2-deficient mice. Taken together, our findings establish that EZH2 exhibits anti-inflammatory effects through inhibition of RUNX1 to regulate DC functions and that inhibition of EZH2 alleviates P. acnes plus LPS-induced FHF, probably by inhibiting DC-induced adaptive immune responses. These results highlight the effect of EZH2 on DCs, serving as a guide for the development of a promising immunotherapeutic strategy for FHF.
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Affiliation(s)
- Yanan Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiwei Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bei Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Yuting Gu
- Department of Stomatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongshuang Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Wanlin Yang
- Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Xiaohui Ren
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Fengtao Qian
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Xiaonan Zhao
- Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Yanyun Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China. .,Institutes for Translational Medicine, Soochow University, Suzhou, China.
| | - Min Jin
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China. .,Department of Stomatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Meiling Zhu
- Department of Oncology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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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: 66] [Impact Index Per Article: 13.2] [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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Dorairaj V, Sulaiman SA, Abu N, Abdul Murad NA. Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update. Biomolecules 2020; 10:biom10111494. [PMID: 33143043 PMCID: PMC7693409 DOI: 10.3390/biom10111494] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/22/2020] [Accepted: 10/24/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum of liver damage disease from a simple fatty liver (steatosis) to more severe liver conditions such as non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Extracellular vesicles (EVs) are a heterogeneous group of small membrane vesicles released by various cells in normal or diseased conditions. The EVs carry bioactive components in their cargos and can mediate the metabolic changes in recipient cells. In the context of NAFLD, EVs derived from adipocytes are implicated in the development of whole-body insulin resistance (IR), the hepatic IR, and fatty liver (steatosis). Excessive fatty acid accumulation is toxic to the hepatocytes, and this lipotoxicity can induce the release of EVs (hepatocyte-EVs), which can mediate the progression of fibrosis via the activation of nearby macrophages and hepatic stellate cells (HSCs). In this review, we summarized the recent findings of adipocyte- and hepatocyte-EVs on NAFLD disease development and progression. We also discussed previous studies on mesenchymal stem cell (MSC) EVs that have garnered attention due to their effects on preventing liver fibrosis and increasing liver regeneration and proliferation.
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Yang X, Meng Y, Han Z, Ye F, Wei L, Zong C. Mesenchymal stem cell therapy for liver disease: full of chances and challenges. Cell Biosci 2020; 10:123. [PMID: 33117520 PMCID: PMC7590738 DOI: 10.1186/s13578-020-00480-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
Liver disease is a major health problem that endangers human health worldwide. Currently, whole organ allograft transplantation is the gold standard for the treatment of end-stage liver disease. A shortage of suitable organs, high costs and surgical complications limit the application of liver transplantation. Mesenchymal stem cell therapy has been considered as a promising alternative approach for end-stage liver disease. Some clinical trials have confirmed the effectiveness of MSC therapy for liver disease, but its application has not been promoted and approved. There are still many issues that should be solved prior to using MSC therapy in clinical applications. The types of liver disease that are most suitable for MSC application should be determined, and the preparation and engraftment of MSCs should be standardized. These may be bottlenecks that limit the use of MSCs. We investigated 22 completed and several ongoing clinical trials to discuss these questions from a clinical perspective. We also discussed the important mechanisms by which MSCs play a therapeutic role in liver disease. Finally, we also proposed novel prospective approaches that can improve the therapeutic effect of MSCs.
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Affiliation(s)
- Xue Yang
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
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Guo HL, Shi FD, Zhou Q, Liu QY, Wang YX, Song Y, Wu ZS, Shi YH, Zhang L, Xu KZ, Song GD. Interleukin-1β Protection Against Experimental Sepsis in Mice. Inflammation 2020; 44:358-370. [PMID: 33044666 PMCID: PMC7548415 DOI: 10.1007/s10753-020-01341-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/21/2020] [Accepted: 09/08/2020] [Indexed: 01/25/2023]
Abstract
The inflammatory response involving interleukin-1β (IL-1β) has been thought to play an important role in the development of late-phase sepsis. However, in this study, we wanted to explore the possibility of using IL-1β to improve the prognosis of sepsis by triggering local differentiation of bone marrow cells (BMCs) into regulatory dendritic cells (DCs) in vivo, thereby reversing the immune paralysis in late-phase sepsis. Sepsis mouse models were induced by cecal ligation and puncture (CLP) and lethal Escherichia coli O18 infection. Mice were injected intraperitoneally with IL-1β after CLP and after the lethal infection. Septic BMCs and liver immune cells were isolated at 0, 3, 6, 9, and 14 days post-CLP. BMCs and liver cells isolated from septic mice treated with IL-1β were adoptively transferred into CLP mice. GFP+-C57BL/6 parabiosis models were established. Serum IL-1β levels were determined by enzyme-linked immunosorbent assay (ELISA) kit, and the number, ratio, and phenotype of immune cells were observed by flow cytometry. IL-1β treatment improved the survival of sepsis and increased the numbers of BMCs and liver immune cells in septic mice. Moreover, IL-1β stimulation increased the number and the percentage of CD11c−CD45RBhigh DCs in septic BM and liver. Adoptive transfer of septic BMCs, liver immune cells, and CD11c−CD45RBhigh DCs treated with IL-1β into CLP mice attenuated sepsis. IL-1β triggered the redistribution of CD11c−CD45RBhigh DCs as well as BMCs in parabiosis models. IL-1β protects against sepsis by stimulating local proliferation and differentiation of BMCs into CD11c−CD45RBhigh DCs at immune organs and non-immune organs.
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Affiliation(s)
- Hai-Lei Guo
- Department of Burns, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.,Department of Burns, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Fu-Dong Shi
- Department of Orthopedics, Tangshan People's Hospital, Tangshan, Hebei, People's Republic of China
| | - Qi Zhou
- North China University of Science and Technology Graduate School, Tangshan, Hebei, People's Republic of China
| | - Qing-Yang Liu
- Department of Translational Medicine and Nephrology, Emergency General Hospital, Beijing, 100028, People's Republic of China.
| | - Yue-Xin Wang
- First Department of Orthopedics, Tangshan Worker's Hospital Affiliated to Hebei Medical University, Tangshan, Hebei, People's Republic of China
| | - Yang Song
- Department of Translational Medicine and Nephrology, Emergency General Hospital, Beijing, 100028, People's Republic of China
| | - Zong-Sheng Wu
- Department of Emergency, Zhongda Hospital Affiliated to Southeast University, Nanjing, People's Republic of China
| | - Yu-Hao Shi
- North China University of Science and Technology Graduate School, Tangshan, Hebei, People's Republic of China
| | - Liu Zhang
- Department of Translational Medicine and Nephrology, Emergency General Hospital, Beijing, 100028, People's Republic of China
| | - Kai-Zhi Xu
- Department of Anesthesiology, Tangshan Worker's Hospital Affiliated to Hebei Medical University, Tangshan, Hebei, People's Republic of China
| | - Guo-Dong Song
- Department of Burns, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. .,Department of Burns, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
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48
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Petryk N, Shevchenko O. Mesenchymal Stem Cells Anti-Inflammatory Activity in Rats: Proinflammatory Cytokines. J Inflamm Res 2020; 13:293-301. [PMID: 32753930 PMCID: PMC7354011 DOI: 10.2147/jir.s256932] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/27/2020] [Indexed: 01/08/2023] Open
Abstract
Introduction Many widespread intractable diseases are caused or supported by chronic inflammation. Such conditions include the 2nd type of diabetes mellitus, atherosclerosis, neurodegenerative diseases, chronic inflammatory diseases of the connective tissue - ankylosing spondylitis, rheumatoid arthritis, autoimmune myositis, etc. Therefore, the search for targeted treatment of these illnesses is extremely in high demand. Immunomodulatory activity of mesenchymal stem cells is one of their remarkable properties. Several biomarkers (cytokines and nonspecific proteins) are known to be associated with chronic inflammation. Methods Our study aimed to investigate the serum levels of tumor necrosis factor-alpha, interleukin 6 and C-reactive protein in carrageenan myositis in rats, because there is more and more evidence of the significance of these markers in the course and resolution of the diseases mentioned above. For the first time in our experiment, it was shown and evaluated using analysis of variance, how MSCs influence the indicators of proinflammatory cytokines on the model of carrageenan myositis. The levels of α-TNF, IL-6 and CRP in the plasma of rats were studied in groups with chronic carrageenan inflammation and chronic inflammation with local injection of MSCs into the affected area. Results Our study proved the effectiveness of MSCs by showing a significant decrease in the levels of inflammatory mediators in the plasma of the studied animals. Discussion and Conclusions Thus, the administration of MSCs is a promising tool in the pathogenic treatment of chronic inflammation and concomitant conditions. ![]()
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Affiliation(s)
- Nataliia Petryk
- Department of Pathology, Kharkiv National Medical University, Kharkiv, Ukraine
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49
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Zhu M, Chu Y, Shang Q, Zheng Z, Li Y, Cao L, Chen Y, Cao J, Lee OK, Wang Y, Melino G, Lv G, Shao C, Shi Y. Mesenchymal stromal cells pretreated with pro-inflammatory cytokines promote skin wound healing through VEGFC-mediated angiogenesis. Stem Cells Transl Med 2020; 9:1218-1232. [PMID: 32534464 PMCID: PMC7519767 DOI: 10.1002/sctm.19-0241] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 03/14/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
Skin is the largest organ of the human body. Skin wound is one of the most common forms of wound. Mesenchymal stromal cells (MSCs) have been used to aid skin wound healing via their paracrine factors. Because the secretome of MSCs can be greatly enriched and amplified by treatment with IFN‐γ and TNF‐α (IT), we here tested whether supernatant derived from MSCs pretreated with IT, designated as S‐MSCs‐IT, possesses improved wound healing effect by using a murine model of cutaneous excision, S‐MSCs‐IT was found to be more potent in promoting angiogenesis, constricting collagen deposition and accelerating wound closure than control supernatant (S‐MSCs) during the healing of skin wound. VEGFC, but not VEGFA, was greatly upregulated by IT and was found to be a key factor in mediating the improved wound healing effect of S‐MSCs‐IT. Our results indicate that the beneficial paracrine effect of MSCs on wound healing can be enhanced by pretreatment with inflammatory cytokines. IT treatment may represent a new strategy for optimizing the therapeutic effect of MSCs on skin injuries.
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Affiliation(s)
- Mengting Zhu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China.,Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', Rome, Italy
| | - Yunpeng Chu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China
| | - Qianwen Shang
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China
| | - Zhiyuan Zheng
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China
| | - Yanan Li
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China.,Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', Rome, Italy
| | - Lijuan Cao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China
| | - Yongjing Chen
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China
| | - Jianchang Cao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, People's Republic of China
| | - Oscar K Lee
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, HongKong, People's Republic of China
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, People's Republic of China
| | - Gerry Melino
- Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', Rome, Italy
| | - Guozhong Lv
- Department of Burn Surgery, The 3rd People's Hospital of Wuxi and Wuxi Medical College of Jiangnan University, Wuxi, People's Republic of China
| | - Changshun Shao
- State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, People's Republic of China
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People's Republic of China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, People's Republic of China
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50
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Cao Y, Ji C, Lu L. Mesenchymal stem cell therapy for liver fibrosis/cirrhosis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:562. [PMID: 32775363 PMCID: PMC7347778 DOI: 10.21037/atm.2020.02.119] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Liver fibrosis represents a common outcome of most chronic liver diseases. Advanced fibrosis leads to cirrhosis for which no effective treatment is available except liver transplantation. Because of the limitations of liver transplantation, alternative therapeutic strategies are an urgent need to find. Recently, mesenchymal stem cells (MSCs) based therapy has been suggested as an attractive therapeutic option for liver fibrosis and cirrhosis, based on the promising results from preclinical and clinical studies. Although the precise mechanisms of MSC transplantation are still not fully understood, accumulating evidence has indicated that MSCs eliminate the progression of fibrosis due to their immune-modulatory properties. In this review, we summarise the properties of MSCs and their clinical application in the treatment of liver fibrosis and cirrhosis. We also discuss the mechanisms involved in MSC-dependent regulation of immune microenvironment in the context of liver fibrosis and cirrhosis.
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Affiliation(s)
- Yan Cao
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Chenbo Ji
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Ling Lu
- Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing 210029, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 210029, China
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