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Khalili MR, Ahmadloo S, Mousavi SA, Joghataei MT, Brouki Milan P, Naderi Gharahgheshlagh S, Mohebi SL, Haramshahi SMA, Hosseinpour Sarmadi V. Navigating mesenchymal stem cells doses and delivery routes in heart disease trials: A comprehensive overview. Regen Ther 2025; 29:117-127. [PMID: 40162019 PMCID: PMC11952810 DOI: 10.1016/j.reth.2025.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/13/2025] [Accepted: 02/27/2025] [Indexed: 04/02/2025] Open
Abstract
In recent years, various clinical trials have been designed and implemented using mesenchymal stem cells (MSCs) for the treatment of heart diseases. Clinical trials exploring MSC-based treatments have proliferated, yet the lack of standardized protocols for MSC administration remains a significant challenge. Despite the growing popularity of MSC trials, questions persist regarding optimal dosing, administration routes, and frequency to achieve safety and efficacy, particularly in the context of cardiac regeneration. The current study has reviewed the clinical trials that have used MSCs for the treatment of heart diseases since 2009. The findings reveal diverse transplantation methods and varying MSCs quantities, highlighting the absence of a universal guideline for MSCs utilization in heart disease clinical trials.
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Affiliation(s)
- Mohammad Reza Khalili
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Salma Ahmadloo
- Institute for Cognitive and Brain Science, Shahid Beheshti University, Tehran, Iran
| | - Seyed Amin Mousavi
- Department of Plastic and Reconstructive Surgery, Hazrat Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Peiman Brouki Milan
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Seyedeh Lena Mohebi
- Institutes of Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Haramshahi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vahid Hosseinpour Sarmadi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
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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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Xu Y, Wang XS, Zhou XL, Lu WM, Tang XK, Jin Y, Ye JS. Mesenchymal stem cell therapy for liver fibrosis need "partner": Results based on a meta-analysis of preclinical studies. World J Gastroenterol 2024; 30:3766-3782. [PMID: 39221071 PMCID: PMC11362880 DOI: 10.3748/wjg.v30.i32.3766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/22/2024] [Accepted: 08/06/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND The efficacy of mesenchymal stem cells (MSCs) in treating liver fibrosis has been demonstrated in several clinical studies. However, their low survival and liver implantation rates remain problematic. In recent years, a large number of studies in animal models of liver fibrosis have shown that MSCs combined with drugs can improve the efficacy of MSCs in the treatment of liver fibrosis alone and inhibit its progression to end-stage liver disease. This has inspired new ways of thinking about treating liver fibrosis. AIM To investigate the effectiveness and mechanisms of MSCs combined with drugs in treating liver fibrosis. METHODS Data sources included four electronic databases and were constructed until January 2024. The subjects, interventions, comparators, outcomes, and study design principle were used to screen the literature, and the quality of the literature was evaluated to assess the risk of bias. Relevant randomised controlled trials were selected, and the final 13 studies were included in the final study. RESULTS A total of 13 studies were included after screening. Pooled analysis showed that MSCs combined with drug therapy significantly improved liver function, promoted the repair of damaged liver tissues, reduced the level of liver fibrosis-related indexes, and effectively ameliorated hepatic fibrosis by modulating the hepatic inflammatory microenvironment, promoting the homing of MSCs, and regulating the relevant signaling pathways, and the treatment efficacy was superior to MSCs alone. However, the combined treatment statistics showed no ame-lioration in serum albumin levels (standardized mean difference = 0.77, 95% confidence interval: -0.13 to 1.68, P = 0.09). CONCLUSION In conclusion, MSCs combined with drugs for treating liver fibrosis effectively make up for the shortcomings of MSCs in their therapeutic effects. However, due to the different drugs, the treatment mechanism and effect also differ. Therefore, more randomized controlled trials are needed to compare the therapeutic efficacy of different drugs in combination with MSCs, aiming to select the "best companion" of MSCs in treating hepatic fibrosis.
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Affiliation(s)
- Yan Xu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xue-Song Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xiao-Lei Zhou
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Wen-Ming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xing-Kun Tang
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yu Jin
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Jun-Song Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cere-brovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
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Czekaj P, Król M, Kolanko E, Wieczorek P, Bogunia E, Hermyt M, Grajoszek A, Prusek A. Optimization of methods for intrasplenic administration of human amniotic epithelial cells in order to perform safe and effective cell-based therapy for liver diseases. Stem Cell Rev Rep 2024; 20:1599-1617. [PMID: 38769232 PMCID: PMC11319411 DOI: 10.1007/s12015-024-10735-1] [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] [Accepted: 05/11/2024] [Indexed: 05/22/2024]
Abstract
In animal experimental models the administration of stem cells into the spleen should ensure high effectiveness of their implantation in the liver due to a direct vascular connection between the two organs. The aim of this study was to update the methods of experimental intrasplenic cell transplantation using human amniotic epithelial cells (hAECs) which are promising cells in the treatment of liver diseases. BALB/c mice were administered intrasplenically with 0.5, 1, and 2 million hAECs by direct bolus injection (400 µl/min) and via a subcutaneous splenic port by fast (20 μl/min) and slow (10 μl/min) infusion. The port was prepared by translocating the spleen to the skin pocket. The spleen, liver, and lungs were collected at 3 h, 6 h, and 24 h after the administration of cells. The distribution of hAECs, histopathological changes in the organs, complete blood count, and biochemical markers of liver damage were assessed. It has been shown that the method of intrasplenic cell administration affects the degree of liver damage. The largest number of mice showing significant liver damage was observed after direct administration and the lowest after slow administration through a port. Liver damage increased with the number of administered cells, which, paradoxically, resulted in increased liver colonization efficiency. It was concluded that the administration of 1 × 106 hAECs by slow infusion via a subcutaneous splenic port reduces the incidence of complications at the expense of a slight decrease in the effectiveness of implantation of the transplanted cells in the liver.
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Affiliation(s)
- Piotr Czekaj
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 18, Katowice, 40-752, Poland.
| | - Mateusz Król
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 18, Katowice, 40-752, Poland
| | - Emanuel Kolanko
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 18, Katowice, 40-752, Poland
| | - Patrycja Wieczorek
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 18, Katowice, 40-752, Poland
| | - Edyta Bogunia
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 18, Katowice, 40-752, Poland
| | - Mateusz Hermyt
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 18, Katowice, 40-752, Poland
| | - Aniela Grajoszek
- Department of Experimental Medicine, Medical University of Silesia in Katowice, Medyków 4, Katowice, 40-752, Poland
| | - Agnieszka Prusek
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 18, Katowice, 40-752, Poland
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Wang X, Wang Y, Lu W, Qu J, Zhang Y, Ye J. Effectiveness and mechanisms of mesenchymal stem cell therapy in preclinical animal models of hepatic fibrosis: a systematic review and meta-analysis. Front Bioeng Biotechnol 2024; 12:1424253. [PMID: 39104627 PMCID: PMC11299041 DOI: 10.3389/fbioe.2024.1424253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 06/26/2024] [Indexed: 08/07/2024] Open
Abstract
Background Liver damage due to long-term viral infection, alcohol consumption, autoimmune decline, and other factors could lead to the gradual development of liver fibrosis. Unfortunately, until now, there has been no effective treatment for liver fibrosis. Mesenchymal stem cells, as a promising new therapy for liver fibrosis, can slow the progression of fibrosis by migrating to the site of liver injury and by altering the microenvironment of the fibrotic area. Aim By including all relevant studies to date to comprehensively assess the efficacy of mesenchymal stem cells for the treatment of hepatic fibrosis and to explore considerations for clinical translation and therapeutic mechanisms. Methods Data sources included PubMed, Web of Science, Embase, and Cochrane Library, and were constructed until October 2023. Data for each study outcome indicator were extracted for comprehensive analysis. Results The overall meta-analysis showed that mesenchymal stem cells significantly improved liver function. Moreover, it inhibited the expression level of transforming growth factor-β [SMD = 4.21, 95% CI (3.02,5.40)], which in turn silenced hepatic stellate cells and significantly reduced the area of liver fibrosis [SMD = 3.61, 95% CI (1.41,5.81)]. Conclusion Several outcome indicators suggest that mesenchymal stem cells therapy is relatively reliable in the treatment of liver fibrosis. The therapeutic effect is cell dose-dependent over a range of doses, but not more effective at higher doses. Bone-marrow derived mesenchymal stem cells were more effective in treating liver fibrosis than mesenchymal stem cells from other sources. Systematic Review Registration Identifier CRD42022354768.
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Affiliation(s)
- Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine Gannan Medical University, Ganzhou, Jiangxi, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, China
| | - Yue Wang
- College of Nursing, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine Gannan Medical University, Ganzhou, Jiangxi, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, China
| | - Jiayang Qu
- Rehabilitation Assessment and Treatment Center, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yang Zhang
- School of Rehabilitation Medicine Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou, Jiangxi, China
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Gunardi H, Alatas FS, Antarianto RD, Rahayatri TH. The Effect of Intrahepatic and Intrasplenic Administration of Mesenchymal Stem Cell to Liver Function and Degree of Liver Fibrosis in Common Bile Duct Ligation Model in Rabbit. J Pediatr Surg 2024; 59:634-639. [PMID: 38160190 DOI: 10.1016/j.jpedsurg.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 12/03/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSC) is a promising alternative method in liver cirrhosis management. Several administration routes of MSC have been studied, but few studies compared one to another. The purpose of this study is to compare the intrahepatic and intrasplenic route of MSC administration in terms of liver function and degree of liver fibrosis in the bile duct ligation model in rabbits. METHOD Experimental study was conducted using rabbits (Oryctolagus cuniculus) model undergoing bile duct ligation (BDL). The subjects were randomized into 4 groups: sham surgery; bile duct ligation; bile duct ligation followed by intrahepatic route of MSC (BDL + IH MSC), and bile duct ligation followed by intrasplenic route of MSC (BDL + IS MSC). Umbilical cord mesenchymal stem cell (UC MSC) was administered on the fifth day after bile duct ligation, and the subjects were observed until the fourteenth day after bile duct ligation. The liver function was evaluated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total and direct bilirubin. The degree of fibrosis was evaluated with Laennec score, fibrosis area fraction, the number of viable and necrosis hepatocytes, and the number of hepatic progenitor cells. RESULT The subjects were randomized into 4 groups: 2 in sham surgery group, and 7 in each of the following groups: BDL, BDL + IH MSC and BDL + IS MSC groups. The mortality rate in BDL group was 57.1 %, while mortality in BDL + IH MSC and BDL + IS MSC groups were 14.3 % and 28.6 % respectively. No significant difference was found regarding liver function in each group, such as AST, ALT, total, and direct bilirubin. Histopathology examination in almost every subject undergone bile duct ligation (regardless of MSC administration) showed degree of fibrosis of Laennec 4B. Fibrosis area fraction, the number of viable and necrotic hepatocytes, and progenitor cells were analyzed; no significant difference was found between BDL + IH MSC and BDL + IS MSC groups, but the groups administered with MSC showed a larger number of viable hepatocytes compared to BDL group. No difference was found between BDL + IH MSC and BDL + IS MSC groups in terms of liver function and histologic parameters. CONCLUSION Administration of MSC increases the number of viable hepatocytes, but no difference was found in terms of liver function and degree of liver fibrosis between the intrahepatic route and intrasplenic route of administration. TYPE OF STUDY Animal Research, Randomized Controlled Study. LEVEL OF EVIDENCE Level I? (animal research is not indicated in the levels of evidence table in the journal website).
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Affiliation(s)
- Hardian Gunardi
- Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia.
| | - Fatima Safira Alatas
- Department of Pediatric and Adolescent Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
| | | | - Tri Hening Rahayatri
- Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
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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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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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Wang J, Li Q, Li W, Méndez-Sánchez N, Liu X, Qi X. Stem Cell Therapy for Liver Diseases: Current Perspectives. FRONT BIOSCI-LANDMRK 2023; 28:359. [PMID: 38179765 DOI: 10.31083/j.fbl2812359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/03/2023] [Accepted: 10/17/2023] [Indexed: 01/06/2024]
Abstract
Stem cell therapy offers a promising avenue for advanced liver disease cases as an alternative to liver transplantation. Clinical studies are underway to explore the potential of stem cells from various sources in treating different liver diseases. However, due to the variability among current studies, further validation is needed to ensure the safety and effectiveness of stem cell therapy. To establish a strong foundation for optimal stem cell therapy applications, selection of suitable stem cell sources, standardization of transplantation protocols, and patient criteria are vital. This review comprehensively examines existing literature on stem cell sources, transplantation methods, and patient selection. Additionally, we discuss novel strategies, including stem cell preconditioning, cell-free therapy, genetic modification of stem cells, and the use of liver organoids, addressing the limitations of current stem cell therapies. Nevertheless, these innovative approaches require further validation.
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Affiliation(s)
- Jing Wang
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Qun Li
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Wenbo Li
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, 14050 Mexico City, Mexico
| | - Xiaofeng Liu
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), 110840 Shenyang, Liaoning, China
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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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Jin Y, Zhang J, Xu Y, Yi K, Li F, Zhou H, Wang H, Chan HF, Lao YH, Lv S, Tao Y, Li M. Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure. Bioact Mater 2023; 28:112-131. [PMID: 37250866 PMCID: PMC10209199 DOI: 10.1016/j.bioactmat.2023.05.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 04/07/2023] [Accepted: 05/02/2023] [Indexed: 05/31/2023] Open
Abstract
Reactive oxygen species (ROS)-associated oxidative stress, inflammation storm, and massive hepatocyte necrosis are the typical manifestations of acute liver failure (ALF), therefore specific therapeutic interventions are essential for the devastating disease. Here, we developed a platform consisting of versatile biomimetic copper oxide nanozymes (Cu NZs)-loaded PLGA nanofibers (Cu NZs@PLGA nanofibers) and decellularized extracellular matrix (dECM) hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells (hADMSCs-derived HLCs) (HLCs/Cu NZs@fiber/dECM). Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF, and reduce the massive accumulation of pro-inflammatory cytokines, herein efficiently preventing the deterioration of hepatocytes necrosis. Moreover, Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted HLCs. Meanwhile, HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF therapy. The dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of HLCs. In addition, the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host liver. Hence, HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF mice. This strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.
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Affiliation(s)
- Yuanyuan Jin
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
| | - Jiabin Zhang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
| | - Yanteng Xu
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
| | - Ke Yi
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Fenfang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Huicong Zhou
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- School of Materials Science and Engineering, Peking University, Beijing, 100871, China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Hon Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Science, The Chinese University of Hong Kong, 999077, Hong Kong, China
| | - Yeh-Hsing Lao
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA
| | - Shixian Lv
- School of Materials Science and Engineering, Peking University, Beijing, 100871, China
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
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12
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Wang Z, Yao L, Hu X, Yuan M, Chen P, Liu P, Zhang Q, Xiong Z, Dai K, Jiang Y. Advancements in mesenchymal stem cell therapy for liver cirrhosis: Unveiling origins, treatment mechanisms, and current research frontiers. Tissue Cell 2023; 84:102198. [PMID: 37604091 DOI: 10.1016/j.tice.2023.102198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/17/2023] [Accepted: 08/16/2023] [Indexed: 08/23/2023]
Abstract
Chronic liver disease inevitably progresses to liver cirrhosis, significantly compromising patients' overall survival and quality of life. However, a glimmer of hope emerges with the emergence of mesenchymal stem cells, possessing remarkable abilities for self-renewal, differentiation, and immunomodulation. Leveraging their potential, MSCs have become a focal point in both basic and clinical trials, offering a promising therapeutic avenue to impede fibrosis progression and enhance the life expectancy of individuals battling hepatic cirrhosis. This comprehensive review serves to shed light on the origin of MSCs, the intricate mechanisms underlying cirrhosis treatment, and the cutting-edge advancements in basic and clinical research surrounding MSC-based therapies for liver cirrhosis patients.
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Affiliation(s)
- Zheng Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - 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
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - Ping Chen
- 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
| | - Zhiyu Xiong
- 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
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China.
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Song Y, Lu Z, Shu W, Xiang Z, Wang Z, Wei X, Xu X. Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases. CELL INSIGHT 2023; 2:100115. [PMID: 37719773 PMCID: PMC10502372 DOI: 10.1016/j.cellin.2023.100115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 09/19/2023]
Abstract
Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.
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Affiliation(s)
- Yisu Song
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Zhengyang Lu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Zhejiang Chinese Medical University, Hangzhou, 310053, PR China
| | - Wenzhi Shu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University Shanghai, 200040, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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14
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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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15
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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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16
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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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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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18
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Sitbon A, Delmotte PR, Goumard C, Turco C, Gautheron J, Conti F, Aoudjehane L, Scatton O, Monsel A. Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review. Minerva Anestesiol 2023; 89:690-706. [PMID: 37079286 DOI: 10.23736/s0375-9393.23.17265-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Liver failure includes distinct subgroups of diseases: Acute liver failure (ALF) without preexisting cirrhosis, acute-on-chronic liver failure (ACLF) (severe form of cirrhosis associated with organ failures and excess mortality), and liver fibrosis (LF). Inflammation plays a key role in ALF, LF, and more specifically in ACLF for which we have currently no treatment other than liver transplantation (LT). The increasing incidence of marginal liver grafts and the shortage of liver grafts require us to consider strategies to increase the quantity and quality of available liver grafts. Mesenchymal stromal cells (MSCs) have shown beneficial pleiotropic properties with limited translational potential due to the pitfalls associated with their cellular nature. MSC-derived extracellular vesicles (MSC-EVs) are innovative cell-free therapeutics for immunomodulation and regenerative purposes. MSC-EVs encompass further advantages: pleiotropic effects, low immunogenicity, storage stability, good safety profile, and possibility of bioengineering. Currently, no human studies explored the impact of MSC-EVs on liver disease, but several preclinical studies highlighted their beneficial effects. In ALF and ACLF, data showed that MSC-EVs attenuate hepatic stellate cells activation, exert antioxidant, anti-inflammatory, anti-apoptosis, anti-ferroptosis properties, and promote regeneration of the liver, autophagy, and improve metabolism through mitochondrial function recovery. In LF, MSC-EVs demonstrated anti-fibrotic properties associated with liver tissue regeneration. Normothermic-machine perfusion (NMP) combined with MSC-EVs represents an attractive therapy to improve liver regeneration before LT. Our review suggests a growing interest in MSC-EVs in liver failure and gives an appealing insight into their development to rehabilitate marginal liver grafts through NMP.
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Affiliation(s)
- Alexandre Sitbon
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France -
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France -
| | - Pierre-Romain Delmotte
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Claire Goumard
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Célia Turco
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Liver Transplantation Unit, Department of Digestive and Oncologic Surgery, University Hospital of Besançon, Besançon, France
| | - Jérémie Gautheron
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
| | - Filomena Conti
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Lynda Aoudjehane
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Olivier Scatton
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- INSERM UMRS-959 Immunology-Immunopathology-Immunotherapy (I3), Sorbonne University, Paris, France
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Shibu MA, Huang CY, Ding DC. Comparison of two hepatocyte differentiation protocols in human umbilical cord mesenchymal stem cells: In vitro study. Tissue Cell 2023; 83:102153. [PMID: 37413859 DOI: 10.1016/j.tice.2023.102153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 06/28/2023] [Accepted: 06/29/2023] [Indexed: 07/08/2023]
Abstract
Human umbilical cord mesenchymal stromal cells (HUCMSCs) are an emerging source of cell therapy due to their self-renew and differentiation ability. They can differentiate into three germ layers, including the potential to generate hepatocytes. This study determined the transplantation efficiency and suitability of HUCMSCs-derived hepatocyte-like cells (HLCs) for their therapeutic application for liver diseases. This study aims to formulate ideal conditions to induce HUCMSCs into the hepatic lineage and investigate the efficiency of the differentiated HLCs based on their expression characteristics and capacity to integrate into the damaged liver of CCl4-challenged mice. Hepatocyte growth factor (HGF) and Activin A, Wnt3a were found to optimally promote the endodermal expansion of HUCMSCs, which showed phenomenal expression of hepatic markers upon differentiation in the presence of oncostatin M and dexamethasone. HUCMSCs expressed MSC-related surface markers and could undergo tri-lineage differentiations. Two hepatogenic differentiation protocols (differentiated hepatocyte protocol 1 [DHC1]: 32 days and DHC2: 15 days) were experimented with. The proliferation rate was faster in DHC2 than in DHC1 on day 7 of differentiation. The migration capability was the same in both DHC1 and DHC2. Hepatic markers like CK18, CK19, ALB, and AFP were upregulated. The mRNA levels of albumin, α1AT, αFP, CK18, TDO2, CYP3A4, CYP7A1, HNF4A, CEBPA, PPARA, and PAH were even higher in the HUCMSCs-derived HCLs than in the primary hepatocytes. Western blot confirmed HNF3B and CK18 protein expression in a step-wise manner differentiated from HUCMSCs. The metabolic function of differentiated hepatocytes was evident by increasing PAS staining and urea production. Pre-treating HUCMSCs with a hepatic differentiation medium containing HGF can drive their differentiation towards endodermal and hepatic lineages, enabling efficient integration into the damaged liver. This approach represents a potential alternative protocol for cell-based therapy that could enhance the integration potential of HUCMSC-derived HLCs.
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Affiliation(s)
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Biological Science and Technology, Asia University, Taichung 413, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University Hospital, Taichung 404, Taiwan
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan; Graduate Institute of Medical Science, Tzu Chi University, Hualien 970, Taiwan.
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Colli A, Fraquelli M, Prati D, Casazza G. Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease. Cochrane Database Syst Rev 2023; 6:CD013532. [PMID: 37278488 PMCID: PMC10243114 DOI: 10.1002/14651858.cd013532.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
BACKGROUND Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival. OBJECTIVES To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type. SELECTION CRITERIA We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language. DATA COLLECTION AND ANALYSIS We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I2 statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses. MAIN RESULTS We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, β-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I2 = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I2 = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I2 = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence). AUTHORS' CONCLUSIONS G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Prati
- Department of Transfusion Medicine and Haematology, Ospedale Alessandro Manzoni, Lecco, Italy
| | - Giovanni Casazza
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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21
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Sani F, Sani M, Moayedfard Z, Darayee M, Tayebi L, Azarpira N. Potential advantages of genetically modified mesenchymal stem cells in the treatment of acute and chronic liver diseases. Stem Cell Res Ther 2023; 14:138. [PMID: 37226279 DOI: 10.1186/s13287-023-03364-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 05/04/2023] [Indexed: 05/26/2023] Open
Abstract
Liver damage caused by toxicity can lead to various severe conditions, such as acute liver failure (ALF), fibrogenesis, and cirrhosis. Among these, liver cirrhosis (LC) is recognized as the leading cause of liver-related deaths globally. Unfortunately, patients with progressive cirrhosis are often on a waiting list, with limited donor organs, postoperative complications, immune system side effects, and high financial costs being some of the factors restricting transplantation. Although the liver has some capacity for self-renewal due to the presence of stem cells, it is usually insufficient to prevent the progression of LC and ALF. One potential therapeutic approach to improving liver function is the transplantation of gene-engineered stem cells. Several types of mesenchymal stem cells from various sources have been suggested for stem cell therapy for liver disease. Genetic engineering is an effective strategy that enhances the regenerative potential of stem cells by releasing growth factors and cytokines. In this review, we primarily focus on the genetic engineering of stem cells to improve their ability to treat damaged liver function. We also recommend further research into accurate treatment methods that involve safe gene modification and long-term follow-up of patients to increase the effectiveness and reliability of these therapeutic strategies.
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Affiliation(s)
- Farnaz Sani
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahsa Sani
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Moayedfard
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Darayee
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI, 53233, USA
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, P.O. Box: 7193711351, Shiraz, Iran.
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22
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The Efficiency of Stem Cells (SCs) Differentiation into Functional Hepatocytes for Treating Liver Disorders: A Systematic Review. BIOMED RESEARCH INTERNATIONAL 2023; 2023:4868048. [PMID: 36685673 PMCID: PMC9851781 DOI: 10.1155/2023/4868048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 11/29/2022] [Accepted: 12/14/2022] [Indexed: 01/15/2023]
Abstract
Stem cells provided new opportunity to treat various diseases, including liver disorders. Stem cells are unspecialized cells, stimulating influential research interest be indebted to their multipotent self-renewal capacity and differentiation characteristics into several specialized cell types. Many factors contribute to their differentiation into different cell types such as insulin producing cells, osteoblast, and hepatocytes. Accordingly, wide range methods and materials have been used to transform stem cells into hepatocytes, but effectiveness of differentiation is different and depends on several factors such as cell-to-cell adhesion, cell-to-cell contact, and cell biological change. Search was done in PubMed, Scopus, and WOS to evaluate results of studies about stem cells differentiation for higher efficacy. Among more than 28000 papers, 51 studies were considered eligible for more evaluations. Results indicated that most studies were performed on mesenchymal stem cells compared with other types. Acute liver failure was the most investigated liver disorder, and tissue engineering was the most investigated differentiation methods. Also, functional parameters were the most evaluated parameters in assessing differentiation efficacy. We summarize recent advances in increasing efficiency of stem cells differentiation using varied materials, since promising results of this review, further studies are needed to assess efficiency and safety of these cells transplantation in some liver disease treatment.
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23
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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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24
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Li TT, Wang ZR, Yao WQ, Linghu EQ, Wang FS, Shi L. Stem Cell Therapies for Chronic Liver Diseases: Progress and Challenges. Stem Cells Transl Med 2022; 11:900-911. [PMID: 35993521 PMCID: PMC9492280 DOI: 10.1093/stcltm/szac053] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic liver diseases have become a significant health issue worldwide and urgently require the development of novel therapeutic approaches, in addition to liver transplantation. Recent clinical and preclinical studies have shown that cell-based therapeutic strategies may contribute to the improvement of chronic liver diseases and offer new therapeutic options to restore liver function through their roles in tissue impairment and immunomodulation. In this review, we summarize the current progress and analyze the challenges for different types of cell therapies used in the treatment of chronic liver diseases currently explored in clinical trials and preclinical studies in animal models. We also discuss some critical issues regarding the use of mesenchymal stem cells (MSCs, the most extensive cell source of stem cells), including therapeutic dosage, transfusion routine, and pharmacokinetics/pharmacodynamics (PK/PD) of transfused MSCs.
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Affiliation(s)
- Tian-Tian Li
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People’s Republic of China
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China
| | - Ze-Rui Wang
- Department of Gastroenterology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Wei-Qi Yao
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- National Industrial Base for Stem Cell Engineering Products, Tianjin, People’s Republic of China
| | - En-Qiang Linghu
- Department of Gastroenterology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Fu-Sheng Wang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People’s Republic of China
| | - Lei Shi
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People’s Republic of China
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25
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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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26
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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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27
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Fagoonee S, Shukla SP, Dhasmana A, Birbrair A, Haque S, Pellicano R. Routes of Stem Cell Administration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:63-82. [PMID: 35389198 DOI: 10.1007/5584_2022_710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Stem cells are very promising for the treatment of a plethora of human diseases. Numerous clinical studies have been conducted to assess the safety and efficacy of various stem cell types. Factors that ensure successful therapeutic outcomes in patients are cell-based parameters such as source, viability, and number, as well as frequency and timing of intervention and disease stage. Stem cell administration routes should be appropriately chosen as these can affect homing and engraftment of the cells and hence reduce therapeutic effects, or compromise safety, resulting in serious adverse events. In this chapter, we will describe the use of stem cells in organ repair and regeneration, in particular, the liver and the available routes of cell delivery in the clinic for end-stage liver diseases. Factors affecting homing and engraftment of stem cells for each administration route will be discussed.
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Affiliation(s)
- Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council (CNR), Molecular Biotechnology Center, Turin, Italy.
| | - Shiv Poojan Shukla
- Department of Dermatology & Cutaneous Biology, Sydney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA
- Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Bursa Uludağ University Faculty of Medicine, Nilüfer, Bursa, Turkey
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Hazrati A, Malekpour K, Soudi S, Hashemi SM. Mesenchymal Stromal/Stem Cells and Their Extracellular Vesicles Application in Acute and Chronic Inflammatory Liver Diseases: Emphasizing on the Anti-Fibrotic and Immunomodulatory Mechanisms. Front Immunol 2022; 13:865888. [PMID: 35464407 PMCID: PMC9021384 DOI: 10.3389/fimmu.2022.865888] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
Abstract
Various factors, including viral and bacterial infections, autoimmune responses, diabetes, drugs, alcohol abuse, and fat deposition, can damage liver tissue and impair its function. These factors affect the liver tissue and lead to acute and chronic liver damage, and if left untreated, can eventually lead to cirrhosis, fibrosis, and liver carcinoma. The main treatment for these disorders is liver transplantation. Still, given the few tissue donors, problems with tissue rejection, immunosuppression caused by medications taken while receiving tissue, and the high cost of transplantation, liver transplantation have been limited. Therefore, finding alternative treatments that do not have the mentioned problems is significant. Cell therapy is one of the treatments that has received a lot of attention today. Hepatocytes and mesenchymal stromal/stem cells (MSCs) are used in many patients to treat liver-related diseases. In the meantime, the use of mesenchymal stem cells has been studied more than other cells due to their favourable characteristics and has reduced the need for liver transplantation. These cells increase the regeneration and repair of liver tissue through various mechanisms, including migration to the site of liver injury, differentiation into liver cells, production of extracellular vesicles (EVs), secretion of various growth factors, and regulation of the immune system. Notably, cell therapy is not entirely excellent and has problems such as cell rejection, undesirable differentiation, accumulation in unwanted locations, and potential tumorigenesis. Therefore, the application of MSCs derived EVs, including exosomes, can help treat liver disease and prevent its progression. Exosomes can prevent apoptosis and induce proliferation by transferring different cargos to the target cell. In addition, these vesicles have been shown to transport hepatocyte growth factor (HGF) and can promote the hepatocytes'(one of the most important cells in the liver parenchyma) growths.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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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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30
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Xie Y, Yao J, Jin W, Ren L, Li X. Induction and Maturation of Hepatocyte-Like Cells In Vitro: Focus on Technological Advances and Challenges. Front Cell Dev Biol 2021; 9:765980. [PMID: 34901010 PMCID: PMC8662991 DOI: 10.3389/fcell.2021.765980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 11/08/2021] [Indexed: 12/17/2022] Open
Abstract
Limited by the poor proliferation and restricted sources of adult hepatocytes, there is an urgent need to find substitutes for proliferation and cultivation of mature hepatocytes in vitro for use in disease treatment, drug approval, and toxicity testing. Hepatocyte-like cells (HLCs), which originate from undifferentiated stem cells or modified adult cells, are considered good candidates because of their advantages in terms of cell source and in vitro expansion ability. However, the majority of induced HLCs are in an immature state, and their degree of differentiation is heterogeneous, diminishing their usability in basic research and limiting their clinical application. Therefore, various methods have been developed to promote the maturation of HLCs, including chemical approaches, alteration of cell culture systems, and genetic manipulation, to meet the needs of in vivo transplantation and in vitro model establishment. This review proposes different cell types for the induction of HLCs, and provide a comprehensive overview of various techniques to promote the generation and maturation of HLCs in vitro.
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Affiliation(s)
- Ye Xie
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Jia Yao
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Weilin Jin
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Institute of Cancer Neuroscience, The First Hospital of Lanzhou University, Lanzhou, China.,The Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou, China
| | - Longfei Ren
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xun Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.,The Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou, China.,The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China.,Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, China
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31
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Nazarie (Ignat) SR, Gharbia S, Hermenean A, Dinescu S, Costache M. Regenerative Potential of Mesenchymal Stem Cells' (MSCs) Secretome for Liver Fibrosis Therapies. Int J Mol Sci 2021; 22:ijms222413292. [PMID: 34948088 PMCID: PMC8705326 DOI: 10.3390/ijms222413292] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic liver injuries lead to liver fibrosis and then to end-stage liver cirrhosis. Liver transplantation is often needed as a course of treatment for patients in critical conditions, but limitations associated with transplantation prompted the continuous search for alternative therapeutic strategies. Cell therapy with stem cells has emerged as an attractive option in order to stimulate tissue regeneration and liver repair. Transplanted mesenchymal stem cells (MSCs) could trans-differentiate into hepatocyte-like cells and, moreover, show anti-fibrotic and immunomodulatory effects. However, cell transplantation may lead to some uncontrolled side effects, risks associated with tumorigenesis, and cell rejection. MSCs' secretome includes a large number of soluble factors and extracellular vesicles (EVs), through which they exert their therapeutic role. This could represent a cell-free strategy, which is safer and more effective than MSC transplantation. In this review, we focus on cell therapies based on MSCs and how the MSCs' secretome impacts the mechanisms associated with liver diseases. Moreover, we discuss the important therapeutic role of EVs and how their properties could be further used in liver regeneration.
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Affiliation(s)
- Simona-Rebeca Nazarie (Ignat)
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
| | - Sami Gharbia
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldiș” Western University of Arad, 310025 Arad, Romania
| | - Anca Hermenean
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldiș” Western University of Arad, 310025 Arad, Romania
| | - Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- The Research Institute of the University of Bucharest (ICUB), University of Bucharest, 050663 Bucharest, Romania
- Correspondence:
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- The Research Institute of the University of Bucharest (ICUB), University of Bucharest, 050663 Bucharest, Romania
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Role of the Microenvironment in Mesenchymal Stem Cell-Based Strategies for Treating Human Liver Diseases. Stem Cells Int 2021; 2021:5513309. [PMID: 34824587 PMCID: PMC8610645 DOI: 10.1155/2021/5513309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/23/2021] [Accepted: 10/30/2021] [Indexed: 11/17/2022] Open
Abstract
Liver disease is a severe health problem that endangers human health worldwide. Mesenchymal stem cell (MSC) therapy is a novel treatment for patients with different liver diseases due to its vast expansion potential and distinctive immunomodulatory properties. Despite several preclinical trials having confirmed the considerable efficacy of MSC therapy in liver diseases, the questionable safety and efficacy still limit its application. As a precursor cell, MSCs can adjust their characteristics in response to the surrounding microenvironment. The microenvironment provides physical and chemical factors essential for stem cell survival, proliferation, and differentiation. However, the mechanisms are still not completely understood. We, therefore, summarized the mechanisms underlying the MSC immune response, especially the interaction between MSCs and the liver microenvironment, discussing how to achieve better therapeutic effects.
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Lee C, Kim M, Han J, Yoon M, Jung Y. Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis. Biomedicines 2021; 9:1598. [PMID: 34829827 PMCID: PMC8615475 DOI: 10.3390/biomedicines9111598] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis.
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Affiliation(s)
- Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Minju Kim
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Jinsol Han
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Myunghee Yoon
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Biomedical Research Institute, Pusan National University, Pusan 46241, Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
- Departments of Biological Sciences, Pusan National University, Pusan 46241, Korea
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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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Saito Y, Ikemoto T, Tokuda K, Miyazaki K, Yamada S, Imura S, Miyake M, Morine Y, Oyadomari S, Shimada M. Effective three-dimensional culture of hepatocyte-like cells generated from human adipose-derived mesenchymal stem cells. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:705-715. [PMID: 34318615 DOI: 10.1002/jhbp.1024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/27/2021] [Accepted: 07/08/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND The aim of this study was to clarify the effectiveness of a new three-dimensional (3D) culture system for hepatocyte-like cells (HLCs) generated from human adipose-derived mesenchymal stem cells (ADSCs). METHODS Human ADSCs (2 × 104 ) with or without 0.1 mg/mL human recombinant peptide μ-piece per well were seeded in a 96-well U-bottom plate and then our three-step differentiation protocol was applied for 21 days. At each step, cell morphology and gene expression were investigated. Mature hepatocyte functions were evaluated after HLC differentiation. These parameters were compared between 2D- and 3D-cultured HLCs, and, DNA microarray analysis was also performed. Finally, HLCs were transplanted in to CCl4 induced acute liver failure model mice. RESULTS Two-dimensional-cultured HLCs at day 21 did not have a spindle shape and had formed spheroids after day 6, which gradually increased in size for 3D-cultured HLCs. Definitive endoderm, hepatoblast, and hepatocyte genes showed significantly higher expression in the 3D culture group. Three-dimensional-cultured HLCs also had higher albumin expression, CYP3A4 activity, urea synthesis, and ammonium metabolism, and much higher expression of ion transporter, blood coagulation, and cell communication genes. HLC transplantation improved serum liver function, especially in T-Bil levels, and engrafted into immunodeficient mice with HLA class I positive staining. CONCLUSION Our new 3D culture protocol is effective to improve hepatocyte functions. Our HLCs might be promising for clinical cell transplantation to treat metabolic disease.
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Affiliation(s)
- Yu Saito
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Kazunori Tokuda
- Department of Surgery, Tokushima University, Tokushima, Japan
| | | | | | - Satoru Imura
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Masato Miyake
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Seiichi Oyadomari
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
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Zhang L, Pu K, Liu X, Bae SDW, Nguyen R, Bai S, Li Y, Qiao L. The Application of Induced Pluripotent Stem Cells Against Liver Diseases: An Update and a Review. Front Med (Lausanne) 2021; 8:644594. [PMID: 34277651 PMCID: PMC8280311 DOI: 10.3389/fmed.2021.644594] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 06/04/2021] [Indexed: 11/13/2022] Open
Abstract
Liver diseases are a major health concern globally, and are associated with poor survival and prognosis of patients. This creates the need for patients to accept the main alternative treatment of liver transplantation to prevent progression to end-stage liver disease. Investigation of the molecular mechanisms underpinning complex liver diseases and their pathology is an emerging goal of stem cell scope. Human induced pluripotent stem cells (hiPSCs) derived from somatic cells are a promising alternative approach to the treatment of liver disease, and a prospective model for studying complex liver diseases. Here, we review hiPSC technology of cell reprogramming and differentiation, and discuss the potential application of hiPSC-derived liver cells, such as hepatocytes and cholangiocytes, in refractory liver-disease modeling and treatment, and drug screening and toxicity testing. We also consider hiPSC safety in clinical applications, based on genomic and epigenetic alterations, tumorigenicity, and immunogenicity.
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Affiliation(s)
- Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, Lanzhou, China
| | - Ke Pu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Xiaojun Liu
- Department of Medical Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Sarah Da Won Bae
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Clinical School, Westmead, NSW, Australia
| | - Romario Nguyen
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Clinical School, Westmead, NSW, Australia
| | - Suyang Bai
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Yi Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Clinical School, Westmead, NSW, Australia
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Abstract
PURPOSE OF REVIEW Liver transplantation is the gold standard for the treatment of end-stage liver disease. However, a shortage of donor organs, high cost, and surgical complications limit the use of this treatment. Cellular therapies using hepatocytes, hematopoietic stem cells, bone marrow mononuclear cells, and mesenchymal stem cells (MSCs) are being investigated as alternative treatments to liver transplantation. The purpose of this review is to describe studies using MSC transplantation for liver diseases based on the reported literature and to discuss prospective research designed to improve the efficacy of MSC therapy. RECENT FINDINGS MSCs have several properties that show potential to regenerate injured tissues or organs, such as homing, transdifferentiation, immunosuppression, and cellular protective capacity. Additionally, MSCs can be noninvasively isolated from various tissues and expanded ex vivo in sufficient numbers for clinical evaluation. SUMMARY Currently, there is no approved MSC therapy for the treatment of liver disease. However, MSC therapy is considered a promising alternative treatment for end-stage liver diseases and is reported to improve liver function safely with no side effects. Further robust preclinical and clinical studies will be needed to improve the therapeutic efficacy of MSC transplantation.
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Kang SH, Kim MY, Eom YW, Baik SK. Mesenchymal Stem Cells for the Treatment of Liver Disease: Present and Perspectives. Gut Liver 2021; 14:306-315. [PMID: 31581387 PMCID: PMC7234888 DOI: 10.5009/gnl18412] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/14/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cell transplantation is an emerging therapy for treating chronic liver diseases. The potential of this treatment has been evaluated in preclinical and clinical studies. Although the mechanisms of mesenchymal stem cell transplantation are still not completely understood, accumulating evidence has revealed that their immunomodulation, differentiation, and antifibrotic properties play a crucial role in liver regeneration. The safety and therapeutic effects of mesenchymal stem cells in patients with chronic liver disease have been observed in many clinical studies. However, only modest improvements have been seen, partly because of the limited feasibility of transplanted cells at present. Here, we discuss several strategies targeted at improving viable cell engraftment and the potential challenges in the use of extracellular vesicle-based therapies for liver disease in the future.
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Affiliation(s)
- Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Young Woo Eom
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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Al-Dhamin Z, Liu LD, Li DD, Zhang SY, Dong SM, Nan YM. Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies. World J Gastroenterol 2020; 26:7444-7469. [PMID: 33384547 PMCID: PMC7754546 DOI: 10.3748/wjg.v26.i47.7444] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/31/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.
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Affiliation(s)
- Zaid Al-Dhamin
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Ling-Di Liu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Dong-Dong Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Si-Yu Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Shi-Ming Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
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Yang X, Meng Y, Han Z, Ye F, Wei L, Zong C. Mesenchymal stem cell therapy for liver disease: full of chances and challenges. Cell Biosci 2020; 10:123. [PMID: 33117520 PMCID: PMC7590738 DOI: 10.1186/s13578-020-00480-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
Liver disease is a major health problem that endangers human health worldwide. Currently, whole organ allograft transplantation is the gold standard for the treatment of end-stage liver disease. A shortage of suitable organs, high costs and surgical complications limit the application of liver transplantation. Mesenchymal stem cell therapy has been considered as a promising alternative approach for end-stage liver disease. Some clinical trials have confirmed the effectiveness of MSC therapy for liver disease, but its application has not been promoted and approved. There are still many issues that should be solved prior to using MSC therapy in clinical applications. The types of liver disease that are most suitable for MSC application should be determined, and the preparation and engraftment of MSCs should be standardized. These may be bottlenecks that limit the use of MSCs. We investigated 22 completed and several ongoing clinical trials to discuss these questions from a clinical perspective. We also discussed the important mechanisms by which MSCs play a therapeutic role in liver disease. Finally, we also proposed novel prospective approaches that can improve the therapeutic effect of MSCs.
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Affiliation(s)
- Xue Yang
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
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Zhou GP, Jiang YZ, Sun LY, Zhu ZJ. Therapeutic effect and safety of stem cell therapy for chronic liver disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res Ther 2020; 11:419. [PMID: 32977828 PMCID: PMC7519526 DOI: 10.1186/s13287-020-01935-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/10/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Background Stem cell therapy is becoming an emerging therapeutic option for chronic liver disease (CLD). However, whether stem cell therapy is more effective than conventional treatment remains questionable. We performed a large-scale meta-analysis of randomized controlled trials (RCTs) to evaluate the therapeutic effects and safety of stem cell therapy for CLD. Methods We systematically searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases for the period from inception through March 16, 2020. Primary outcomes were all-cause mortality and adverse events related to stem cell therapy. Secondary outcomes included the model for end-stage liver disease score, total bilirubin, albumin, alanine aminotransferase, prothrombin activity, and international normalized ratio. The standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a random-effects model. Results Twenty-four RCTs were included and the majority of these studies showed a high risk of bias. The meta-analysis indicated that compared with conventional treatment, stem cell therapy was associated with improved survival and liver function including the model of end-stage liver disease score, total bilirubin, and albumin levels. However, it had no obvious beneficial effects on alanine aminotransferase level, prothrombin activity, and international normalized ratio. Subgroup analyses showed stem cell therapy conferred a short-term survival benefit for patients with acute-on-chronic liver failure (ACLF), a single injection was more effective than multiple injections, hepatic arterial infusion was more effective than intravenous infusion, and bone marrow-derived stem cells were more effective than those derived from the umbilical cord. Thirteen trials reported adverse events related to stem cell therapy, but no serious adverse events were reported. Conclusions Stem cell therapy is a safe and effective therapeutic option for CLD, while patients with ACLF benefit the most in terms of improved short-term survival. A single injection administration of bone marrow-derived stem cells via the hepatic artery has superior therapeutic effects.
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Affiliation(s)
- Guang-Peng Zhou
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
| | - Yi-Zhou Jiang
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
| | - Li-Ying Sun
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Zhi-Jun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China. .,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.
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Mazhari S, Gitiara A, Baghaei K, Hatami B, Rad RE, Asadirad A, Joharchi K, Tokhanbigli S, Hashemi SM, Łos MJ, Aghdaei HA, Zali MR, Ghavami S. Therapeutic potential of bone marrow-derived mesenchymal stem cells and imatinib in a rat model of liver fibrosis. Eur J Pharmacol 2020; 882:173263. [PMID: 32535098 DOI: 10.1016/j.ejphar.2020.173263] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/03/2020] [Accepted: 06/08/2020] [Indexed: 12/13/2022]
Abstract
Considering the global increase in the prevalence of hepatic fibrosis and ineffective disease treatment, novel therapies are urgently needed. The current study is focused on comparing the therapeutic effects of mesenchymal stem cells (MSC)/imatinib combination therapy to single (MSCs or imatinib) therapy, in a rat model of carbon tetrachloride (CCL4)-induced liver fibrosis. Using rats, hepatic fibrosis was induced by injection of CCL4. Rats were divided into 5 groups: CCL4-induced hepatic fibrosis, phosphate buffered saline (PBS) treatment (vehicle control), Bone marrow-MSCs (BM_MSCs), imatinib, and bone marrow-MSCs/imatinib co-treatment. The therapeutic impact of these approaches was determined using histopathology, sirius-red staining, serum markers, and qRT-PCR for over expression of matrix components. IHC and Western blot were conducted for further confirmation of the results. Single treatment with MSCs or imatinib and the combination therapy, all significantly reduced serum levels of ALT, AST, and ALP concomitant with down-regulation of α-SMA, pro-collagen I, pro-collagen III, collagen IV, and laminin. A significant reduction of ECM components deposits and a decrease in α-SMA expression were detected in all treatment groups. Pathological observations demonstrated that 20% and 40% of the rats in the MSC and MSC/imatinib group were in grade F0 respectively, while 80% of the rats of the imatinib group were in grade 2. Even though all treatment strategies studied resulted in an equally potent reduction in the mRNA and protein expression levels of pro-fibrotic markers, in aspect of pathological observations, our results demonstrate the highest therapeutic potential of utilizing combination of BM-MSCs and imatinib.
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Affiliation(s)
- Sogol Mazhari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atoosa Gitiara
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rozbeh Eslami Rad
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Asadirad
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Khojasteh Joharchi
- Department of Pharmacology, School of Medicine and Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marek J Łos
- Department of Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, ON, Canada; Faculty of Medicine, University of Technology in Katowice, Katowice, Poland.
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43
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Saito Y, Ikemoto T, Morine Y, Shimada M. Current status of hepatocyte-like cell therapy from stem cells. Surg Today 2020; 51:340-349. [PMID: 32754843 DOI: 10.1007/s00595-020-02092-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/14/2020] [Indexed: 12/17/2022]
Abstract
Organ liver transplantation and hepatocyte transplantation are not performed to their full potential because of donor shortage, which could be resolved by identifying new donor sources for the development of hepatocyte-like cells (HLCs). HLCs have been differentiated from some stem cell sources as alternative primary hepatocytes throughout the world; however, the currently available techniques cannot differentiate HLCs to the level of normal adult primary hepatocytes. The outstanding questions are as follows: which stem cells are the best cell sources? which protocol is the best way to differentiate them into HLCs? what is the definition of differentiated HLCs? how can we enforce the function of HLCs? what is the difference between HLCs and primary hepatocytes? what are the problems with HLC transplantation? This review summarizes the current status of HLCs, focusing on stem cell sources, the differentiation protocol for HLCs, the general characterization of HLCs, the generation of more functional HLCs, comparison with primary hepatocytes, and HLCs in cell-transplantation-based liver regeneration.
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Affiliation(s)
- Yu Saito
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
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Eom YW, Kang SH, Kim MY, Lee JI, Baik SK. Mesenchymal stem cells to treat liver diseases. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:563. [PMID: 32775364 PMCID: PMC7347787 DOI: 10.21037/atm.2020.02.163] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are being developed for stem cell therapy and can be efficiently used in regenerative medicine. To date, more than 1,000 clinical trials have used MSCs; of these, more than 80 clinical trials have targeted liver disease. MSCs migrate to damaged liver tissues, differentiate into hepatocytes, reduce liver inflammatory responses, reduce liver fibrosis, and act as antioxidants. According to the reported literature, MSCs are safe, have no side effects, and improve liver function; however, their regenerative therapeutic effects are unsatisfactory. Here, we explain, in detail, the basic therapeutic effects and recent clinical advances of MSCs. Furthermore, we discuss future research directions for improving the regenerative therapeutic effects of MSCs.
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Affiliation(s)
- Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seong Hee Kang
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jong In Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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45
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Lee JY, Hong SH. Hematopoietic Stem Cells and Their Roles in Tissue Regeneration. Int J Stem Cells 2020; 13:1-12. [PMID: 31887851 PMCID: PMC7119209 DOI: 10.15283/ijsc19127] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 11/18/2019] [Accepted: 12/01/2019] [Indexed: 12/22/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are regarded as one of essential cell sources for treating regenerative diseases. Among many stem cells, the feasibility of using adult-derived hematopoietic stem cells in therapeutic approaches is very diverse, and is unarguably regarded as an important cell source in stem cell biology. So far, many investigators are exploring HSCs and modified HSCs for use in clinical and basic science. In the present review, we briefly summarized HSCs and their application in pathophysiologic conditions, including non-hematopoietic tissue regeneration as well as blood disorders. HSCs and HSCs-derived progenitors are promising cell sources in regenerative medicine and their contributions can be properly applied to treat pathophysiologic conditions. Among many adult stem cells, HSCs are a powerful tool to treat patients with diseases such as hematologic malignancies and liver disease. Since HSCs can be differentiated into diverse progenitors including endothelial progenitors, they may be useful for constructing strategies for effective therapy.
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Affiliation(s)
- Ji Yoon Lee
- CHA Advanced Research Institute, CHA University, Seongnam, Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea
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Paik KY, Kim KH, Park JH, Lee JI, Kim OH, Hong HE, Seo H, Choi HJ, Ahn J, Lee TY, Kim SJ. A novel antifibrotic strategy utilizing conditioned media obtained from miR-150-transfected adipose-derived stem cells: validation of an animal model of liver fibrosis. Exp Mol Med 2020; 52:438-449. [PMID: 32152450 PMCID: PMC7156430 DOI: 10.1038/s12276-020-0393-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 12/13/2019] [Accepted: 01/29/2020] [Indexed: 12/14/2022] Open
Abstract
The limitations of stem cells have led researchers to investigate the secretome, which is the secretory materials in stem cells, since the principal mechanism of action of stem cells is mediated by the secretome. In this study, we determined the antifibrotic potential of the secretome released from miR-150-transfected adipose-derived stromal cells (ASCs). The secretome released from ASCs that were transfected with antifibrotic miR-150 was obtained (referred to as the miR-150 secretome). To validate the antifibrotic effects of the miR-150 secretome, we generated in vitro and in vivo models of liver fibrosis by treating human hepatic stellate cells (LX2 cells) with thioacetamide (TAA) and subcutaneous injection of TAA into mice, respectively. In the in vitro model, more significant reductions in the expression of fibrosis-related markers, such as TGFβ, Col1A1, and α-SMA, were observed by using the miR-150 secretome than the control secretome, specifically in TAA-treated LX2 cells. In the in vivo model, infusion of the miR-150 secretome into mice with liver fibrosis abrogated the increase in serum levels of systemic inflammatory cytokines, such as IL-6 and TNF-α, and induced increased expression of antifibrotic, proliferation, and antioxidant activity markers in the liver. Our in vitro and in vivo experiments indicate that the miR-150 secretome is superior to the naive secretome in terms of ameliorating liver fibrosis, minimizing systemic inflammatory responses, and promoting antioxidant enzyme expression. Therefore, we conclude that miR-150 transfection into ASCs has the potential to induce the release of secretory materials with enhanced antifibrotic, proliferative, and antioxidant properties. A mixture of molecules produced by genetically modified stem cells could help repair the damage associated with liver fibrosis. Fat-derived adipose stem cells (ASCs) secrete proteins and nucleic acids that can facilitate tissue regeneration, but the natural mixture of molecules secreted (the ‘secretome’) is insufficient to reverse advanced fibrosis. Researchers led by Say-June Kim of the Catholic University of Korea, Seoul, South Korea, have boosted the potency of this cell-derived treatment by engineering ASCs to produce an RNA called miR-150. This RNA inhibits biological processes that drive fibrosis. Experiments in cultured cells and a mouse model of fibrosis confirmed that miR-150 consistently improved the ASC secretome’s capacity to control liver fibrosis and minimize systemic inflammatory responses. This approach could thus offer a safe strategy for promoting tissue regeneration and preventing liver failure.
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Affiliation(s)
- Kwang Yeol Paik
- Department of Surgery, Yeouido St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Kee-Hwan Kim
- Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Hyun Park
- Department of Surgery, Eunpeong St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Im Lee
- Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Ok-Hee Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Ha-Eun Hong
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Haeyeon Seo
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Joseph Ahn
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Tae Yun Lee
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Say-June Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea. .,Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.
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47
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Stem and Progenitor Cells in the Pathogenesis and Treatment of Digestive Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:125-157. [PMID: 31898785 DOI: 10.1007/978-3-030-31206-0_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The global epidemic of chronic degenerative diseases expands rapidly. The pathogenesis of these noncommunicable disorders revolves around innate immunity, microbiome, and stem cell alterations. Understanding the mechanisms behind stem cell biology and their regulatory pathways is a key to understanding the origin of human disease. Stem cells are involved in tissue and organ damage and regeneration. The evidence is mounting that not only eukaryotic cells but also gut microbiota may release extracellular microvesicles that are absorbed from the gut into the portal and systemic circulation. Linking the fields of stem cells, innate immunity and microbiome research opens up new avenues to develop novel diagnostic (e.g., biomarkers), therapeutic (e.g., microbiome modulation, stem cell-based medicines), and prognostic (personalized diets) tools. In this chapter, we present the short overview of various stem and progenitor cells of adult tissues circulating in peripheral blood and their role in the pathogenesis and treatment of digestive diseases. We also briefly discuss the role of host-stem cell-microbial interactions as a new frontier of research in gastroenterology.
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Shi D, Xin J, Lu Y, Ding W, Jiang J, Zhou Q, Sun S, Guo B, Zhou X, Li J. Transcriptome Profiling Reveals Distinct Phenotype of Human Bone Marrow Mesenchymal Stem Cell-derived Hepatocyte-like cells. Int J Med Sci 2020; 17:263-273. [PMID: 32038110 PMCID: PMC6990879 DOI: 10.7150/ijms.36255] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 12/12/2019] [Indexed: 12/30/2022] Open
Abstract
Background: Human bone marrow mesenchymal stem cell-derived hepatocyte-like cells (hBMSC-HLCs) are a promising alternative for primary human hepatocytes (HHs) for treating liver disease. However, the molecular characteristics of HLCs remain unclear. Here, we aimed to clarify the transcriptome characteristics of hBMSC-HLCs for future clinical application. Materials and Methods: hBMSCs were isolated from the bone marrow of healthy volunteers and differentiated into hepatocytes. mRNA sequencing was used in the transcriptome profiling of hBMSC-HLCs, with hBMSCs and HHs as controls. Results: hBMSC-HLCs exhibited a polygonal morphology, glycogen accumulation and albumin expression. A total of 630 upregulated and 1082 downregulated genes were observed in hBMSC-HLCs and HHs compared with undifferentiated hBMSCs. The upregulated genes were mainly involved in hepatic metabolism and inflammatory and immune responses. The downregulated genes were mainly associated with stem cell characteristics (multipotent differentiation, cell cycle regulation, etc.). Confirmatory qRT-PCR of 9 upregulated and 9 downregulated genes with log2 fold changes > 5 showed similar results. In vivo transdifferentiation of hBMSCs in pigs with fulminant hepatic failure confirmed the similarly upregulated expression of 5 hepatogenic genes (TDO2, HP, SERPINA3, LBP and SAA1), showing a 150-fold change in liver tissues at 7 days after hBMSC transplantation. These 5 genes mainly contributed to liver metabolism and inflammation. Conclusion: hBMSC-HLCs possess a hepatic transcriptome profile and express hepatic-specific genes in vitro and in vivo, which might be useful for future clinical applications. The five upregulated genes identified herein could be potential biomarkers for the characterization of hBMSC-HLCs.
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Affiliation(s)
- Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Yingyan Lu
- Clinical Medical Laboratory, Tongde Hospital of Zhejiang Province. 234 Gucui Rd., Hangzhou, 310012. China
| | - Wenchao Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Qian Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Suwan Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Beibei Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Xingping Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine. 79 Qingchun Rd., Hangzhou, 310003. China.,Taizhou Central Hospital, Taizhou University Hospital. 999 Donghai Rd., Taizhou, 318000. China
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Kuse Y, Taniguchi H. Present and Future Perspectives of Using Human-Induced Pluripotent Stem Cells and Organoid Against Liver Failure. Cell Transplant 2019; 28:160S-165S. [PMID: 31838891 PMCID: PMC7016460 DOI: 10.1177/0963689719888459] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Organ failure manifests severe symptoms affecting the whole body that may cause death. However, the number of organ donors is not enough for patients requiring transplantation worldwide. Illegal transplantation is also sometimes conducted. To help address this concern, primary hepatocytes are clinically transplanted in the liver. However, donor shortage and host rejection via instant blood-mediated inflammatory reactions are worrisome. Induced pluripotent stem cell-derived hepatocyte-like cells have been developed as an alternative treatment. Recently, organoid technology has been developed to investigate the pathology and mechanism of organoids in cultures. Organoids can be transplanted with vascularization and connected to host blood vessels, and functionally mature better in vivo than in vitro. Hepatic organoids improve pathology in liver disease models. In this review, we introduce induced pluripotent stem cell- and organoid-based therapies against liver diseases considering present and future perspectives.
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Affiliation(s)
- Yoshiki Kuse
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Japan.,Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Japan
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50
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Exploring the Most Promising Stem Cell Therapy in Liver Failure: A Systematic Review. Stem Cells Int 2019; 2019:2782548. [PMID: 31871465 PMCID: PMC6913162 DOI: 10.1155/2019/2782548] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/09/2019] [Accepted: 09/17/2019] [Indexed: 12/16/2022] Open
Abstract
Background Alternative approaches to transplantation for liver failure are needed. One of the alternative approaches is stem cell therapy. However, stem cell therapy in liver failure is not standardized yet, as every centre have their own methods. This systematic review is aimed at compiling and analyzing the various studies that use stem cells to treat liver failure, to get an insight into potential protocols in terms of safety and efficacy by comparing them to controls. Methods This systematic review was done according to PRISMA guidelines and submitted for registration in PROSPERO (registration number CRD42018106119). All published studies in PubMed/MEDLINE and Cochrane Library, using key words: “human” and “stem cell” AND “liver failure” on 16th June 2018, without time restriction. In addition, relevant articles that are found during full-text search were added. Inclusion criteria included all original articles on stem cell use in humans with liver failure. Data collected included study type, treatment and control number, severity of disease, concomitant therapy, type and source of cells, passage of cells, dose, administration route, repeats, and interval between repeats, outcomes, and adverse events compared to controls. Data were analyzed descriptively to determine the possible causes of adverse reactions, and which protocols gave a satisfactory outcome, in terms of safety and efficacy. Results There were 25 original articles, i.e., eight case studies and 17 studies with controls. Conclusion Among the various adult stem cells that were used in human studies, MSCs from the bone marrow or umbilical cord performed better compared to other types of adult stem cells, though no study showed a complete and sustainable performance in the outcome measures. Intravenous (IV) route was equal to invasive route. Fresh or cryopreserved, and autologous or allogeneic MSCs were equally beneficial; and giving too many cells via intraportal or the hepatic artery might be counterproductive.
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