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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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2
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Chen L, Zhang N, Huang Y, Zhang Q, Fang Y, Fu J, Yuan Y, Chen L, Chen X, Xu Z, Li Y, Izawa H, Xiang C. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev Rep 2023; 19:2192-2224. [PMID: 37498509 DOI: 10.1007/s12015-023-10583-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Lu Chen
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Xin Chen
- Department of Hematology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310027, People's Republic of China
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Hiromi Izawa
- Jingugaien Woman Life Clinic, Jingu-Gaien 3-39-5 2F, Shibuya-Ku, Tokyo, Japan
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China.
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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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Li S, Wang J, Jiang B, Jiang J, Luo L, Zheng B, Si W. Mesenchymal stem cells derived from different perinatal tissues donated by same donors manifest variant performance on the acute liver failure model in mouse. Stem Cell Res Ther 2022; 13:231. [PMID: 35659084 PMCID: PMC9166497 DOI: 10.1186/s13287-022-02909-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 04/16/2022] [Indexed: 01/30/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) derived from different tissues have variant biological characteristics, which may induce different performances in the treatment of diseases. At present, it is difficult to know which type of MSC is most suitable for acute liver failure (ALF), and there is no parallel study to compare MSCs from different tissues of the same donor. Methods In this study, we derived MSCs from three different perinatal tissues of the same donor: cord lining (CL), cord–placenta junction (CPJ) and fetal placenta (FP), respectively, for compared gene expression profiles by transcriptome sequencing, and ability of proliferation and immune regulation in vitro. In addition, the therapeutic effects (e.g., survival rate, histological evaluation, biochemical analysis) of CL-MSCs, FP-MSCs and CPJ-MSCs on ALF mouse model were compared. Results The transcriptome analysis showed that FP-MSCs have significantly high expression of chemokines compared to CPJ-MSCs and CL-MSCs, similar to the q-PCR result. Of note, we found that CPJ-MSCs and FP-MSCs could improve the survival rate of mice with ALF induced by carbon tetrachloride, but CL-MSCs had no difference with Sham group. Moreover, we also found that biomarkers of ALF (e.g., MDA, SOD and GSH-px) significantly improved post-CPJ-MSCs and FP-MSCs treatment, but not CL-MSCs and Sham group. However, CL-MSCs treatment leads to inflammatory reaction in the early stage (day 3) of ALF treatment but not found with other groups. Conclusions It is important to select the MSCs derived from different tissues with variant performance for therapeutic purpose, and the CPJ-MSCs and FP-MSCs cells can significantly improve the syndrome of ALF which is highly recommended for a potential therapeutic options for ALF. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02909-w.
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Affiliation(s)
- Shanshan Li
- School of Medicine, Yunnan University, Kunming, 650000, Yunnan, China.,State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650000, China
| | - Junfeng Wang
- Department of Hepatic and Bile Duct Surgery, The First People's Hospital of Yunnan Province, Kunming, 650000, China
| | - Bin Jiang
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650000, China
| | - Jiang Jiang
- Department of Obstetrics, The First People's Hospital of Yunnan Province, Kunming, 650000, China
| | - Lilin Luo
- Department of Pathology, The First People's Hospital of Yunnan Province, Kunming, 650000, China
| | - Bingrong Zheng
- School of Medicine, Yunnan University, Kunming, 650000, Yunnan, China.
| | - Wei Si
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650000, China.
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Wang L, Zhang Y, Zhong J, Zhang Y, Zhou S, Xu C. Mesenchymal Stem Cell Therapy for Acetaminophen-Related Liver Injury: A Systematic Review and Meta-Analysis of Experimental Studies in Vivo. Curr Stem Cell Res Ther 2021; 17:825-838. [PMID: 34620060 DOI: 10.2174/1574888x16666211007092055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/22/2021] [Accepted: 05/24/2021] [Indexed: 12/09/2022]
Abstract
OBJECTIVE The efficacy of mesenchymal stem cell (MSC) therapy in acetaminophen-induced liver injury has been investigated in animal experiments, but individual studies with a small sample size cannot be used to draw a clear conclusion. Therefore, we conducted a systematic review and meta-analysis of preclinical studies to explore the potential of using MSCs in acetaminophen-induced liver injury. METHODS Eight databases were searched for studies reporting the effects of MSCs on acetaminophen hepatoxicity. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used. SYRCLE's risk of bias tool for animal studies was applied to assess the methodological quality. A meta-analysis was performed by using RevMan 5.4 and STATA/SE 16.0 software. RESULTS Eleven studies involving 159 animals were included according to PRISMA statement guidelines. Significant associations were found for MSCs with the levels of alanine transaminase (ALT) (standardized mean difference (SMD) - 2.58, p < 0.0001), aspartate aminotransferase (AST) (SMD - 1.75, p = 0.001), glutathione (GSH) (SMD 3.7, p < 0.0001), superoxide dismutase (SOD) (SMD 1.86, p = 0.022), interleukin 10 (IL-10) (SMD 5.14, p = 0.0002) and tumor necrosis factor-α (TNF-α) (SMD - 4.48, p = 0.011) compared with those in the control group. The subgroup analysis showed that the tissue source of MSCs significantly affected the therapeutic efficacy (p < 0.05). CONCLUSION Our meta-analysis results demonstrate that MSCs could be a potential treatment for acetaminophen-related liver injury.
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Affiliation(s)
- Li Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou. China
| | - Yiwen Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou. China
| | - Jiajun Zhong
- Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou. China
| | - Yuan Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou. China
| | - Shuisheng Zhou
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou. China
| | - Chengfang Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou. China
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Nouri N, Aghebati-Maleki L, Yousefi M. Adipose-Derived Mesenchymal Stem Cells: A Promising Tool in the Treatment of pre mature ovarian failure. J Reprod Immunol 2021; 147:103363. [PMID: 34450435 DOI: 10.1016/j.jri.2021.103363] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 08/03/2021] [Accepted: 08/15/2021] [Indexed: 12/12/2022]
Abstract
Despite being rare, primary ovarian insufficiency (POI) is a significant cause of infertility and deficiency of ovarian hormone in women. Several health risks are also associated with POI, which include dry eye syndrome, reduced density of bones and enhanced fracture risks, troublesome menopausal symptoms, early development of cardiovascular disease, and psychological effects such as declined cognition, reduced perceived psychological support, anxiety, and depression. Replacing premenopausal levels of ovarian sex steroids through proper hormone replacement therapy could improve the quality of life for POI women and ameliorate related health risks. Herein, POI and its complications, in addition to hormone replacement therapies, which are safe and effective, are discussed. It is proposed that the use of HRT) Hormone replacement therapy (formulations which mimic normal production of ovarian hormones could reduce POI-associated morbidity rates if they are continued by the age 50, which is approximately the natural age of menopause. Particular populations of POI women are also addressed, which include those with enhanced risk of ovarian or breast cancer, those with Turner syndrome, those approaching natural menopause, and those who are breastfeeding. It is generally predicted that stem cell-based therapies would be both safe and effective. In fact, several types of cells have been described as safe, though their effectiveness and therapeutic application are yet to be defined. Several factors exist which could affect the results of treatment, such as cell handling, ex-vivo preparation strategies, variations in tissue of origin, potency, and immunocompatibility. Accordingly, cell types potentially effective in regenerative medicine could be recognized. Notably, products of MSCs from various sources of tissues show different levels of regenerative capabilities. The ultimate focus of the review is on adipose tissue-derive MCSs (ADMSCs), which possess exceptional features such as general availability, great ability to proliferate and differentiate, immunomodulatory capabilities, and low immunogenicity.
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Affiliation(s)
- Narges Nouri
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mehdi Yousefi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Science, Tabriz, Iran.
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Luan Y, Kong X, Feng Y. Mesenchymal stem cells therapy for acute liver failure: Recent advances and future perspectives. LIVER RESEARCH 2021; 5:53-61. [PMID: 39959343 PMCID: PMC11791815 DOI: 10.1016/j.livres.2021.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/16/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
Acute liver failure (ALF) is a life-threatening disease characterized by the rapid development of hepatocyte death and a systemic inflammatory response, which leads to high mortality. Despite the prevention of ALF complications, therapeutic effectiveness remains limited because of the rapid disease progression. Thus, there is a need to explore various therapeutic approaches. Currently, the only effective treatment is liver transplantation; However, the lack of donors, surgical complications, immunosuppression, and high medical costs limit its clinical application. Recently, mesenchymal stem cells (MSCs) have been found to exert hepatoprotective effects in ALF through suppression of inflammation, immunoregulation, promotion of mitosis, anti-apoptosis effects, and alleviation of the metabolic and oxidative stress imbalance. In this review, we summarize the advantages and disadvantages of MSCs from different sources and their molecular mechanisms in ALF treatment, along with future perspectives that may provide guidance to improve the current status of MSCs therapy for ALF.
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Affiliation(s)
- Yuling Luan
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Feng
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Liu S, Guo R, Hou X, Zhang Y, Jiang X, Wang T, Wu X, Xu K, Pan X, Qiao L. Adipose-tissue derived porcine mesenchymal stem cells efficiently ameliorate CCl 4-induced acute liver failure in mice. Cytotechnology 2020; 72:327-341. [PMID: 32335812 PMCID: PMC7225243 DOI: 10.1007/s10616-020-00370-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 01/09/2020] [Indexed: 01/16/2023] Open
Abstract
Adipose tissue derived mesenchymal stem cells (ADMSCs) may be an attractive therapeutic source for acute liver injury because of their high accessibility and non-invasiveness. Here, we investigated the therapeutic potentials of porcine ADMSCs for acute liver failure (ALF). The morphology, differentiation potential, expression patterns of cell surface markers and liver-specific genes were compared between the ADMSCs derived from the pigs with or without ALF. For therapeutic studies, the expanded porcine ADMSCs from either ALF pig (ALF-ADMSCs) or healthy control pig (Nor-ADMSCs) of passage 3 were transplanted into CCl4-induced ALF mice, and the liver histology and functional tests were performed at days 1, 7, 14, and 21 after cell transplantation. ALF-ADMSCs expressed higher mRNA level of hepatic growth factor (HGF) than the Nor-ADMSCs. Both ALF-ADMSCs and Nor-ADMSCs improved liver histology, functions, and mouse survival rate. Higher level of porcine hepatocyte-specific genes was seen in the livers of ALF-ADMSCs transplanted mice as compared to the Nor-ADMSCs transplanted mice. In particular, ALF-ADMSCs transplanted mice expressed significantly higher level of albumin and cytokeratin 18 in the liver tissues as compared to the Nor-ADMSCs transplanted mice. ALF-ADMSCs might be superior to Nor-ADMSCs in the treatment of ALF as the former possesses stronger hepatic differentiation potential.
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Affiliation(s)
- Shourong Liu
- Department of Liver Diseases, Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310014, China.
| | - Ruihong Guo
- The Fourth Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiaoli Hou
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yue Zhang
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiawei Jiang
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Tiantian Wang
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiaoyu Wu
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Keyang Xu
- The Fourth Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiaoping Pan
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia.
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Nobakht Lahrood F, Saheli M, Farzaneh Z, Taheri P, Dorraj M, Baharvand H, Vosough M, Piryaei A. Generation of Transplantable Three-Dimensional Hepatic-Patch to Improve the Functionality of Hepatic Cells In Vitro and In Vivo. Stem Cells Dev 2020; 29:301-313. [PMID: 31856676 DOI: 10.1089/scd.2019.0130] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Cell therapy and tissue engineering (TE) are considered alternative therapeutic approaches to organ transplantation. Since cell therapy approaches achieved little success for liver failure treatment, liver TE is considered a more promising alternative. In this study, we produced a liver tissue equivalent (called "liver-derived extracellular matrix scaffold [LEMS]-Patch") by co-culture of human bone marrow stromal cells, human umbilical vein endothelial cells, and a hepatoma cell line, Huh7, within an artificial three-dimensional liver-extracellular matrix scaffold. The results showed significant increase in the liver-specific gene expression and hepatic functions, in terms of albumin (ALB) and fibrinogen secretion, urea production, and cytochrome inducibility in the LEMS-Patch compared to controls. In addition, transplanted LEMS-Patch was successfully incorporated into the recipient liver of acute liver failure mice and produced human ALB. Consequently, our data demonstrated that the generated LEMS-Patch could be used as a good platform for functional improvement of hepatic cells in vitro and in vivo.
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Affiliation(s)
- Fatemeh Nobakht Lahrood
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mona Saheli
- Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Farzaneh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Payam Taheri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahshad Dorraj
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, and School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Hu C, Zhao L, Li L. Current understanding of adipose-derived mesenchymal stem cell-based therapies in liver diseases. Stem Cell Res Ther 2019; 10:199. [PMID: 31287024 PMCID: PMC6613269 DOI: 10.1186/s13287-019-1310-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The liver, the largest organ with multiple synthetic and secretory functions in mammals, consists of hepatocytes, cholangiocytes, hepatic stellate cells (HSCs), sinusoidal endothelial cells, Kupffer cells (KCs), and immune cells, among others. Various causative factors, including viral infection, toxins, autoimmune defects, and genetic disorders, can impair liver function and result in chronic liver disease or acute liver failure. Mesenchymal stem cells (MSCs) from various tissues have emerged as a potential candidate for cell transplantation to promote liver regeneration. Adipose-derived MSCs (ADMSCs) with high multi-lineage potential and self-renewal capacity have attracted great attention as a promising means of liver regeneration. The abundance source and minimally invasive procedure required to obtain ADMSCs makes them superior to bone marrow-derived MSCs (BMMSCs). In this review, we comprehensively analyze landmark studies that address the isolation, proliferation, and hepatogenic differentiation of ADMSCs and summarize the therapeutic effects of ADMSCs in animal models of liver diseases. We also discuss key points related to improving the hepatic differentiation of ADMSCs via exposure of the cells to cytokines and growth factors (GFs), extracellular matrix (ECM), and various physical parameters in in vitro culture. The optimization of culturing methods and of the transplantation route will contribute to the further application of ADMSCs in liver regeneration and help improve the survival rate of patients with liver diseases. To this end, ADMSCs provide a potential strategy in the field of liver regeneration for treating acute or chronic liver injury, thus ensuring the availability of ADMSCs for research, trial, and clinical applications in various liver diseases in the future.
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Affiliation(s)
- Chenxia Hu
- 0000 0004 1759 700Xgrid.13402.34Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Lingfei Zhao
- 0000 0004 1759 700Xgrid.13402.34Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Lanjuan Li
- 0000 0004 1759 700Xgrid.13402.34Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
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Improvement of mesenchymal stromal cells and their derivatives for treating acute liver failure. J Mol Med (Berl) 2019; 97:1065-1084. [DOI: 10.1007/s00109-019-01804-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 04/28/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023]
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Acun A, Oganesyan R, Uygun BE. Liver Bioengineering: Promise, Pitfalls, and Hurdles to Overcome. CURRENT TRANSPLANTATION REPORTS 2019; 6:119-126. [PMID: 31289714 PMCID: PMC6615568 DOI: 10.1007/s40472-019-00236-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW In this review, we discuss the recent advancements in liver bioengineering and cell therapy and future advancements to improve the field towards clinical applications. RECENT FINDINGS 3D printing, hydrogel-based tissue fabrication, and the use of native decellularized liver extracellular matrix as a scaffold are used to develop whole or partial liver substitutes. The current focus is on developing a functional liver graft through achieving a non-leaky endothelium and a fully constructed bile duct. Use of cell therapy as a treatment is less invasive and less costly compared to transplantation, however, lack of readily available cell sources with low or no immunogenicity and contradicting outcomes of clinical trials are yet to be overcome. SUMMARY Liver bioengineering is advancing rapidly through the development of in vitro and in vivo tissue and organ models. Although there are major challenges to overcome, through optimization of the current methods and successful integration of induced pluripotent stem cells, the development of readily available, patient-specific liver substitutes can be achieved.
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Affiliation(s)
- Aylin Acun
- Center for Engineering in Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, 51 Blossom Street, Boston, MA 02114, USA
| | - Ruben Oganesyan
- Center for Engineering in Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, 51 Blossom Street, Boston, MA 02114, USA
| | - Basak E. Uygun
- Center for Engineering in Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, 51 Blossom Street, Boston, MA 02114, USA
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Alwahsh SM, Rashidi H, Hay DC. Liver cell therapy: is this the end of the beginning? Cell Mol Life Sci 2018; 75:1307-1324. [PMID: 29181772 PMCID: PMC5852182 DOI: 10.1007/s00018-017-2713-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 11/08/2017] [Accepted: 11/13/2017] [Indexed: 12/13/2022]
Abstract
The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration.
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Affiliation(s)
- Salamah M Alwahsh
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
| | - Hassan Rashidi
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - David C Hay
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
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Xu LJ, Wang SF, Wang DQ, Ma LJ, Chen Z, Chen QQ, Wang J, Yan L. Adipose-derived stromal cells resemble bone marrow stromal cells in hepatocyte differentiation potential in vitro and in vivo. World J Gastroenterol 2017; 23:6973-6982. [PMID: 29097870 PMCID: PMC5658315 DOI: 10.3748/wjg.v23.i38.6973] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 07/20/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether mesenchymal stem cells (MSCs) from adipose-derived stromal cells (ADSCs) and bone marrow stromal cells (BMSCs) have similar hepatic differentiation potential.
METHODS Mouse ADSCs and BMSCs were isolated and cultured. Their morphological and phenotypic characteristics, as well as their multiple differentiation capacity were compared. A new culture system was established to induce ADSCs and BMSCs into functional hepatocytes. Reverse transcription polymerase chain reaction, Western blot, and immunofluorescence analyses were performed to identify the induced hepatocyte-like cells. CM-Dil-labeled ADSCs and BMSCs were then transplanted into a mouse model of CCl4-induced acute liver failure. Fluorescence microscopy was used to track the transplanted MSCs. Liver function was tested by an automatic biochemistry analyzer, and liver tissue histology was observed by hematoxylin and eosin (HE) staining.
RESULTS ADSCs and BMSCs shared a similar morphology and multiple differentiation capacity, as well as a similar phenotype (with expression of CD29 and CD90 and no expression of CD11b or CD45). Morphologically, ADSCs and BMSCs became round and epithelioid following hepatic induction. These two cell types differentiated into hepatocyte-like cells with similar expression of albumin, cytokeratin 18, cytokeratin 19, alpha fetoprotein, and cytochrome P450. Fluorescence microscopy revealed that both ADSCs and BMSCs were observed in the mouse liver at different time points. Compared to the control group, both the function of the injured livers and HE staining showed significant improvement in the ADSC- and BMSC-transplanted mice. There was no significant difference between the two MSC groups.
CONCLUSION ADSCs share a similar hepatic differentiation capacity and therapeutic effect with BMSCs in an acute liver failure model. ADSCs may represent an ideal seed cell type for cell transplantation or a bio-artificial liver support system.
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Affiliation(s)
- Li-Juan Xu
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
| | - Shu-Fang Wang
- Department of Blood Transfusion, Chinese PLA General Hospital, Beijing 100853, China
| | - De-Qing Wang
- Department of Blood Transfusion, Chinese PLA General Hospital, Beijing 100853, China
| | - Lian-Jun Ma
- Department of Endoscopics, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Zheng Chen
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
| | - Qian-Qian Chen
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
| | - Jun Wang
- Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Li Yan
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
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