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Lu W, Yan L, Peng L, Wang X, Tang X, Du J, Lin J, Zou Z, Li L, Ye J, Zhou L. Efficacy and safety of mesenchymal stem cell therapy in acute on chronic liver failure: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther 2025; 16:197. [PMID: 40254564 PMCID: PMC12010635 DOI: 10.1186/s13287-025-04303-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 04/01/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Acute-on-chronic liver failure has become a serious global health burden, which is characterized by an acute deterioration of liver function, rapidly evolving organ failure, and high short-term mortality in patients with chronic liver disease. The pathogenesis includes extensive hepatic necrosis, which is related to intense systemic inflammation and subsequently causes the inflammatory cytokine storm, resulting in portal hypertension, organ dysfunction, and organ failure. Mesenchymal stem cells can function as seed cells to remodel and repair damaged liver tissues, thus showing potential therapeutic alternatives for patients with chronic liver disease. However, standard treatment protocols for mesenchymal stem cells in acute-on-chronic liver failure patients have not been established. METHODS We conducted a detailed search from PubMed/Medline, Web of Science, EMBASE, and Cochrane Library to find randomized controlled trials published before October 23, 2021. We formulated criteria for the literature screening according to the PICOS principle (Population, Intervention, Comparison, Outcome, Study design). Subsequently, the bias risk assessment tool was used to assess the quality of all enrolled studies. Finally, outcome measurements including the model of end-stage liver disease score, albumin, total bilirubin, coagulation function, and aminotransferase were extracted for statistical analysis. RESULTS A total of 7 clinical trials were included. The results of enrolled studies indicated that patients with acute-on-chronic liver failure who received mesenchymal stem cells inoculation showed a decreased MELD score in 4 weeks and 24 weeks, compared with counterparts who received conventional treatment. Reciprocally, mesenchymal stem cells inoculation improved the ALB levels in 4 weeks and 24 weeks. For secondary indicators, mesenchymal stem cells treatment significantly reduced INR levels and ALT levels, compared with the control group. Our results showed no significant differences in the incidence of adverse reactions or serious adverse events monitored in patients after mesenchymal stem cells inoculation. CONCLUSION This meta-analysis indicated that mesenchymal stem cell infusion is effective and safe in the treatment of patients with acute-on-chronic liver failure. Without increasing the incidence of adverse events or serious adverse events, MSC treatment improved liver function including a decrease in MELD score and an increase in ALB levels in patients with acute-on-chronic liver failure. However, large-cohort randomized controlled trials with longer follow-up periods are required to further confirm our conclusions.
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Affiliation(s)
- Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Longxiang Yan
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Lulu Peng
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Xingkun Tang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Jing Du
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Jing Lin
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
- Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Key Laboratory for Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China.
- Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
- Key Laboratory for Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
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Zhu WY, Li X, Xie JL, Lu Q, Ma YJ, Zhu ZJ, Liu J. Hotspots and trends in stem cell therapy for liver fibrosis and cirrhosis: A bibliometric analysis. World J Hepatol 2025; 17:96105. [PMID: 39871895 PMCID: PMC11736489 DOI: 10.4254/wjh.v17.i1.96105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 10/29/2024] [Accepted: 11/19/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments. In the past two decades, there has been a surge in research on stem cell therapy for liver fibrosis and cirrhosis. This study aimed to conduct a comprehensive analysis of the research hotspots and trends in this field through bibliometrics. AIM To conduct a bibliometric analysis on hotspots and trends in stem cell therapy for treatment of liver fibrosis and cirrhosis. METHODS Publications on stem cell therapy for liver fibrosis and cirrhosis were retrieved from the Web of Science Core Collection database. The distribution and collaboration among literature, authors, countries, and institutions were analyzed visually using Excel, CiteSpace, Bibliometrix R-package, VOSviewer and Pajek software. Additionally, an investigation of keywords, burst keywords, and clusters was conducted. RESULTS As of September 20, 2024, a total of 1935 documents were retrieved dating from 2004 to 2024, with 1186 strongly relevant publications obtained after screening. China, the United States, and Japan were the major contributors in this field. Cairo University, Zhejiang University and Yamaguchi University were the major institution in this field. The journal Stem Cell Research & Therapy published the most papers. There were 686 authors, with Shuji Terai, Isao Sakaida, Soon Koo Baik, and Lanjuan Li publishing the most papers. The research focused on alcoholic cirrhosis and nonalcoholic fatty liver disease. The emerging areas of interest were extracellular vesicles, exosomes, and their enriched microRNAs. The field is experiencing rapid growth due to the changing research trends and increasing literature. CONCLUSION These findings provide a thorough overview of stem cell therapy in the field of liver fibrosis and cirrhosis.
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Affiliation(s)
- Wen-Yan Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Xiang Li
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jia-Ling Xie
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Qin Lu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Ying-Jie Ma
- Office of Scientific Research of Army Medical Center, Army Medical University, Chongqing 400042, China
| | - Zhao-Jing Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Juan Liu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China.
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Huang WC, Li YC, Chen PX, Ma KSK, Wang LT. Mesenchymal stem cell therapy as a game-changer in liver diseases: review of current clinical trials. Stem Cell Res Ther 2025; 16:3. [PMID: 39762946 PMCID: PMC11705688 DOI: 10.1186/s13287-024-04127-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025] Open
Abstract
Chronic liver diseases, including cirrhosis and liver failure, remain formidable challenges due to their complex progression and limited therapeutic options. Mesenchymal stem cell (MSC) therapy has emerged as a game-changing approach, leveraging its potent immunomodulatory, anti-fibrotic, and regenerative capabilities, along with the ability to transdifferentiate into hepatocytes. This review delves into the latest advances in MSC-based treatments for chronic and end-stage liver diseases, as highlighted in current clinical trials. MSCs derived from bone marrow and umbilical cord have shown remarkable promise in reversing liver damage, improving liver function, and providing hope for patients who do not respond to conventional therapies. When administered through hepatic, portal, or peripheral veins, MSCs have significantly improved liver histology, reduced fibrosis, and restored functional capacity. Furthermore, MSC-derived materials, such as extracellular vesicles and exosomes, are emerging as cutting-edge tools for treating liver failure and mitigating post-transplant complications. While autologous MSC-derived hepatocytes hold promise for non-fatal cirrhosis, allogeneic MSCs are being applied in more severe conditions, including liver failure and transplantation cases. Despite these promising early outcomes, larger trials and long-term studies are essential to fully harness MSCs as a transformative, off-the-shelf alternative to liver transplantation, heralding a new era in regenerative liver therapies.
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Affiliation(s)
- Wei-Chen Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Laboratory of Clinical Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Yuan-Chi Li
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Pin-Xuan Chen
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Kevin Sheng-Kai Ma
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Li-Tzu Wang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan.
- Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
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Jeropoulos RM, Arroyo J, Davenport M. Predicting and optimising outcome for biliary atresia. Semin Pediatr Surg 2024; 33:151479. [PMID: 39884180 DOI: 10.1016/j.sempedsurg.2025.151479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025]
Abstract
Biliary atresia (BA) remains a disease of significant morbidity and mortality world-wide. Early and accurate diagnosis facilitates early intervention and improves outcomes. The gold standard in diagnosing BA is a liver biopsy followed by cholangiography, usually performed intra-operatively. Serum markers, like the aspartate aminotransferase-to-platelet ratio, matrix metalloproteinase-7 and several inflammatory cytokines have been recently investigated as non-invasive alternatives with varying degrees of success. Newer immunohistochemical analysis of liver biopsies, such as the expression of secretin receptors and Ki-67, from infants with BA have improved our understanding of the disease process and has shed a little light in predicting post-operative outcomes. There is little standardisation in the care of BA post operatively, though administration of steroids, prevention and treatment of cholangitis with antibiotics and anti-viral therapy for CMV+ve infants are becoming universally accepted as treatment. Experimental stem cell treatments show promise although remain in the out-of-reach future for now in routine clinical practice. This chapter aims to comprehensively describe recent knowledge on predicting the clinical outcomes of infants with BA, as well as optimising their care post operatively.
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Affiliation(s)
- Renos M Jeropoulos
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Jorge Arroyo
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Mark Davenport
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom.
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Lin S, Gao H, Ma H, Liao Z, Zhang D, Pan J, Zhu Y. A comprehensive meta-analysis of stem cell therapy for liver failure: Assessing treatment efficacy and modality. Ann Hepatol 2024; 30:101586. [PMID: 39293783 DOI: 10.1016/j.aohep.2024.101586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 08/14/2024] [Accepted: 09/05/2024] [Indexed: 09/20/2024]
Abstract
INTRODUCTION AND OBJECTIVES This meta-analysis aims to evaluate the efficacy of stem cell therapy (SCT) for liver failure. MATERIALS AND METHODS The study adhered to the recommended guidelines of the PRISMA statement. Eligible studies published prior to May 13, 2023, were comprehensively searched in databases including PubMed, Web of Science, and Embase. Quality assessment was conducted using the Cochrane risk-of-bias tool, and the standard mean differences were calculated for the clinical parameters. The hazard ratios were determined by extracting individual patient data from the Kaplan-Meier curve. RESULTS A total of 2,937 articles were retrieved, and eight studies were included in the final analysis. Most of the studies focused on HBV-related liver failure and were randomized controlled trials. All studies utilized mesenchymal stem cells (MSCs), with the majority (62.5%) being allogeneic. The analysis revealed that combining stem cell therapy with standard medical treatment or plasma exchange significantly enhanced patient survival and reduced MELD scores. Specifically, allogeneic stem cells showed superior efficacy in improving survival outcomes compared to autologous stem cells. Furthermore, deep vessel injection plus a single injection demonstrated better effectiveness than peripheral vessel injection plus multiple injections in reducing MELD scores. CONCLUSIONS This comprehensive analysis underscores the potential of MSC therapy in significantly improving survival and clinical outcomes in patients with liver failure, highlighting the superior benefits of allogeneic MSCs and deep vessel plus single injection administration.
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Affiliation(s)
- Shenglong Lin
- Department of Severe Hepatopathy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province 350028, China; Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province 350005, China
| | - Haibing Gao
- Department of Severe Hepatopathy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province 350028, China
| | - Huaxi Ma
- Department of Severe Hepatopathy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province 350028, China
| | - Ziyuan Liao
- Department of Severe Hepatopathy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province 350028, China
| | - Dongqing Zhang
- Department of Severe Hepatopathy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province 350028, China
| | - Jinshui Pan
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province 350005, China; Fujian Clinical Research Center for Liver and Intestinal Diseases, Fuzhou, Fujian Province 350005, China
| | - Yueyong Zhu
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province 350005, China; Fujian Clinical Research Center for Liver and Intestinal Diseases, Fuzhou, Fujian Province 350005, China.
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Mahmoudi A, Meidany P, Almahmeed W, Jamialahmadi T, Sahebkar A. Stem Cell Therapy as a Potential Treatment of Non-Alcoholic Steatohepatitis-Related End-Stage Liver Disease: A Narrative Review. CURRENT STEM CELL REPORTS 2024; 10:85-107. [DOI: 10.1007/s40778-024-00241-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 01/04/2025]
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Raoufinia R, Arabnezhad A, Keyhanvar N, Abdyazdani N, Saburi E, Naseri N, Niazi F, Niazi F, Namdar AB, Rahimi HR. Leveraging stem cells to combat hepatitis: a comprehensive review of recent studies. Mol Biol Rep 2024; 51:459. [PMID: 38551743 DOI: 10.1007/s11033-024-09391-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 02/27/2024] [Indexed: 04/02/2024]
Abstract
Hepatitis is a significant global public health concern, with viral infections being the most common cause of liver inflammation. Antiviral medications are the primary treatments used to suppress the virus and prevent liver damage. However, the high cost of these drugs and the lack of awareness and stigma surrounding the disease create challenges in managing hepatitis. Stem cell therapy has arisen as a promising therapeutic strategy for hepatitis by virtue of its regenerative and immunomodulatory characteristics. Stem cells have the exceptional capacity to develop into numerous cell types and facilitate tissue regeneration, rendering them a highly promising therapeutic avenue for hepatitis. In animal models, stem cell therapy has demonstrated worthy results by reducing liver inflammation and improving liver function. Furthermore, clinical trials have been undertaken to assess the safety and effectiveness of stem cell therapy in individuals with hepatitis. This review aims to explore the involvement of stem cells in treating hepatitis and highlight the findings from studies conducted on both animals and humans. The objective of this review is to primarily concentrate on the ongoing and future clinical trials that assess the application of stem cell therapy in the context of hepatitis, including the transplantation of autologous bone marrow-derived stem cells, human induced pluripotent stem cells, and other mesenchymal stem cells. In addition, this review will explore the potential merits and constraints linked to stem cell therapy for hepatitis, as well as its prospective implications in the management of this disease.
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Affiliation(s)
- Ramin Raoufinia
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Arabnezhad
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Keyhanvar
- Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA, 94107, USA
| | - Nima Abdyazdani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Naseri
- Department of Biochemistry, School of medicine, Hamadan University of medical sciences, Hamadan, Iran
| | - Fereshteh Niazi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Niazi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Beheshti Namdar
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yan M, Yao J, Xie Y, Jiang P, Yan J, Li X. Bioreactor-based stem cell therapy for liver fibrosis. Biofabrication 2024; 16:025028. [PMID: 38442726 DOI: 10.1088/1758-5090/ad304d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 03/05/2024] [Indexed: 03/07/2024]
Abstract
Stem cell therapy, achieved using mesenchymal stem cells (MSCs), has been highlighted for the treatment of liver fibrosis. Infusion into the circulatory system is a traditional application of MSCs; however, this approach is limited by phenotypic drift, stem cell senescence, and vascular embolism. Maintaining the therapeutic phenotype of MSCs while avoiding adverse infusion-related reactions is the key to developing next-generation stem cell therapy technologies. Here, we propose a bioreactor-based MSCs therapy to avoid cell infusion. In this scheme, 5% liver fibrosis serum was used to induce the therapeutic phenotype of MSCs, and a fluid bioreactor carrying a co-culture system of hepatocytes and MSCs was constructed to produce the therapeutic medium. In a rat model of liver fibrosis, the therapeutic medium derived from the bioreactor significantly alleviated liver fibrosis. Therapeutic mechanisms include immune regulation, inhibition of hepatic stellate cell activation, establishment of hepatocyte homeostasis, and recovery of liver stem cell subsets. Overall, the bioreactor-based stem cell therapy (scheme) described here represents a promising new strategy for the treatment of liver fibrosis and will be beneficial for the development of 'cell-free' stem cell therapy.
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Affiliation(s)
- Mengchao Yan
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, People's Republic of China
- The Medical School, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Jia Yao
- The Medical School, Lanzhou University, Lanzhou 730000, People's Republic of China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, People's Republic of China
| | - Ye Xie
- The Medical School, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Pan Jiang
- State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, People's Republic of China
| | - Jun Yan
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, People's Republic of China
- The Medical School, Lanzhou University, Lanzhou 730000, People's Republic of China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, People's Republic of China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, People's Republic of China
- The Medical School, Lanzhou University, Lanzhou 730000, People's Republic of China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, People's Republic of China
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Cuadra B, Silva V, Huang YL, Diaz Y, Rivas C, Molina C, Simon V, Bono MR, Morales B, Rosemblatt M, Silva S, Acuña R, Ezquer F, Ezquer M. The Immunoregulatory and Regenerative Potential of Activated Human Stem Cell Secretome Mitigates Acute-on-Chronic Liver Failure in a Rat Model. Int J Mol Sci 2024; 25:2073. [PMID: 38396750 PMCID: PMC10889754 DOI: 10.3390/ijms25042073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/31/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully understood. This study explores the therapeutic properties of human mesenchymal stem cell (MSC) secretome, particularly focusing on its enhanced anti-inflammatory and pro-regenerative properties after the in vitro preconditioning of the cells. We evaluated the efficacy of the systemic administration of MSC secretome in preventing liver failure and AKI in a rat ACLF model where chronic liver disease was induced using by the administration of porcine serum, followed by D-galN/LPS administration to induce acute failure. After ACLF induction, animals were treated with saline (ACLF group) or MSC-derived secretome (ACLF-secretome group). The study revealed that MSC-secretome administration strongly reduced liver histological damage in the ACLF group, which was correlated with higher hepatocyte proliferation, increased hepatic and systemic anti-inflammatory molecule levels, and reduced neutrophil and macrophage infiltration. Additionally, renal examination revealed that MSC-secretome treatment mitigated tubular injuries, reduced apoptosis, and downregulated injury markers. These improvements were linked to increased survival rates in the ACLF-secretome group, endorsing MSC secretomes as a promising therapy for multiorgan failure in ACLF.
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Affiliation(s)
- Barbara Cuadra
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Veronica Silva
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Ya-Lin Huang
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Yael Diaz
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Claudio Rivas
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Cristobal Molina
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Valeska Simon
- Departamento de Biología, Facultad de Ciencias, Universidad del Chile, Las Encinas 3370, Ñuñoa, Santiago 7800020, Chile; (V.S.); (M.R.B.)
| | - Maria Rosa Bono
- Departamento de Biología, Facultad de Ciencias, Universidad del Chile, Las Encinas 3370, Ñuñoa, Santiago 7800020, Chile; (V.S.); (M.R.B.)
| | - Bernardo Morales
- Facultad de Ciencias de la Salud, Universidad del Alba, Atrys Chile, Guardia Vieja 339, Providencia, Santiago 7510249, Chile;
| | - Mario Rosemblatt
- Centro de Ciencia & Vida, Av. Del Valle Norte 725, Huechuraba, Santiago 8580702, Chile;
| | - Sebastian Silva
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Rodrigo Acuña
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
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10
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Zhang H, Chen Q, Hu D, Lai J, Yan M, Wu Z, Yang Z, Zheng S, Liu W, Zhang L, Bai L. Manipulating HGF signaling reshapes the cirrhotic liver niche and fills a therapeutic gap in regeneration mediated by transplanted stem cells. Exp Cell Res 2024; 434:113867. [PMID: 38043723 DOI: 10.1016/j.yexcr.2023.113867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/05/2023]
Abstract
Long-term stem cell survival in the cirrhotic liver niche to maintain therapeutic efficacy has not been achieved. In a well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis animal model, we previously showed that liver-resident stem/progenitor cells (MLpvNG2+ cells) or immune cells have improved survival in the fibrotic liver environment but died via apoptosis in the cirrhotic liver environment, and increased levels of hepatocyte growth factor (HGF) mediated this cell death. We tested the hypothesis that inhibiting HGF signaling during the cirrhotic phase could keep the cells alive. We used adeno-associated virus (AAV) vectors designed to silence the c-Met (HGF-only receptor) gene or a neutralizing antibody (anti-cMet-Ab) to block the c-Met protein in the DEN-induced liver cirrhosis mouse model transplanted with MLpvNG2+ cells between weeks 6 and 7 after DEN administration, which is the junction of liver fibrosis and cirrhosis at the site where most intrahepatic stem cells move toward apoptosis. After 4 weeks of treatment, the transplanted MLpvNG2+ cells survived better in c-Met-deficient mice than in wild-type mice, and cell activity was similar to that of the mice that received MLpvNG2+ cells at 5 weeks after DEN administration (liver fibrosis phase when most of these cells proliferated). Mechanistically, a lack of c-Met signaling remodeled the cirrhotic environment, which favored transplanted MLpvNG2+ cell expansion to differentiation into mature hepatocytes and initiate endogenous regeneration by promoting mature host hepatocyte generation and mediating functional improvements. Therapeutically, c-Met-mediated regeneration can be mimicked by anti-cMet-Ab to interfere functions, which is a potential drug for cell-based treatment of liver fibrosis/cirrhosis.
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Affiliation(s)
- Hongyu Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Quanyu Chen
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Deyu Hu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Bioengineering College, Chongqing University, No. 175 Gaotan, ShapingBa Distract, Chongqing 400044, China
| | - Jiejuan Lai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Min Yan
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Zhifang Wu
- Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Zhiqing Yang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Shuguo Zheng
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Wei Liu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Leida Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Bioengineering College, Chongqing University, No. 175 Gaotan, ShapingBa Distract, Chongqing 400044, China; Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China.
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11
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Xie Q, Gu J. Therapeutic and Safety Promise of Mesenchymal Stem Cells for Liver Failure: From Preclinical Experiment to Clinical Application. Curr Stem Cell Res Ther 2024; 19:1351-1368. [PMID: 37807649 DOI: 10.2174/011574888x260690230921174343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 08/11/2023] [Accepted: 08/17/2023] [Indexed: 10/10/2023]
Abstract
Liver failure (LF) is serious liver damage caused by multiple factors, resulting in severe impairment or decompensation of liver synthesis, detoxification, metabolism, and biotransformation. The general prognosis of LF is poor with high mortality in non-transplant patients. The clinical treatments for LF are mainly internal medicine comprehensive care, artificial liver support system, and liver transplantation. However, none of the above treatment strategies can solve the problems of all liver failure patients and has its own limitations. Mesenchymal stem cells (MSCs) are a kind of stem cells with multidirectional differentiation potential and paracrine function, which play an important role in immune regulation and tissue regeneration. In recent years, MSCs have shown multiple advantages in the treatment of LF in pre-clinical experiments and clinical trials. In this work, we reviewed the biological characteristics of MSCs, the possible molecular mechanisms of MSCs in the treatment of liver failure, animal experiments, and clinical application, and also discussed the existing problems of MSCs in the treatment of liver failure.
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Affiliation(s)
- Qiong Xie
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin, 300457, China
| | - Jundong Gu
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin, 300457, China
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12
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Abdellateif MS, Zekri ARN. Stem cell therapy for hepatocellular carcinoma and end-stage liver disease. J Egypt Natl Canc Inst 2023; 35:35. [PMID: 37926787 DOI: 10.1186/s43046-023-00194-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 10/20/2023] [Indexed: 11/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide, especially for patients who are suffering from end-stage liver disease (ESLD). The ESLD is considered a great challenge for clinicians due to the limited chance for liver transplantation, which is the only curative treatment for those patients. Stem cell-based therapy as a part of regenerative medicine represents a promising application for ESLD patients. Many clinical trials were performed to assess the utility of bone marrow-derived stem cells as a potential therapy for patients with liver diseases. The aim of the present study is to present and review the various types of stem cell-based therapy, including the mesenchymal stem cells (MSCs), BM-derived mononuclear cells (BM-MNCs), CD34 + hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and cancer stem cells.Though this type of therapy achieved promising results for the treatment of ESLD, however still there is a confounding data regarding its clinical application. A large body of evidence is highly required to evaluate the stem cell-based therapy after long-term follow-up, with respect to the incidence of toxicity, immunogenicity, and tumorigenesis that developed in many patients.
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Affiliation(s)
- Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt.
| | - Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, NCI, Cairo University, Cairo, 11976, Egypt
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13
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Lu W, Qu J, Yan L, Tang X, Wang X, Ye A, Zou Z, Li L, Ye J, Zhou L. Efficacy and safety of mesenchymal stem cell therapy in liver cirrhosis: a systematic review and meta-analysis. Stem Cell Res Ther 2023; 14:301. [PMID: 37864199 PMCID: PMC10590028 DOI: 10.1186/s13287-023-03518-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/22/2023] [Indexed: 10/22/2023] Open
Abstract
AIM Although the efficacy and safety of mesenchymal stem cell therapy for liver cirrhosis have been demonstrated in several studies. Clinical cases of mesenchymal stem cell therapy for patients with liver cirrhosis are limited and these studies lack the consistency of treatment effects. This article aimed to systematically investigate the efficacy and safety of mesenchymal stem cells in the treatment of liver cirrhosis. METHOD The data source included PubMed/Medline, Web of Science, EMBASE, and Cochrane Library, from inception to May 2023. Literature was screened by the PICOS principle, followed by literature quality evaluation to assess the risk of bias. Finally, the data from each study's outcome indicators were extracted for a combined analysis. Outcome indicators of the assessment included liver functions and adverse events. Statistical analysis was performed using Review Manager 5.4. RESULTS A total of 11 clinical trials met the selection criteria. The pooled analysis' findings demonstrated that both primary and secondary indicators had improved. Compared to the control group, infusion of mesenchymal stem cells significantly increased ALB levels in 2 weeks, 1 month, 3 months, and 6 months, and significantly decreased MELD score in 1 month, 2 months, and 6 months, according to a subgroup analysis using a random-effects model. Additionally, the hepatic arterial injection favored improvements in MELD score and ALB levels. Importantly, none of the included studies indicated any severe adverse effects. CONCLUSION The results showed that mesenchymal stem cell was effective and safe in the treatment of liver cirrhosis, improving liver function (such as a decrease in MELD score and an increase in ALB levels) in patients with liver cirrhosis and exerting protective effects on complications of liver cirrhosis and the incidence of hepatocellular carcinoma. Although the results of the subgroup analysis were informative for the selection of mesenchymal stem cells for clinical treatment, a large number of high-quality randomized controlled trials validations are still needed.
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Affiliation(s)
- Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Jiayang Qu
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Longxiang Yan
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Xingkun Tang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Anqi Ye
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
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14
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Mbituyimana B, Adhikari M, Qi F, Shi Z, Fu L, Yang G. Microneedle-based cell delivery and cell sampling for biomedical applications. J Control Release 2023; 362:692-714. [PMID: 37689252 DOI: 10.1016/j.jconrel.2023.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/16/2023] [Accepted: 09/04/2023] [Indexed: 09/11/2023]
Abstract
Cell-based therapeutics are novel therapeutic strategies that can potentially treat many presently incurable diseases through novel mechanisms of action. Cell therapies may benefit from the ease, safety, and efficacy of administering therapeutic cells. Despite considerable recent technological and biological advances, several barriers remain to the clinical translation and commercialization of cell-based therapies, including low patient compliance, personal handling inconvenience, poor biosafety, and limited biocompatibility. Microneedles (MNs) are emerging as a promising biomedical device option for improved cell delivery with little invasion, pain-free administration, and simplicity of disposal. MNs have shown considerable promise in treating a wide range of diseases and present the potential to improve cell-based therapies. In this review, we first summarized the latest advances in the various types of MNs developed for cell delivery and cell sampling. Emphasis was given to the design and fabrication of various types of MNs based on their structures and materials. Then we focus on the recent biomedical applications status of MNs-mediated cell delivery and sampling, including tissue repair (wound healing, heart repair, and endothelial repair), cancer treatment, diabetes therapy, cell sampling, and other applications. Finally, the current status of clinical application, potential perspectives, and the challenges for clinical translation are also highlighted.
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Affiliation(s)
- Bricard Mbituyimana
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Manjila Adhikari
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Fuyu Qi
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Zhijun Shi
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
| | - Lina Fu
- College of Medicine, Huanghuai University, Zhumadian, Henan 463000, China; Zhumadian Central Hospital, Zhumadian, Henan 463000, China.
| | - Guang Yang
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
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15
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Chen L, Zhang N, Huang Y, Zhang Q, Fang Y, Fu J, Yuan Y, Chen L, Chen X, Xu Z, Li Y, Izawa H, Xiang C. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev Rep 2023; 19:2192-2224. [PMID: 37498509 DOI: 10.1007/s12015-023-10583-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Lu Chen
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Xin Chen
- Department of Hematology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310027, People's Republic of China
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Hiromi Izawa
- Jingugaien Woman Life Clinic, Jingu-Gaien 3-39-5 2F, Shibuya-Ku, Tokyo, Japan
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China.
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16
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Liu BC, Cheng MR, Lang L, Li L, Si YH, Li AJ, Xu Q, Zhang H. Autologous bone marrow infusion via portal vein combined with splenectomy for decompensated liver cirrhosis: A retrospective study. World J Gastrointest Surg 2023; 15:1919-1931. [PMID: 37901728 PMCID: PMC10600764 DOI: 10.4240/wjgs.v15.i9.1919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/08/2023] [Accepted: 07/11/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND In a previous study, autologous bone marrow infusion (ABMI) was performed in patients with decompensated liver cirrhosis (DLC) and acquired immunodeficiency syndrome and achieved good results, but whether splenectomy affected outcome was unclear. AIM To investigate the efficacy of ABMI combined with splenectomy for treatment of DLC. METHODS Eighty-three patients with DLC were divided into an intervention group (43 cases) and control group (40 cases) according to whether splenectomy was performed. The control group was treated with ABMI through the right omental vein, and the intervention group was additionally treated with splenectomy. RESULTS After ABMI, the prothrombin time, serum total bilirubin levels, ascites volume and model for end-stage liver disease score in both groups were significantly lower, while the albumin levels were significantly higher than before ABMI (P < 0.01), but there were no significant differences between the groups (P > 0.05). After ABMI, the white blood cell and platelets counts in both groups were significantly higher than before ABMI (P < 0.01), and the counts in the intervention group were significantly higher than in the control group (P < 0.01). After ABMI the CD4+ and CD8+ T cell counts in both groups were significantly higher than before ABMI (P < 0.01). The CD8+ T cell counts in the intervention group increased continuously and the increase had a shorter duration compared with control group. CONCLUSION ABMI through the portal vein in patients with DLC can significantly improve liver synthetic and secretory functions, and splenectomy promotes improvement of bone marrow hematopoietic and cellular immune functions.
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Affiliation(s)
- Bao-Chi Liu
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- He Nuo Medical Clinic, Shanghai New Hongqiao International Medical Center, Shanghai 201100, China
| | - Ming-Rong Cheng
- Department of Anorectal Surgery, The Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, Guizhou Province, China
| | - Lin Lang
- He Nuo Medical Clinic, Shanghai New Hongqiao International Medical Center, Shanghai 201100, China
| | - Lei Li
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yan-Hui Si
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Ai-Jun Li
- Department of Hepatobiliary Surgery, Oriental Hepatobiliary Surgery Hospital, Shanghai 200433, China
| | - Qing Xu
- Department of Hepatobiliary Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Hui Zhang
- Department of Hepatobiliary Surgery, Shanghai Oriental Hospital Affiliated to Tongji University, Shanghai 200120, China
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17
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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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18
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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19
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Yu S, Yu S, Liu H, Liao N, Liu X. Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases. Stem Cell Res Ther 2023; 14:235. [PMID: 37667383 PMCID: PMC10478247 DOI: 10.1186/s13287-023-03476-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/25/2023] [Indexed: 09/06/2023] Open
Abstract
Although mesenchymal stem cell (MSC) transplantation provides an alternative strategy for end-stage liver disease (ESLD), further widespread application of MSC therapy is limited owing to low cell engraftment efficiency. Improving cell engraftment efficiency plays a critical role in enhancing MSC therapy for liver diseases. In this review, we summarize the current status and challenges of MSC transplantation for ESLD. We also outline the complicated cell-homing process and highlight how low cell engraftment efficiency is closely related to huge differences in extracellular conditions involved in MSC homing journeys ranging from constant, controlled conditions in vitro to variable and challenging conditions in vivo. Improving cell survival and homing capabilities enhances MSC engraftment efficacy. Therefore, we summarize the current strategies, including hypoxic priming, drug pretreatment, gene modification, and cytokine pretreatment, as well as splenectomy and local irradiation, used to improve MSC survival and homing capability, and enhance cell engraftment and therapeutic efficiency of MSC therapy. We hope that this review will provide new insights into enhancing the efficiency of MSC engraftment in liver diseases.
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Affiliation(s)
- Shaoxiong Yu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Saihua Yu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Haiyan Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China.
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20
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Khan S, Mahgoub S, Fallatah N, Lalor PF, Newsome PN. Liver Disease and Cell Therapy: Advances Made and Remaining Challenges. Stem Cells 2023; 41:739-761. [PMID: 37052348 PMCID: PMC10809282 DOI: 10.1093/stmcls/sxad029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 02/27/2023] [Indexed: 04/14/2023]
Abstract
The limited availability of organs for liver transplantation, the ultimate curative treatment for end stage liver disease, has resulted in a growing and unmet need for alternative therapies. Mesenchymal stromal cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties have therefore emerged as a promising therapeutic agent in treating inflammatory liver disease. Significant strides have been made in exploring their biological activity. Clinical application of MSC has shifted the paradigm from using their regenerative potential to one which harnesses their immunomodulatory properties. Reassuringly, MSCs have been extensively investigated for over 30 years with encouraging efficacy and safety data from translational and early phase clinical studies, but questions remain about their utility. Therefore, in this review, we examine the translational and clinical studies using MSCs in various liver diseases and their impact on dampening immune-mediated liver damage. Our key observations include progress made thus far with use of MSCs for clinical use, inconsistency in the literature to allow meaningful comparison between different studies and need for standardized protocols for MSC manufacture and administration. In addition, the emerging role of MSC-derived extracellular vesicles as an alternative to MSC has been reviewed. We have also highlighted some of the remaining clinical challenges that should be addressed before MSC can progress to be considered as therapy for patients with liver disease.
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Affiliation(s)
- Sheeba Khan
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Sara Mahgoub
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Nada Fallatah
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Patricia F Lalor
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
| | - Philip N Newsome
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
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21
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Cardinale V, Lanthier N, Baptista PM, Carpino G, Carnevale G, Orlando G, Angelico R, Manzia TM, Schuppan D, Pinzani M, Alvaro D, Ciccocioppo R, Uygun BE. Cell transplantation-based regenerative medicine in liver diseases. Stem Cell Reports 2023; 18:1555-1572. [PMID: 37557073 PMCID: PMC10444572 DOI: 10.1016/j.stemcr.2023.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 08/11/2023] Open
Abstract
This review aims to evaluate the current preclinical state of liver bioengineering, the clinical context for liver cell therapies, the cell sources, the delivery routes, and the results of clinical trials for end-stage liver disease. Different clinical settings, such as inborn errors of metabolism, acute liver failure, chronic liver disease, liver cirrhosis, and acute-on-chronic liver failure, as well as multiple cellular sources were analyzed; namely, hepatocytes, hepatic progenitor cells, biliary tree stem/progenitor cells, mesenchymal stromal cells, and macrophages. The highly heterogeneous clinical scenario of liver disease and the availability of multiple cellular sources endowed with different biological properties make this a multidisciplinary translational research challenge. Data on each individual liver disease and more accurate endpoints are urgently needed, together with a characterization of the regenerative pathways leading to potential therapeutic benefit. Here, we critically review these topics and identify related research needs and perspectives in preclinical and clinical settings.
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Affiliation(s)
- Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
| | - Nicolas Lanthier
- Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc, Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Pedro M Baptista
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas (CIBERehd), Madrid, Spain; Fundación ARAID, Zaragoza, Spain; Department of Biomedical and Aerospace Engineering, Universidad Carlos III de Madrid, Madrid, Spain
| | - Guido Carpino
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Italy
| | - Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry, and Morphological Sciences with Interest in Transplant, Oncology, and Regenerative Medicine, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Giuseppe Orlando
- Section of Transplantation, Department of Surgery, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Roberta Angelico
- Hepatobiliary Surgery and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Tommaso Maria Manzia
- Hepatobiliary Surgery and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Detlef Schuppan
- Institute of Translational Immunology, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, London, UK
| | - Domenico Alvaro
- Department of Translation and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.
| | - Basak E Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
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22
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Wakil A, Niazi M, Lunsford KE, Pyrsopoulos N. Future Approaches and Therapeutic Modalities for Acute-on-Chronic Liver Failure. Clin Liver Dis 2023; 27:777-790. [PMID: 37380297 DOI: 10.1016/j.cld.2023.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Acute-on-chronic liver failure (ACLF) results from an acute decompensation of cirrhosis due to exogenous insult. The condition is characterized by a severe systemic inflammatory response, inappropriate compensatory anti-inflammatory response, multisystem extrahepatic organ failure, and high short-term mortality. Here, the authors evaluate the current status of potential treatments for ACLF and assess their efficacy and therapeutic potential.
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Affiliation(s)
- Ali Wakil
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H536, Newark, NJ 07103, USA
| | - Mumtaz Niazi
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H536, Newark, NJ 07103, USA
| | - Keri E Lunsford
- Department of Surgery, Division of Liver Transplant and HPB Surgery, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H536, Newark, NJ 07103, USA
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H536, Newark, NJ 07103, USA.
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23
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Khandelwal V, Sharma T, Gupta S, Singh S, Sharma MK, Parashar D, Kashyap VK. Stem cell therapy: a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2. Mol Biol Rep 2023; 50:2663-2683. [PMID: 36536185 PMCID: PMC9762873 DOI: 10.1007/s11033-022-07957-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 09/17/2022] [Indexed: 12/23/2022]
Abstract
The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.
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Affiliation(s)
- Vishal Khandelwal
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Tarubala Sharma
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Shoorvir Singh
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Manish Kumar Sharma
- Department of Microbiology, Dr. Ram Manohar Lohia Avadh University, Faizabad, Uttar Pradesh, 224001, India
| | - Deepak Parashar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
| | - Vivek K Kashyap
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA. .,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA.
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24
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Abou Rayia DM, Ashour DS, Abo Safia HS, Abdel Ghafar MT, Amer RS, Saad AE. Human umbilical cord blood mesenchymal stem cells as a potential therapy for schistosomal hepatic fibrosis: an experimental study. Pathog Glob Health 2023; 117:190-202. [PMID: 35435145 PMCID: PMC9970248 DOI: 10.1080/20477724.2022.2064795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
The objective of our study was to assess the effect of human umbilical cord blood (HUCB) mesenchymal stem cells (MSCs) transplantation on schistosomal hepatic fibrosis in mice. The study animals were divided into three groups. Group I is a control group, where the mice were infected with Schistosoma mansoni cercariae and remained untreated. The mice of the other two groups were infected and treated with either praziquantel (Group II) or HUCB-MSCs (Group III). Liver function tests, as well as histopathological evaluation of liver fibrosis using hematoxylin and eosin and Masson's trichrome stains, were performed. Additionally, an immunohistochemical study was carried out using anti-glial fibrillary acidic protein (GFAP) in hepatic stellate cells. Compared to the control group, the treated (praziquantel and MSCs) groups showed a substantial improvement, with a significant difference regarding the histopathological evaluation of liver fibrosis in the MSCs-treated group. In conclusion, MSCs could be a promising and efficient cell therapy for liver fibrosis.
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Affiliation(s)
- Dina M Abou Rayia
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dalia S Ashour
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hend S Abo Safia
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Rania S Amer
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Abeer E Saad
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.,Medical Parasitology Sub-unit, Pathology Department, College of Medicine, Jouf University, Sakaka, Saudi Arabia
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25
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Therapeutic Efficiency of Nasal Mucosa-Derived Ectodermal Mesenchymal Stem Cells in Rats with Acute Hepatic Failure. Stem Cells Int 2023; 2023:6890299. [PMID: 36655034 PMCID: PMC9842420 DOI: 10.1155/2023/6890299] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/06/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Background Liver transplantation is limited by the insufficiency of liver organ donors when treating end-stage liver disease or acute liver failure (ALF). Ectodermal mesenchymal stem cells (EMSCs) derived from nasal mucosa have emerged as an alternative cell-based therapy. However, the role of EMSCs in acute liver failure remains unclear. Methods EMSCs were obtained from the nasal mucosa tissue of rats. First, EMSCs were seeded on the gelatin-chitosan scaffolds, and the biocompatibility was evaluated. Next, the protective effects of EMSCs were investigated in carbon tetrachloride- (CCl4-) induced ALF rats. Finally, we applied an indirect coculture system to analyze the paracrine effects of EMSCs on damaged hepatocytes. A three-step nontransgenic technique was performed to transform EMSCs into hepatocyte-like cells (HLCs) in vitro. Results EMSCs exhibited a similar phenotype to other mesenchymal stem cells along with self-renewal and multilineage differentiation capabilities. EMSC-seeded gelatin-chitosan scaffolds can increase survival rates and ameliorate liver function and pathology of ALF rat models. Moreover, transplanted EMSCs can secrete paracrine factors to promote hepatocyte regeneration, targeted migration, and transdifferentiate into HLCs in response to the liver's microenvironment, which will then repair or replace the damaged hepatocytes. Similar to mature hepatocytes, HLCs generated from EMSCs possess functions of expressing specific hepatic markers, storing glycogen, and producing urea. Conclusions These results confirmed the feasibility of EMSCs in acute hepatic failure treatment. To our knowledge, this is the first time that EMSCs are used in the therapy of liver diseases. EMSCs are expected to be a novel and promising cell source in liver tissue engineering.
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26
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Zhu H, Wang K, Du W, Cao H, Zhong Q, Yin S, Zhong J, Li F. H3K9 acetylation modification and TLR9 immune regulation mechanism in patients after anti-HBV treatment. Medicine (Baltimore) 2022; 101:e32431. [PMID: 36596032 PMCID: PMC9803445 DOI: 10.1097/md.0000000000032431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
To improve the curative effect of anti-hepatitis B virus (HBV) drugs, methods such as thymosin and entecavir combination have become a focus of clinical investigation. The aim of this retrospective experimental study was to explore the potential mechanism of action of thymosin a1 (Ta1) combined with entecavir in the treatment of HBV infection. A total of 28 patients with chronic hepatitis B, 29 patients treated with thymosin a1 and entecavir combination, and 15 healthy individuals were enrolled in this study. RT-qPCR was conducted to evaluate the mRNA levels of TLR9 in peripheral blood mononuclear cells (PBMCs). The serum level of TLR9 protein was analyzed by ELISA. The binding of TLR9 gene to the protein H3K9Ac in PBMCs was assessed by chromatin immunoprecipitation, and serum inflammatory factors were detected by Luminex technology. The expression levels of TLR9 mRNA and serum TLR9 protein in patients with HBV infection were significantly lower than those in subjects in the control group before treatment but increased after treatment with the Ta1 and entecavir combination. Moreover, the acetylation protein H3K9Ac was significantly bound to the promoter region of the TLR9 gene in patients with HBV infection treated with the Ta1 and entecavir combination compared to that in patients with HBV infection without treatment. Furthermore, the expression levels of interleukin 6 (IL-6), interleukin 12 (IL-12), interferon gamma, and necrosis factor alpha in patients with HBV infection after the combination treatment were slightly decreased compared to those in patients with HBV infection without treatment. In conclusion, the histone acetylation modification of TLR9 was significantly improved in patients with HBV infection after treatment with the Ta1 and entecavir combination, which elevated the expression of TLR9 at the mRNA and protein levels and further regulated the expression of IL-6, IL-12, and other cytokines.
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Affiliation(s)
- Haipeng Zhu
- Department of Infectious Diseases, the Dongguan People’s Hospital, Dongguan, Guangdong, P.R. China
- * Correspondence: Hai-Peng Zhu, Department of Infectious Diseases, Dongguan People’s Hospital, Dongguan, Guangdong 523059, P.R. China (e-mail: )
| | - Ke Wang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China
| | - Wei Du
- Department of Infectious Diseases, the Dongguan People’s Hospital, Dongguan, Guangdong, P.R. China
| | - Huanhuan Cao
- Department of Infectious Diseases, the Dongguan People’s Hospital, Dongguan, Guangdong, P.R. China
| | - Qingyang Zhong
- Department of Infectious Diseases, the Dongguan People’s Hospital, Dongguan, Guangdong, P.R. China
| | - Sichun Yin
- Department of Infectious Diseases, the Dongguan People’s Hospital, Dongguan, Guangdong, P.R. China
| | - Jianbo Zhong
- Department of Infectious Diseases, the Dongguan People’s Hospital, Dongguan, Guangdong, P.R. China
| | - Fawu Li
- Department of Infectious Diseases, the Dongguan People’s Hospital, Dongguan, Guangdong, P.R. China
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27
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Human stem cells for decompensated cirrhosis in adults. Cochrane Database Syst Rev 2022; 2022:CD015173. [PMCID: PMC9531721 DOI: 10.1002/14651858.cd015173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of stem cell treatment in adults with decompensated cirrhosis, regardless of ethnicity, sex, types of stem cells, route of stem cell injection, and administered dose.
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28
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Cellular Therapies in Pediatric Liver Diseases. Cells 2022; 11:cells11162483. [PMID: 36010561 PMCID: PMC9406752 DOI: 10.3390/cells11162483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/30/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022] Open
Abstract
Liver transplantation is the gold standard for the treatment of pediatric end-stage liver disease and liver based metabolic disorders. Although liver transplant is successful, its wider application is limited by shortage of donor organs, surgical complications, need for life long immunosuppressive medication and its associated complications. Cellular therapies such as hepatocytes and mesenchymal stromal cells (MSCs) are currently emerging as an attractive alternative to liver transplantation. The aim of this review is to present the existing world experience in hepatocyte and MSC transplantation and the potential for future effective applications of these modalities of treatment.
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29
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Nevens F, van der Merwe S. Mesenchymal Stem Cell Transplantation in Liver Diseases. Semin Liver Dis 2022; 42:283-292. [PMID: 36049782 DOI: 10.1055/s-0042-1755328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Promising preclinical data suggested that bone marrow-derived mesenchymal stem cells (BM-MSC) can reduce hepatic fibrosis and stimulate liver regeneration. Preclinical studies moreover suggested that the immunomodulatory and anti-inflammatory functions of MSCs may reduce hepatic inflammation, improve liver function, and decrease infection incidences which are deemed especially important in the case of acute-on-chronic liver failure (ACLF). Studies in patients with decompensated cirrhosis demonstrated that injection of BM-MSC resulted in an improvement of biochemical tests and led to a survival benefit in ACLF. Most of these studies were performed in hepatitis B virus infected patients. However, two adequately powered studies performed in Europe could not confirm these data. A possible alternative to mobilize BM-MSC into the liver is the use of granulocyte colony-stimulating factor (G-CSF) which has proregenerative and immunomodulatory effects. In Indian studies, the use of G-CSF was associated with improvement of survival, although this finding could not be confirmed in European studies. Human allogeneic liver-derived progenitor cell therapy represents a potential treatment for ACLF, of which the main action is paracrine. These human liver-derived MSC can perform various functions, including the downregulation of proinflammatory responses. The clinical beneficial effect of these cells is further explored in patients with alcoholic cirrhosis and ACLF in Europe.
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Affiliation(s)
- Frederik Nevens
- Department of Chronic Diseases, Laboratory of Hepatology, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Division of Hepatology, Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium
| | - Schalk van der Merwe
- Department of Chronic Diseases, Laboratory of Hepatology, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Division of Hepatology, Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium
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30
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
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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] [MESH Headings] [Grants] [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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The assessment of mesenchymal stem cells therapy in acute on chronic liver failure and chronic liver disease: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther 2022; 13:204. [PMID: 35578365 PMCID: PMC9109309 DOI: 10.1186/s13287-022-02882-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/04/2022] [Indexed: 11/29/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) therapy is showing potential therapeutic effects on liver function improvement in patients with chronic liver disease; however, the consensus on efficacy and safety of MSCs has not been reached. Methods We performed this systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of MSCs therapy for patients with chronic liver disease. A detailed search of the Cochrane Library, MEDLINE, Web of Science, and EMBASE databases was conducted to find studies published prior to September 15, 2021. The outcome measures were survival rate, model of end-stage liver disease (MELD) score, albumin, total bilirubin, coagulation function, and aminotransferase. Results A literature search resulted in 892 citations. Of these, 12 studies met the inclusion criteria. It was found that compared with conventional treatment, MSCs therapy was associated with improved liver function including the MELD score, albumin levels, and coagulation function. However, it had no obvious beneficial effects on survival rate and aminotransferase levels. Subgroup analyses indicated that MSCs therapy had therapeutic effects on patients with both acute on chronic liver failure (ACLF) and cirrhosis. BM-MSCs and UC-MSCs treatment had similar efficacy to improve liver function. The effectiveness varied slightly between the peripheral intravenous injection and hepatic arterial injection. Five studies reported that the only adverse event of the MSCs therapy was fever, and no serious adverse events and side effects were reported. Analysis on clinical symptoms showed that encephalopathy and gastrointestinal hemorrhage events were reduced after MSCs therapy. Conclusions In conclusion, this study suggested that MSCs therapy could be a potential therapeutic alternative for patients with chronic liver disease in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02882-4.
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Shokravi S, Borisov V, Zaman BA, Niazvand F, Hazrati R, Khah MM, Thangavelu L, Marzban S, Sohrabi A, Zamani A. Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review. Stem Cell Res Ther 2022; 13:192. [PMID: 35527304 PMCID: PMC9080215 DOI: 10.1186/s13287-022-02825-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepatocytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes. Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF. Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs, genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
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Affiliation(s)
- Samin Shokravi
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Vitaliy Borisov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Burhan Abdullah Zaman
- Basic Sciences Department, College of Pharmacy, University of Duhok, Duhok, Kurdistan Region Iraq
| | - Firoozeh Niazvand
- School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Raheleh Hazrati
- Department of Medicinal Chemistry, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Meysam Mohammadi Khah
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Sima Marzban
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Armin Sohrabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Yuan M, Hu X, Yao L, Jiang Y, Li L. Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease. Stem Cell Res Ther 2022; 13:179. [PMID: 35505419 PMCID: PMC9066724 DOI: 10.1186/s13287-022-02858-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver through differentiation into hepatocyte-like cells, immune regulation, and anti-fibrotic mechanisms. Multiple clinical trials have confirmed that MSC transplantation restores liver function and alleviates liver damage. A sufficient number of MSCs must be home to the target tissues after administration for successful application. However, inefficient homing of MSCs after systemic administration is a major limitation in MSC therapy. Here, we review the mechanisms and clinical application status of MSCs in the treatment of liver disease and comprehensively summarize the molecular mechanisms of MSC homing, and various strategies for promoting MSC homing to improve the treatment of liver disease.
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Affiliation(s)
- Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Lanjuan Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China. .,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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35
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The Potential Clinical Use of Stem/Progenitor Cells and Organoids in Liver Diseases. Cells 2022; 11:cells11091410. [PMID: 35563716 PMCID: PMC9101582 DOI: 10.3390/cells11091410] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/11/2022] [Accepted: 04/19/2022] [Indexed: 02/07/2023] Open
Abstract
The liver represents the most important metabolic organ of the human body. It is evident that an imbalance of liver function can lead to several pathological conditions, known as liver failure. Orthotropic liver transplantation (OLT) is currently the most effective and established treatment for end-stage liver diseases and acute liver failure (ALF). Due to several limitations, stem-cell-based therapies are currently being developed as alternative solutions. Stem cells or progenitor cells derived from various sources have emerged as an alternative source of hepatic regeneration. Therefore, hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are also known to differentiate into hepatocyte-like cells (HPLCs) and liver progenitor cells (LPCs) that can be used in preclinical or clinical studies of liver disease. Furthermore, these cells have been shown to be effective in the development of liver organoids that can be used for disease modeling, drug testing and regenerative medicine. In this review, we aim to discuss the characteristics of stem-cell-based therapies for liver diseases and present the current status and future prospects of using HLCs, LPCs or liver organoids in clinical trials.
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36
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Yao W, Shi L, Zhang Y, Dong H, Zhang Y. Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: potential mechanisms, current clinical evidence, and future perspectives. Stem Cell Res Ther 2022; 13:124. [PMID: 35321737 PMCID: PMC8942612 DOI: 10.1186/s13287-022-02810-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/07/2022] [Indexed: 12/20/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread into more than 200 countries and infected approximately 203 million people globally. COVID-19 is associated with high mortality and morbidity in some patients, and this disease still does not have effective treatments with reproducibly appreciable outcomes. One of the leading complications associated with COVID-19 is acute respiratory distress syndrome (ARDS); this is an anti-viral host inflammatory response, and it is usually caused by a cytokine storm syndrome which may lead to multi-organ failure and death. Currently, COVID-19 patients are treated with approaches that mostly fall into two major categories: immunomodulators, which promote the body's fight against viruses efficiently, and antivirals, which slow or stop viruses from multiplying. These treatments include a variety of novel therapies that are currently being tested in clinical trials, including serum, IL-6 antibody, and remdesivir; however, the outcomes of these therapies are not consistently appreciable and remain a subject of debate. Mesenchymal stem/stromal cells (MSCs), the multipotent stem cells that have previously been used to treat viral infections and various respiratory diseases such as ARDS exhibit immunomodulatory properties and can ameliorate tissue damage. Given that SARS-CoV-2 targets the immune system and causes tissue damage, it is presumable that MSCs are being explored to treat COVID-19 patients. This review summarizes the potential mechanisms of action of MSC therapy, progress of MSC, and its related products in clinical trials for COVID-19 therapy based on the outcomes of these clinical studies.
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Affiliation(s)
- Weiqi Yao
- Department of Hematology, Union Hospital, Tong Ji Medical College, Hua Zhong University of Science and Technology, Hubei, China
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China
| | - Lei Shi
- Department of Infectious Diseases, Fifth Medical Center of Chinese, PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Yun Zhang
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
| | - Haibo Dong
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China
- Wuhan Optics Valley VCANBIO Cell & Gene Technology Co., Ltd., Hubei, China
| | - Yu Zhang
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China.
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China.
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China.
- Tianjin Key Laboratory for Blood Cell Therapy Technology, Tianjin, China.
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Autologous bone marrow mononuclear cell infusion for liver cirrhosis after the Kasai operation in children with biliary atresia. Stem Cell Res Ther 2022; 13:108. [PMID: 35287722 PMCID: PMC8919575 DOI: 10.1186/s13287-022-02762-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/01/2022] [Indexed: 02/06/2023] Open
Abstract
Aim To evaluate the safety and early outcomes of autologous bone marrow mononuclear cell (BMMNC) infusion for liver cirrhosis due to biliary atresia (BA) after Kasai operation.
Methods An open-label clinical trial was performed from January 2017 to December 2019. Nineteen children with liver cirrhosis due to BA after Kasai operation were included. Bone marrow was harvested through anterior iliac crest puncture under general anesthesia. Mononuclear cells (MNCs) were isolated by Ficoll gradient centrifugation and then infused into the hepatic artery. The same procedure was repeated 6 months later. Serum bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and prothrombin time were monitored at baseline, 3 months, 6 months, and 12 months after the first transplantation. Esophagoscopies and liver biopsies were performed in patients whose parents provided consent. Mixed-effect analysis was used to evaluate the changes in Pediatric End-Stage Liver Disease (PELD) scores.
Results The average MNC and CD34+ cell counts per kg body weight were 50.1 ± 58.5 × 106/kg and 3.5 ± 2.8 × 106 for the first transplantation and 57.1 ± 42.0 × 106/kg and 3.7 ± 2.7 × 106 for the second transplantation. No severe adverse events associated with the cell therapy were observed in the patients. One patient died 5 months after the first infusion at a provincial hospital due to the rupture of esophageal varices, while 18 patients survived. Liver function was maintained or improved after infusion, as assessed by biochemical tests. The severity of the disease reduced markedly, with a significant reduction in PELD scores.
Conclusion Autologous BMMNC administration for liver cirrhosis due to BA is safe and may maintain or improve liver function. Trial registration ClinicalTrials.gov identifier: NCT03468699. Name of the registry: Vinmec Research Institute of Stem Cell and Gene Technology. https://clinicaltrials.gov/ct2/show/NCT03468699?cond=biliary+atresia&cntry=VN&draw=2&rank=2. Registered on March 16, 2018. The trial results will also be published according to the CONSORT statement at conferences and reported in peer-reviewed journals.
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Jindal A, Jagdish RK, Kumar A. Hepatic Regeneration in Cirrhosis. J Clin Exp Hepatol 2022; 12:603-616. [PMID: 35535091 PMCID: PMC9077225 DOI: 10.1016/j.jceh.2021.08.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/31/2021] [Indexed: 01/03/2023] Open
Abstract
End-stage liver disease is characterized by massive hepatocyte death resulting in clinical decompensation and organ failures. Clinical consequences in cirrhosis are the results of the loss of functional hepatocytes and excessive scarring. The only curative therapy in advanced cirrhosis is orthotropic liver transplantation, but the clinical demand outweighs the availability of acceptable donor organs. Moreover, this also necessitates lifelong immunosuppression and carries associated risks. The liver has a huge capability for regeneration. Self-replication of quiescent differentiated hepatocytes and cholangiocytes occurs in patients with acute liver injury. Due to limited hepatocyte self-renewal capacity in advanced cirrhosis, great interest has therefore been shown in characterizing the possible role of hepatic progenitor cells and bone marrow-derived stem cells to therapeutically aid this process. Transplantation of cells from various sources that can be properly differentiated into functional liver cells or use of growth factors for ex-vivo expansion of progenitor cells is needed at utmost priority. Multiple researches over the last two decades have aided researchers in refining proliferation, differentiation, and storage techniques and understand the functionality of these cells for use in clinical practice. However, these cell-based therapies are still experimental and have to be used in trial settings.
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Key Words
- Ang2, angiopoietin 2
- BM, Bone marrow
- BM-MNCs, bone marrow mononuclear cells
- BMSC, bone marrow stem cells
- DAMPs, Damage associated molecular patterns
- EPCs, endothelial progenitor cells
- ESRP2, epithelial splicing regulatory protein 2
- GCSF
- HGF, hepatocyte growth factor
- HPC, Hepatocyte progenitor cells
- HSCs, hematopoietic stem cells
- Hh, Hedgehog
- HybHP, hybrid periportal hepatocytes
- MMP, matrix metalloprotease
- MSCs, mesenchymal stromal cells
- OLT, Orthotropic liver transplantation
- PAMPs, Pathogen associated molecular patterns
- SAH, severe alcoholic hepatitis
- SDF1, stromal-derived factor 1
- TNFSF12, tumor necrosis factor ligand superfamily member 12
- Terthigh, high Telomerase reverse transcriptase
- [Hnf4a], Hepatocyte Nuclear Factor 4 Alpha
- [Mfsd2a], Major Facilitator Superfamily Domain containing 2A
- acute liver failure
- chronic liver diseases
- hepatocyte transplant
- liver regeneration
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | | | - Anupam Kumar
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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Xu R, Ni B, Wang L, Shan J, Pan L, He Y, Lv G, Lin H, Chen W, Zhang Q. CCR2-overexpressing mesenchymal stem cells targeting damaged liver enhance recovery of acute liver failure. Stem Cell Res Ther 2022; 13:55. [PMID: 35123561 PMCID: PMC8817567 DOI: 10.1186/s13287-022-02729-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 01/12/2022] [Indexed: 12/13/2022] Open
Abstract
Background Mesenchymal stem cell (MSC) transplantation is emerging as a promising cell therapeutic strategy in acute liver failure (ALF) clinical research. The potency of MSCs to migrate and engraft into targeted lesions could largely determine their clinical efficacy, in which chemokine/receptor axes play a crucial role. Unfortunately, the downregulation of chemokine receptors expression after in vitro expansion results in a poor homing capacity of MSCs. Methods By evaluating the chemokine expression profile in the liver of ALF patients and ALF mice, we found that CCL2 expression was highly upregulated in damaged livers, while the corresponding receptor, CCR2, was lacking in cultured MSCs. Thus, we genetically modified MSCs to overexpress CCR2 and investigated the targeted homing capacity and treatment efficacy of MSCCCR2 compared to those of the MSCvector control. Results In vivo and ex vivo near-infrared fluorescence imaging showed that MSCCCR2 rapidly migrated and localized to injured livers in remarkably greater numbers following systemic infusion, and these cells were retained in liver lesions for a longer time than MSCvector. Furthermore, MSCCCR2 exhibited significantly enhanced efficacy in the treatment of ALF in mice, which was indicated by a dramatically improved survival rate, the alleviation of liver injury with reduced inflammatory infiltration and hepatic apoptosis, and the promotion of liver regeneration. Conclusions Altogether, these results indicate that CCR2 overexpression enhances the targeted migration of MSCs to damaged livers, improves their treatment effect, and may provide a novel strategy for improving the efficacy of cell therapy for ALF. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02729-y.
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Wu X, Jin S, Ding C, Wang Y, He D, Liu Y. Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed. Front Microbiol 2022; 12:804813. [PMID: 35046923 PMCID: PMC8761948 DOI: 10.3389/fmicb.2021.804813] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
Microbial diseases are a global health threat, leading to tremendous casualties and economic losses. The strategy to treat microbial diseases falls into two broad categories: pathogen-directed therapy (PDT) and host-directed therapy (HDT). As the typical PDT, antibiotics or antiviral drugs directly attack bacteria or viruses through discerning specific molecules. However, drug abuse could result in antimicrobial resistance and increase infectious disease morbidity. Recently, the exosome therapy, as a HDT, has attracted extensive attentions for its potential in limiting infectious complications and targeted drug delivery. Mesenchymal stem cell-derived exosomes (MSC-Exos) are the most broadly investigated. In this review, we mainly focus on the development and recent advances of the application of MSC-Exos on microbial diseases. The review starts with the difficulties and current strategies in antimicrobial treatments, followed by a comprehensive overview of exosomes in aspect of isolation, identification, contents, and applications. Then, the underlying mechanisms of the MSC-Exo therapy in microbial diseases are discussed in depth, mainly including immunomodulation, repression of excessive inflammation, and promotion of tissue regeneration. In addition, we highlight the latest progress in the clinical translation of the MSC-Exo therapy, by summarizing related clinical trials, routes of administration, and exosome modifications. This review will provide fundamental insights and future perspectives on MSC-Exo therapy in microbial diseases from bench to bedside.
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Affiliation(s)
| | | | | | | | | | - Yan Liu
- Laboratory of Biomimetic Nanomaterials, Department of Orthodontics, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
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Chen K, Obara H, Matsubara Y, Fukuda K, Yagi H, Ono-Uruga Y, Matsubara K, Kitagawa Y. Adipose-Derived Mesenchymal Stromal/Stem Cell Line Prevents Hepatic Ischemia/Reperfusion Injury in Rats by Inhibiting Inflammasome Activation. Cell Transplant 2022; 31:9636897221089629. [PMID: 35438583 PMCID: PMC9021522 DOI: 10.1177/09636897221089629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have shown potential in the treatment of degenerative diseases, including ischemia/reperfusion injury (IRI), which occurs during organ transplantation and represents the main cause of post-transplant graft dysfunction. However, MSCs have heterogeneous characteristics, and studies of MSCs therapy have shown a variety of outcomes. To establish a new effective MSCs therapy, we developed an adipose-derived mesenchymal stromal/stem cell line (ASCL) and compared its therapeutic effects on primary adipose-derived MSCs (ASCs) using a hepatocyte co-culture model of hypoxia/reoxygenation in vitro and a rat model of hepatic IRI in vivo. The results showed that both ASCL and ASCs protect against hypoxia by improving hepatocyte viability, inhibiting reactive oxygen species release, and upregulating transforming growth factor-β in vitro. In vivo, ASCL or ASCs were infused into the spleen 24 h before the induction of rat hepatic IRI. The results showed that ASCL significantly improved the survival outcomes compared with the control (normal saline infusion) with the significantly decreased serum levels of liver enzymes and less damage to liver tissues compared with ASCs. Both ASCL and ASCs suppressed NOD-like receptor family pyrin domain-containing 3 inflammasome activation and subsequently reduced the release of activated IL-1β and IL-18, which is considered an important mechanism underlying ASCL and ASCs infusion in hepatic IRI. In addition, ASCL can promote the release of interleukin-1 receptor antagonist, which was previously reported as a key factor in hampering the inflammatory cascade during hepatic IRI. Our results suggest ASCL as a new candidate for hepatic IRI treatment due to its relatively homogeneous characteristics.
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Affiliation(s)
- Kaili Chen
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hideaki Obara
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yumiko Matsubara
- Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan
| | - Kazumasa Fukuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Yagi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yukako Ono-Uruga
- Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan
| | - Kentaro Matsubara
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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Sukowati CHC, Tiribelli C. Adult Stem Cell Therapy as Regenerative Medicine for End-Stage Liver Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:57-72. [DOI: 10.1007/5584_2022_719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Shaw TD, Krasnodembskaya AD, Schroeder GN, Zumla A, Maeurer M, O’Kane CM. Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases. Clin Microbiol Rev 2021; 34:e0006421. [PMID: 34612662 PMCID: PMC8510528 DOI: 10.1128/cmr.00064-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
There is an urgent need for new antimicrobial strategies for treating complex infections and emerging pathogens. Human mesenchymal stromal cells (MSCs) are adult multipotent cells with antimicrobial properties, mediated through direct bactericidal activity and modulation of host innate and adaptive immune cells. More than 30 in vivo studies have reported on the use of human MSCs for the treatment of infectious diseases, with many more studies of animal MSCs in same-species models of infection. MSCs demonstrate potent antimicrobial effects against the major classes of human pathogens (bacteria, viruses, fungi, and parasites) across a wide range of infection models. Mechanistic studies have yielded important insight into their immunomodulatory and bactericidal activity, which can be enhanced through various forms of preconditioning. MSCs are being investigated in over 80 clinical trials for difficult-to-treat infectious diseases, including sepsis and pulmonary, intra-abdominal, cutaneous, and viral infections. Completed trials consistently report MSCs to be safe and well tolerated, with signals of efficacy against some infectious diseases. Although significant obstacles must be overcome to produce a standardized, affordable, clinical-grade cell therapy, these studies suggest that MSCs may have particular potential as an adjunct therapy in complex or resistant infections.
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Affiliation(s)
- Timothy D. Shaw
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Anna D. Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Gunnar N. Schroeder
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Alimuddin Zumla
- Center for Clinical Microbiology, Division of Infection and Immunity, University College London, NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
| | - Markus Maeurer
- Immunosurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Department of Oncology and Haematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Cecilia M. O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
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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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Lee JH, Lee S, Park HJ, Kim YA, Lee SK. Human Liver Stem Cell Transplantation Alleviates Liver Fibrosis in a Rat Model of CCl 4-Induced Liver Fibrosis. Int J Stem Cells 2021; 14:475-484. [PMID: 34711695 PMCID: PMC8611308 DOI: 10.15283/ijsc21031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 02/05/2023] Open
Abstract
Background and Objectives Mesenchymal stem cells (MSCs) elicit therapeutic effects against liver fibrosis in animal models. Human liver stem cells (HLSCs) are cells isolated from human liver tissue that have mesenchymal morphology and express MSC markers. HLSCs also possess intrahepatic stem cell properties. We introduce a rat model of liver fibrosis and trans-portal transplantation of HLSC to demonstrate alleviation of liver fibrosis. Methods and Results Liver fibrosis was induced by intraperitoneal injection of Carbon tetrachloride (CCl4). Sprague Dawley rats underwent simultaneous partial hepatectomy of the left hepatic lobe and HLSC transplantation via the portal vein. Gross appearance of the liver observed following CCl4 injection showed cholestasis and surface nodularity. Sirius red staining revealed deposition of collagen fibers in the extracellular matrix (ECM). Following HLSC transplantation, human albumin secreting cells were detected by immunohistochemistry in liver specimens. Quantitative measurements of fibrosis area stained by Sirius red were compared between baseline and post-HLSC transplant (1×107 cells) following 10 weeks of CCl4 treatment liver specimens. Fibrosis area (p<0.05), serum markers of liver inflammation and fibrosis (AST, ALT levels and APRI, p<0.05) significantly decreased from baseline after HLSC transplantation. RNA expression in liver tissues revealed significant decrease in tissue inhibitor of matrix metalloproteinase 1 (TIMP1), TIMP2 expression and increase in hepatocyte growth factor expression following HLSC transplantation (p<0.05). Conclusions HLSC transplantation effectively reduced the area of liver fibrosis with increased expression of factors promoting ECM degradation. These findings suggest the potential therapeutic role of HLSCs in various liver diseases presenting with liver fibrosis.
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Affiliation(s)
- Ji-Hyun Lee
- Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Sanghoon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hey-Jung Park
- Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Young-Ah Kim
- Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Suk-Koo Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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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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Amadeo F, Trivino Cepeda K, Littlewood J, Wilm B, Taylor A, Murray P. Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action? Emerg Top Life Sci 2021; 5:549-562. [PMID: 34495324 PMCID: PMC8589440 DOI: 10.1042/etls20210013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/11/2021] [Accepted: 08/27/2021] [Indexed: 01/10/2023]
Abstract
Mesenchymal stromal cells (MSCs) have been found to be safe and effective in a wide range of animal models of human disease. MSCs have been tested in thousands of clinical trials, but results show that while these cells appear to be safe, they tend to lack efficacy. This has raised questions about whether animal models are useful for predicting efficacy in patients. However, a problem with animal studies is that there is a lack of standardisation in the models and MSC therapy regimes used; there appears to be publication bias towards studies reporting positive outcomes; and the reproducibility of results from animal experiments tends not to be confirmed prior to clinical translation. A further problem is that while some progress has been made towards investigating the mechanisms of action (MoA) of MSCs, we still fail to understand how they work. To make progress, it is important to ensure that prior to clinical translation, the beneficial effects of MSCs in animal studies are real and can be repeated by independent research groups. We also need to understand the MoA of MSCs to assess whether their effects are likely to be beneficial across different species. In this review, we give an overview of the current clinical picture of MSC therapies and discuss what we have learned from animal studies. We also give a comprehensive update of what we know about the MoA of MSCs, particularly in relation to their role in immunomodulation.
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Affiliation(s)
- Francesco Amadeo
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Katherine Trivino Cepeda
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - James Littlewood
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Arthur Taylor
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
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Kawakatsu-Hatada Y, Murata S, Mori A, Kimura K, Taniguchi H. Serous Membrane Detachment with Ultrasonic Homogenizer Improves Engraftment of Fetal Liver to Liver Surface in a Rat Model of Cirrhosis. Int J Mol Sci 2021; 22:11589. [PMID: 34769019 PMCID: PMC8584093 DOI: 10.3390/ijms222111589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 11/16/2022] Open
Abstract
Liver transplantation is the most effective treatment for end-stage cirrhosis. However, due to serious donor shortages, new treatments to replace liver transplantation are sorely needed. Recent studies have focused on novel therapeutic methods using hepatocytes and induced pluripotent stem cells, we try hard to develop methods for transplanting these cells to the liver surface. In the present study, we evaluated several methods for their efficiency in the detachment of serous membrane covering the liver surface for transplantation to the liver surface. The liver surface of dipeptidyl peptidase IV (DPPIV)-deficient rats in a cirrhosis model was detached by various methods, and then fetal livers from DPPIV-positive rats were transplanted. We found that the engraftment rate and area as well as the liver function were improved in rats undergoing transplantation following serous membrane detachment with an ultrasonic homogenizer, which mimics the Cavitron Ultrasonic Surgical Aspirator® (CUSA), compared with no detachment. Furthermore, the bleeding amount was lower with the ultrasonic homogenizer method than with the needle and electric scalpel methods. These findings provide evidence that transplantation to the liver surface with serous membrane detachment using CUSA might contribute to the development of new treatments for cirrhosis using cells or tissues.
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Affiliation(s)
- Yumi Kawakatsu-Hatada
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Akihiro Mori
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Kodai Kimura
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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Wiśniewska J, Sadowska A, Wójtowicz A, Słyszewska M, Szóstek-Mioduchowska A. Perspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies. Life (Basel) 2021; 11:life11101068. [PMID: 34685439 PMCID: PMC8538998 DOI: 10.3390/life11101068] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/17/2022] Open
Abstract
Tissue fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components that result from the disruption of regulatory processes responsible for ECM synthesis, deposition, and remodeling. Fibrosis develops in response to a trigger or injury and can occur in nearly all organs of the body. Thus, fibrosis leads to severe pathological conditions that disrupt organ architecture and cause loss of function. It has been estimated that severe fibrotic disorders are responsible for up to one-third of deaths worldwide. Although intensive research on the development of new strategies for fibrosis treatment has been carried out, therapeutic approaches remain limited. Since stem cells, especially mesenchymal stem cells (MSCs), show remarkable self-renewal, differentiation, and immunomodulatory capacity, they have been intensively tested in preclinical studies and clinical trials as a potential tool to slow down the progression of fibrosis and improve the quality of life of patients with fibrotic disorders. In this review, we summarize in vitro studies, preclinical studies performed on animal models of human fibrotic diseases, and recent clinical trials on the efficacy of allogeneic and autologous stem cell applications in severe types of fibrosis that develop in lungs, liver, heart, kidney, uterus, and skin. Although the results of the studies seem to be encouraging, there are many aspects of cell-based therapy, including the cell source, dose, administration route and frequency, timing of delivery, and long-term safety, that remain open areas for future investigation. We also discuss the contemporary status, challenges, and future perspectives of stem cell transplantation for therapeutic options in fibrotic diseases as well as we present recent patents for stem cell-based therapies in organ fibrosis.
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50
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Wu MC, Meng QH. Current understanding of mesenchymal stem cells in liver diseases. World J Stem Cells 2021; 13:1349-1359. [PMID: 34630867 PMCID: PMC8474713 DOI: 10.4252/wjsc.v13.i9.1349] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/01/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.
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Affiliation(s)
- Mu-Chen Wu
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China.
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