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1
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Shih JH, Chern E. Decellularized Porcine Aorta as a Scaffold for Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells in Tissue Engineering. Stem Cell Rev Rep 2025:10.1007/s12015-025-10875-y. [PMID: 40227487 DOI: 10.1007/s12015-025-10875-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 04/15/2025]
Abstract
Tissue engineering has been an integral part of regenerative medicine. Functional biomimetic structures were assembled by combining appropriate scaffolds with specific cells. The decellularization of animal tissue preserved the natural biochemical components and structural properties of the extracellular matrix (ECM) of specific organs, thereby providing a suitable niche for tissue-specific cell differentiation and growth. In this study, the extracellular matrix (ECM) of the porcine aorta was obtained through trypsin-based decellularization. The resulting porcine aortic ECM retained a favorable collagen composition, exhibited no cytotoxicity, and demonstrated chemophilic properties for mesenchymal stem cells. Human adipose-derived mesenchymal stem cells (hADSCs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiMSCs) were transplanted onto the decellularized porcine aortic ECM, where successful differentiation into a mature cartilage layer was observed. These findings suggested that the porcine aortic ECM could serve as a potential scaffold with tubular and linear structures for tissue engineering applications. Functional human iMSCs (induced-mesenchymal stem cells) were generated from human iPSCs (induced-pluripotent stem cells) and analyzed for differences compared to primary MSCs via RNA-seq. The hiMSCs were applied to decellularized porcine aortic ECM (extracellular matrix), demonstrating chondrogenic differentiation and confirming the usability of xenogeneic ECM.
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Affiliation(s)
- Jheng-Hong Shih
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan
| | - Edward Chern
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan.
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, No. 1, Sec. 4 Roosevelt Road, Taipei, 10617, Taiwan.
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Rouzbahani M, Ghanaati H. Intra-Arterial Stem Cell Injection for Treating Various Diseases: A New Frontier in Interventional Radiology. Cardiovasc Intervent Radiol 2025; 48:288-296. [PMID: 39789253 DOI: 10.1007/s00270-024-03947-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 12/15/2024] [Indexed: 01/12/2025]
Abstract
This article provides radiologists with insights into stem cells' functions, sources, and potentially successful clinical treatments via intravascular injection in organs such as the liver, kidney, pancreas, musculoskeletal system, and for ischemic conditions affecting the brain, heart and limbs. Understanding stem cells' significance in interventional radiology and its limitations enables tailored interventions for diverse conditions, ensuring efficient medical care and optimal treatment selection.
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Affiliation(s)
- Maedeh Rouzbahani
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Hossein Ghanaati
- Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran.
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3
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Ruan MF, Yin YH, Shao XD, Qi XS. Bone marrow mesenchymal stem cell transplantation for treatment of liver cirrhosis: Recent advances. Shijie Huaren Xiaohua Zazhi 2025; 33:106-113. [DOI: 10.11569/wcjd.v33.i2.106] [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: 12/17/2024] [Revised: 01/20/2025] [Accepted: 02/20/2025] [Indexed: 02/28/2025] Open
Abstract
The incidence and mortality of cirrhosis have been increasing year by year, making it become an important factor threatening human health. Cirrhosis in the early stage often lacks obvious symptoms, and liver transplantation has become the only effective treatment for end-stage cirrhosis. However, due to the high cost of liver transplantation, the high incidence of complications, and limited donor resources, the application of liver transplantation has been limited. Currently, stem cell therapy has been considered an alternative treatment for cirrhosis. The sources and types of stem cells are diverse, and autologous bone marrow mesenchymal stem cells (BMSCs) have become one of the important cell types involved in tissue regeneration due to their great differentiation potential, abundant content, and ease of obtaining and preparation. This review summarizes the mechanisms, transplantation routes, safety, effectiveness, cell origin, advantages, and limitations of BMSCs in the treatment of cirrhosis by reviewing the relevant literature.
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Affiliation(s)
- Meng-Fan Ruan
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
- Postgraduate College, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Yu-Hang Yin
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
- Postgraduate College, China Medical University, Shenyang 110122, Liaoning Province, China
| | - Xiao-Dong Shao
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
| | - Xing-Shun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
- Postgraduate College, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
- Postgraduate College, China Medical University, Shenyang 110122, Liaoning Province, China
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Tian Y, Jin M, Ye N, Gao Z, Jiang Y, Yan S. Mesenchymal stem cells-derived exosomes attenuate mouse non-heart-beating liver transplantation through Mir-17-5p-regulated Kupffer cell pyroptosis. Stem Cell Res Ther 2025; 16:57. [PMID: 39920844 PMCID: PMC11806715 DOI: 10.1186/s13287-025-04169-w] [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: 07/23/2024] [Accepted: 01/23/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Liver transplantation is the most effective treatment for end-stage liver disease. However, the shortage of donor livers has become a significant obstacle to the advancement of liver transplantation. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been extensively investigated in liver diseases. However, the underlying mechanisms of how they can protect organ donation after cardiac death (DCD) livers remain unclear. METHODS In this study, an arterialized mouse non-heart-beating (NHB) liver transplantation model was used to investigate the effect of MSCs-Exo on NHB liver transplantation. The survival rates, histology, pro-inflammatory cytokine and chemokine expression, and underlying mechanisms were investigated. RESULTS The infusion of MSCs-Exo reduced the injury to DCD liver graft tissue. In vitro and in vivo experiments demonstrated that MSCs-Exo could inhibit hydrogen peroxide-induced pyroptosis of Kupffer cells. We found that miR-17-5p was significantly abundant in MSCs-Exo, targeting and regulating the TXNIP expression. This action inhibited NLRP3-mediated pyroptosis of Kupffer cells through the classical Caspase1-dependent pathway, alleviating DCD liver graft injury. CONCLUSION Our study elucidated a protective role for MSCs-Exo in a NHB liver transplantation model. This mechanism provides a theoretical basis and new strategies for the clinical application of MSCs-Exo to improve liver graft quality and alleviate the organ shortage in liver transplantation.
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Affiliation(s)
- Yang Tian
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China
| | - Ming Jin
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China
| | - Nanwei Ye
- Department of Medical Research Center, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Zhenzhen Gao
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China
| | - Yuancong Jiang
- Department of Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Zhong-Xing North Road #568, Shaoxing, Zhejiang Province, 312000, China.
| | - Sheng Yan
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China.
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5
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Ma X, Peng L, Zhu X, Chu T, Yang C, Zhou B, Sun X, Gao T, Zhang M, Chen P, Chen H. Isolation, identification, and challenges of extracellular vesicles: emerging players in clinical applications. Apoptosis 2025; 30:422-445. [PMID: 39522104 DOI: 10.1007/s10495-024-02036-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Extracellular vesicles (EVs) serve as critical mediators of intercellular communication, encompassing exosomes, microvesicles, and apoptotic vesicles that play significant roles in diverse physiological and pathological contexts. Numerous studies have demonstrated that EVs derived from mesenchymal stem cells (MSC-EVs) play a pivotal role in facilitating tissue and organ repair, alleviating inflammation and apoptosis, enhancing the proliferation of endogenous stem cells within tissues and organs, and modulating immune function-these functions have been extensively utilized in clinical applications. The precise classification, isolation, and identification of MSC-EVs are essential for their clinical applications. This article provides a comprehensive overview of the biological properties of EVs, emphasizing both their advantages and limitations in isolation and identification methodologies. Additionally, we summarize the protein markers associated with MSC-EVs, emphasizing their significance in the treatment of various diseases. Finally, this article addresses the current challenges and dilemmas in developing clinical applications for MSC-EVs, aiming to offer valuable insights for future research.
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Affiliation(s)
- Xiaoxiao Ma
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Lanwei Peng
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Xiaohui Zhu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Tianqi Chu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Changcheng Yang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Bohao Zhou
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Xiangwei Sun
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Tianya Gao
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Mengqi Zhang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Ping Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China.
| | - Haiyan Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China.
- East China Institute of Digital Medical Engineering, Shangrao, 334000, People's Republic of China.
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6
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Zhu WY, Li X, Xie JL, Lu Q, Ma YJ, Zhu ZJ, Liu J. Hotspots and trends in stem cell therapy for liver fibrosis and cirrhosis: A bibliometric analysis. World J Hepatol 2025; 17:96105. [PMID: 39871895 PMCID: PMC11736489 DOI: 10.4254/wjh.v17.i1.96105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 10/29/2024] [Accepted: 11/19/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments. In the past two decades, there has been a surge in research on stem cell therapy for liver fibrosis and cirrhosis. This study aimed to conduct a comprehensive analysis of the research hotspots and trends in this field through bibliometrics. AIM To conduct a bibliometric analysis on hotspots and trends in stem cell therapy for treatment of liver fibrosis and cirrhosis. METHODS Publications on stem cell therapy for liver fibrosis and cirrhosis were retrieved from the Web of Science Core Collection database. The distribution and collaboration among literature, authors, countries, and institutions were analyzed visually using Excel, CiteSpace, Bibliometrix R-package, VOSviewer and Pajek software. Additionally, an investigation of keywords, burst keywords, and clusters was conducted. RESULTS As of September 20, 2024, a total of 1935 documents were retrieved dating from 2004 to 2024, with 1186 strongly relevant publications obtained after screening. China, the United States, and Japan were the major contributors in this field. Cairo University, Zhejiang University and Yamaguchi University were the major institution in this field. The journal Stem Cell Research & Therapy published the most papers. There were 686 authors, with Shuji Terai, Isao Sakaida, Soon Koo Baik, and Lanjuan Li publishing the most papers. The research focused on alcoholic cirrhosis and nonalcoholic fatty liver disease. The emerging areas of interest were extracellular vesicles, exosomes, and their enriched microRNAs. The field is experiencing rapid growth due to the changing research trends and increasing literature. CONCLUSION These findings provide a thorough overview of stem cell therapy in the field of liver fibrosis and cirrhosis.
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Affiliation(s)
- Wen-Yan Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Xiang Li
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jia-Ling Xie
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Qin Lu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Ying-Jie Ma
- Office of Scientific Research of Army Medical Center, Army Medical University, Chongqing 400042, China
| | - Zhao-Jing Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Juan Liu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China.
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7
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Gilglioni EH, Bansal M, St-Pierre-Wijckmans W, Talamantes S, Kasarinaite A, Hay DC, Gurzov EN. Therapeutic potential of stem cell-derived somatic cells to treat metabolic dysfunction-associated steatotic liver disease and diabetes. Obes Rev 2025:e13899. [PMID: 39861937 DOI: 10.1111/obr.13899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 10/22/2024] [Accepted: 12/04/2024] [Indexed: 01/27/2025]
Abstract
Developments in basic stem cell biology have paved the way for technology translation in human medicine. An exciting prospective use of stem cells is the ex vivo generation of hepatic and pancreatic endocrine cells for biomedical applications. This includes creating novel models 'in a dish' and developing therapeutic strategies for complex diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes. In this review, we explore recent advances in the generation of stem cell-derived hepatocyte-like cells and insulin-producing β-like cells. We cover the different differentiation strategies, new discoveries, and the caveats that still exist regarding their routine use. Finally, we discuss the challenges and limitations of stem cell-derived therapies as a clinical strategy to manage metabolic diseases in humans.
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Affiliation(s)
- Eduardo H Gilglioni
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
| | - Mayank Bansal
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
| | | | - Stephanie Talamantes
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
| | - Alvile Kasarinaite
- Institute for Regeneration and Repair, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - David C Hay
- Institute for Regeneration and Repair, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Esteban N Gurzov
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
- WELBIO Department, WEL Research Institute, Wavre, Belgium
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8
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Xiong X, Gao C, Meng X, Liu A, Gong X, Sun Y. Research progress in stem cell therapy for Wilson disease. Regen Ther 2024; 27:73-82. [PMID: 38525238 PMCID: PMC10959646 DOI: 10.1016/j.reth.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/27/2024] [Accepted: 03/09/2024] [Indexed: 03/26/2024] Open
Abstract
Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder characterized by disorganized copper metabolism caused by mutations in the ATP7B gene. Currently, the main treatment options for WD involve medications such as d-penicillamine, trientine hydrochloride, zinc acetate, and liver transplantation. However, there are challenges that encompass issues of poor compliance, adverse effects, and limited availability of liver sources that persist. Stem cell therapy for WD is currently a promising area of research. Due to the advancement in stem cell directed differentiation technology in vitro and the availability of sufficient stem cell donors, it is expected to be a potential treatment option for the permanent correction of abnormal copper metabolism. This article discusses the research progress of stem cell therapy for WD from various sources, as well as the challenges and future prospects of the clinical application of stem cell therapy for WD.
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Affiliation(s)
- Xianlang Xiong
- Hospital of Hunan Guangxiu, Hunan Normal University, Changsha, 410205, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Ce Gao
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Xiangying Meng
- Hospital of Hunan Guangxiu, Hunan Normal University, Changsha, 410205, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Aihui Liu
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Xin Gong
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Yi Sun
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- Hospital of Hunan Guangxiu, Hunan Normal University, Changsha, 410205, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
- Key Laboratory of Stem Cells and Reproductive Engineering, Ministry of Health, Changsha, 410008, China
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10
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Xiao KZ, Liao G, Huang GY, Huang YL, Gu RH. Efficacy of serum-free cultured human umbilical cord mesenchymal stem cells in the treatment of knee osteoarthritis in mice. World J Stem Cells 2024; 16:944-955. [DOI: 10.4252/wjsc.v16.i11.944] [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: 04/22/2024] [Revised: 09/03/2024] [Accepted: 10/18/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND We investigated the efficacy of intra-articular injection of human umbilical cord mesenchymal stem cells (hUC-MSCs) for the treatment of osteoarthritis (OA) progression in the knee joint. Although many experimental studies of hUC-MSCs have been published, these studies have mainly used fetal bovine serum-containing cultures of hUC-MSCs; serum-free cultures generally avoid the shortcomings of serum-containing cultures and are not subject to ethical limitations, have a wide range of prospects for clinical application, and provide a basis or animal experimentation for clinical experiments.
AIM To study the therapeutic effects of serum-free hUC-MSCs (N-hUCMSCs) in a mouse model of knee OA.
METHODS Fifty-five male C57BL/6 mice were randomly divided into six groups: The blank control group, model control group, serum-containing hUC-MSCs (S-hUCMSC) group, N-hUCMSC group and hyaluronic acid (HA) group. After 9 weeks of modeling, the serum levels of interleukin (IL)-1β and IL-1 were determined. Hematoxylin-eosin staining was used to observe the cartilage tissue, and the Mankin score was determined. Immunohistochemistry and western blotting were used to determine the expression of collagen type II, matrix metalloproteinase (MMP)-1 and MMP-13.
RESULTS The Mankin score and serum IL-1 and IL-1β and cartilage tissue MMP-1 and MMP-13 expression were significantly greater in the experimental group than in the blank control group (P < 0.05). Collagen II expression in the experimental group was significantly lower than that in the blank control group (P < 0.05). The Mankin score and serum IL-1 and IL-1β and cartilage tissue MMP-1 and MMP-13 levels the experimental group were lower than those in the model control group (P < 0.05). Collagen II expression in the experimental group was significantly greater than that in the model control group (P < 0.05).
CONCLUSION N-hUCMSC treatment significantly alleviate the pathological damage caused by OA. The treatment effects of the S- hUCMSC group and HA group were similar.
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Affiliation(s)
- Kai-Zhen Xiao
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Graduate School of Guangxi Medical University, Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Gui Liao
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Guang-Yu Huang
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Graduate School of Guangxi Medical University, Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Yun-Long Huang
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Graduate School of Guangxi Medical University, Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Rong-He Gu
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Department of Guangxi Key Laboratory of Intelligent Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
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11
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Miyasako K, Nakashima A, Ishiuchi N, Tanaka Y, Morimoto K, Sasaki K, Nagamatsu S, Matsuda G, Masaki T. Impact of immunosuppressive drugs on efficacy of mesenchymal stem cell therapy for suppressing renal fibrosis. Stem Cells Transl Med 2024; 13:1067-1085. [PMID: 39401338 PMCID: PMC11555481 DOI: 10.1093/stcltm/szae073] [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: 03/17/2024] [Accepted: 08/15/2024] [Indexed: 11/13/2024] Open
Abstract
Preemptive regenerative medicine using mesenchymal stem cells (MSCs) may provide a novel therapeutic approach to prevent the progression from organ damage to organ failure. Although immunosuppressive drugs are often used in patients with organ disorder, their impact on MSC therapy remains unclear. We investigated the effects of immunosuppressive drugs on the therapeutic efficacy of MSCs. We created unilateral ureteral obstruction models, as a well-established model of renal fibrosis, a preliminary stage of organ failure. Three immunosuppressive drugs (methylprednisolone, cyclosporine, and cyclophosphamide) were intraperitoneally administered 3 days after surgery, and MSCs were injected via tail vein the following day. Preadministration of methylprednisolone or cyclophosphamide interfered with MSC activation by reducing expression of interferon-gamma (IFN-γ) and high-mobility group box-1 protein, thus significantly attenuating the therapeutic efficacy of MSCs. Preadministration of cyclophosphamide downregulated the expression of stromal cell-derived factor-1/C-X-C motif ligand 12, which is a potent migration factor for MSCs, resulting in reduced MSC engraftment in the renal cortex. IFN-γ-preconditioned activated MSCs were unaffected by these drugs and maintained their beneficial therapeutic effects. Cyclosporine preadministration had no effect on the therapeutic efficacy of MSCs. Our study demonstrated that the administration of certain immunosuppressive drugs interfered with MSC activation and engraftment at the site of injury, resulting in a significant attenuation of their therapeutic efficacy. These findings provide crucial information for selecting patients suitable for MSC therapy. Use of MSCs preactivated with IFN-γ or other means is preferred for patients on methylprednisolone or cyclophosphamide.
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Affiliation(s)
- Kisho Miyasako
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
| | - Ayumu Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
- Department of Nephrology, Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan
| | - Naoki Ishiuchi
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
| | - Yoshiki Tanaka
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
| | - Keisuke Morimoto
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
| | - Shogo Nagamatsu
- Department of Plastic and Reconstructive Surgery, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
| | - Go Matsuda
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
- TWOCELLS Company, Limited, 16-35 Hijiyama-honmachi, Minami-ku, Hiroshima, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan
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12
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Gao FQ, Zhu JQ, Feng XD. Innovative mesenchymal stem cell treatments for fatty liver disease. World J Stem Cells 2024; 16:846-853. [PMID: 39351260 PMCID: PMC11438732 DOI: 10.4252/wjsc.v16.i9.846] [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: 07/22/2024] [Revised: 08/26/2024] [Accepted: 09/09/2024] [Indexed: 09/24/2024] Open
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.
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Affiliation(s)
- Fei-Qiong Gao
- Department of Endocrinology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310003, Zhejiang Province, China
| | - Jia-Qi Zhu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Xu-Dong Feng
- Department of Clinical Laboratory, Ningbo Medical Center Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo 315000, Zhejiang Province, China.
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13
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Jin YX, Hu HQ, Zhang JC, Xin XY, Zhu YT, Ye Y, Li D. Mechanism of mesenchymal stem cells in liver regeneration: Insights and future directions. World J Stem Cells 2024; 16:842-845. [PMID: 39351263 PMCID: PMC11438733 DOI: 10.4252/wjsc.v16.i9.842] [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: 07/13/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/24/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are a prevalent source for stem cell therapy and play a crucial role in modulating both innate and adaptive immune responses. Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in liver cells and involves immune system activation, leading to histological changes, tissue damage, and clinical symptoms. A recent publication by Jiang et al, highlighted the potential of MSCs to mitigate in NAFLD progression by targeting various molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In this editorial, we comment on their research and discuss the efficacy of MSC therapy in treating NAFLD.
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Affiliation(s)
- Yu-Xin Jin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Hang-Qi Hu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Jia-Cheng Zhang
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Xi-Yan Xin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yu-Tian Zhu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yang Ye
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China.
| | - Dong Li
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
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14
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Rangra S, Rana D, Prajapati A, Benival D, Dwivedi P, Mandoli A. Nutritional and microbiota-based therapeutic interventions for alcohol-associated liver disease: From pathogenesis to therapeutic insights. Life Sci 2024; 352:122852. [PMID: 38909682 DOI: 10.1016/j.lfs.2024.122852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 06/06/2024] [Accepted: 06/14/2024] [Indexed: 06/25/2024]
Abstract
Alcohol-associated liver disease (ALD) manifests as a consequence of prolonged and excessive alcohol consumption. This disease is closely associated with the interplay between gut health and liver function, which can lead to complex pathophysiological changes in the body. This review offers a comprehensive exploration of ALD's multifaceted nature, with a keen focus on its pathogenesis and the potential of nutritional and microbiota-based therapies. Insights derived from diverse case studies are utilized to shed light on how interventions can rebalance the gut microbiome and enhance liver function in ALD patients. Furthermore, the feasibility of liver transplantation and stem cell therapy as ultimate measures for ALD has been discussed, with acknowledgment of the inherent risks and challenges accompanying them. ALD's complexity underscores the necessity for a thorough understanding of its etiology and progression to devise effective treatments that mitigate its profound impact on an individual's health.
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Affiliation(s)
- Shagun Rangra
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Dhwani Rana
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Arvee Prajapati
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Derajram Benival
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India
| | - Pradeep Dwivedi
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS) - Jodhpur, 342005, India
| | - Amit Mandoli
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, India.
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15
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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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16
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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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17
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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18
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Shi X, Zhang K, Qi Q, Zhou W, Yu F, Zhang Y. Human umbilical cord-derived mesenchymal stem cells attenuate hepatic stellate cells activation and liver fibrosis. Mol Biol Rep 2024; 51:734. [PMID: 38874773 PMCID: PMC11178641 DOI: 10.1007/s11033-024-09664-6] [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: 03/15/2024] [Accepted: 05/22/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Liver cirrhosis, a prevalent chronic liver disease, is characterized by liver fibrosis as its central pathological process. Recent advancements highlight the clinical efficacy of umbilical cord mesenchymal stem cell (UC-MSC) therapy in the treatment of liver cirrhosis. METHODS AND RESULTS We investigated the pharmacodynamic effects of UC-MSCs and MSC conditional medium (MSC-CM) in vivo, utilizing a carbon tetrachloride (CCl4)-induced fibrotic rat model. Concurrently, we assessed the in vitro impact of MSCs and MSC-CM on various cellular process of hepatic stellate cells (HSCs), including proliferation, apoptosis, activation, immunomodulatory capabilities, and inflammatory factor secretion. Our results indicate that both MSCs and MSC-CM significantly ameliorate the pathological extent of fibrosis in animal tissues, reducing the collagen content, serum biochemical indices and fibrosis biomarkers. In vitro, MSC-CM significantly inhibited the activation of the HSC line LX-2. Notably, MSC-CM modulated the expression of type I procollagen and TGFβ-1 while increasing MMP1 expression. This modulation restored the MMP1/TIMP1 ratio imbalance and extracellular matrix deposition in TGFβ-1 induced fibrosis. Both MSCs and MSC-CM not only induced apoptosis in HSCs but also suppressed proliferation and inflammatory cytokine release from activated HSCs. Furthermore, MSCs and MSC-CM exerted a suppressive effect on total lymphocyte activation. CONCLUSIONS UC-MSCs and MSC-CM primarily modulate liver fibrosis severity by regulating HSC activation. This study provides both in vivo and in vitro pharmacodynamic evidence supporting the use of MSCs in liver fibrosis treatment.
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Affiliation(s)
- Xiaoyu Shi
- State Industrial Base for Stem Cell Engineering Products, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
- VCANBIO Cell & Gene Engineering Corp., Ltd, Tianjin, China
| | - Kun Zhang
- State Industrial Base for Stem Cell Engineering Products, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
- VCANBIO Cell & Gene Engineering Corp., Ltd, Tianjin, China
| | - Qi Qi
- State Industrial Base for Stem Cell Engineering Products, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
- VCANBIO Cell & Gene Engineering Corp., Ltd, Tianjin, China
| | - Wangyi Zhou
- State Industrial Base for Stem Cell Engineering Products, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
- VCANBIO Cell & Gene Engineering Corp., Ltd, Tianjin, China
| | - Fengshi Yu
- State Industrial Base for Stem Cell Engineering Products, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
- VCANBIO Cell & Gene Engineering Corp., Ltd, Tianjin, China
| | - Yu Zhang
- State Industrial Base for Stem Cell Engineering Products, Tianjin, 300384, China.
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China.
- VCANBIO Cell & Gene Engineering Corp., Ltd, Tianjin, China.
- Tianjin Key Laboratory for Blood Cell Therapy Technology, Tianjin, China.
- Haihe Laboratory of Cell Ecosystem, Tianjin, China.
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19
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Huai Q, Zhu C, Zhang X, Dai H, Li X, Wang H. Mesenchymal stem/stromal cells armored by FGF21 ameliorate alcohol-induced liver injury through modulating polarization of macrophages. Hepatol Commun 2024; 8:e0410. [PMID: 38551384 PMCID: PMC10984668 DOI: 10.1097/hc9.0000000000000410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/01/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Alcohol-associated liver disease (ALD) is a major health care challenge worldwide with limited therapeutic options. Although mesenchymal stem/stromal cells (MSCs) represent a newly emerging therapeutic approach to treat ALD, thus far, there have been extensive efforts to try and enhance their efficacy, including genetically engineering MSCs. FGF21, an endocrine stress-responsive hormone, has been shown to regulate energy balance, glucose, and lipid metabolism and to enhance the homing of MSCs toward injured sites. Therefore, the purpose of this study was to investigate whether MSCs that overexpress FGF21 (FGF21-MSCs) improve the therapeutic effect of MSCs in treating ALD. METHODS Human umbilical cord-derived MSCs served as the gene delivery vehicle for the FGF21 gene. Human umbilical cord-derived MSCs were transduced with the FGF21 gene using lentiviral vectors to mediate FGF21 overexpression. We utilized both chronic Lieber-DeCarli and Gao-binge models of ethanol-induced liver injury to observe the therapeutic effect of FGF21-MSCs. Liver injury was phenotypically evaluated by performing biochemical methods, histology, and inflammatory cytokine levels. RESULTS Compared with MSCs alone, administration of MSCs overexpressing FGF21(FGF21-MSCs) treatment significantly enhanced the therapeutic effect of ALD in mice, as indicated by the alleviation of liver injury with reduced steatosis, inflammatory infiltration, oxidative stress, and hepatic apoptosis, and the promotion of liver regeneration. Mechanistically, FGF21 could facilitate the immunomodulatory function of MSCs on macrophages by setting metabolic commitment for oxidative phosphorylation, which enables macrophages to exhibit anti-inflammatory inclination. CONCLUSIONS Our data elucidate that MSC modification by FGF21 could enhance their therapeutic effect in ALD and may help in the exploration of effective MSCs-based cell therapies for the treatment of ALD.
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Affiliation(s)
- Qian Huai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Cheng Zhu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xu Zhang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Hanren Dai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xiaolei Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
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20
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Ding F, Liu Y, Li J, Wei X, Zhao J, Liu X, Zhang L. TC14012 enhances the anti-fibrosis effects of UC-MSCs on the liver by reducing collagen accumulation and ameliorating inflammation. Stem Cell Res Ther 2024; 15:44. [PMID: 38360740 PMCID: PMC10870604 DOI: 10.1186/s13287-024-03648-w] [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: 06/04/2023] [Accepted: 01/24/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are attracting attention as a promising cell-based therapy for the treatment of liver fibrosis or cirrhosis. However, the strategies and potential mechanisms of MSCs therapy need further investigation. The CXCL12/CXCR4/CXCR7 chemokine axis is well known to regulate cell migration and is involved in the regulation of liver fibrosis. This study aims to treat MSCs with a CXCR7-specific agonist to evaluate its therapeutic effects on hepatic fibrosis and potential mechanisms. METHODS TC14012, a potent agonist of CXCR7, has been used to pretreat human umbilical cord-derived MSCs (UC-MSCs) and assess its effect on proliferation, apoptosis, migration, immunoregulation, and gene regulatory network. Then, CCl4-induced liver fibrosis mice models were used to evaluate the therapeutic effect and mechanism of TC14012-treated UC-MSCs for treating hepatic fibrosis. RESULTS TC14012 increased CXCR7 expression in UC-MSCs. Notably, co-culture of liver sinusoidal endothelial cells (LSEC) with TC14012-pretreated UC-MSCs increased CXCR7 expression in LSEC. Additionally, TC14012 promoted cell migration and mediated the immunoregulation of UC-MSCs. Compared to UC-MSCs without TC14012 pretreatment, UC-MSCs treated with TC14012 ameliorated live fibrosis by restoring CXCR7 expression, reducing collagen fibril accumulation, inhibiting hepatic stellate cells activation, and attenuating the inflammatory response. CONCLUSION This study suggests that TC14012 pretreatment can enhance the therapeutic effects of UC-MSCs on liver fibrosis, mainly by promoting the migration and immunoregulation of MSCs.
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Affiliation(s)
- Fan Ding
- Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Yuting Liu
- Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jia Li
- Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Xiao Wei
- Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jiangdong Zhao
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, Xi'an, 710032, Shaanxi, China.
| | - Xiaojing Liu
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Liqiang Zhang
- Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
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21
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Chen L, Guo W, Mao C, Shen J, Wan M. Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents. J Mater Chem B 2024; 12:1446-1466. [PMID: 38265305 DOI: 10.1039/d3tb02790b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Abstract
Liver fibrosis is a reversible damage-repair response, the pathological features of which mainly include damage to hepatocytes, sinusoid capillarization, hepatic stellate cells activation, excessive accumulation of extracellular matrix and inflammatory response. Although some treatments (including drugs and stem cell therapy) for these pathological features have been shown to be effective, more clinical trials are needed to confirm their effectiveness. In recent years, nanomaterials-based therapies have emerged as an innovative and promising alternative to traditional drugs, being explored for the treatment of liver fibrosis diseases. Natural nanomaterials (including extracellular vesicles) and synthetic nanomaterials (including inorganic nanomaterials and organic nanomaterials) are developed to facilitate drug targeting delivery and combination therapy. In this review, the pathological features of liver fibrosis and the current anti-fibrosis drugs in clinical trials are briefly introduced, followed by a detailed introduction of the therapeutic nanoagents for the precise delivery of anti-fibrosis drugs. Finally, the future development trend in this field is discussed.
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Affiliation(s)
- Lin Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Wenyan Guo
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Jian Shen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
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22
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Taninokuchi Tomassoni M, Zhou Y, Braccischi L, Modestino F, Fukuda J, Mosconi C. Trans-Arterial Stem Cell Injection (TASI): The Role of Interventional Radiology in Regenerative Medicine. J Clin Med 2024; 13:910. [PMID: 38337604 PMCID: PMC10856532 DOI: 10.3390/jcm13030910] [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: 12/13/2023] [Revised: 01/19/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Regenerative medicine is taking a step forward in treating multiple diseases. The possibility of renewing damaged tissues with stem cells has become a topic of interest in recent decades. Still a relatively new research topic, many issues in this discipline are being addressed, from cell culturing to the study of different graft materials, and, moreover, cell delivery. For instance, direct intravenous injection has a big downfall regarding its lack of precision and poorly targeted treatment. Trans-arterial and direct percutaneous infusion to the aimed tissue/organ are both considered ideal for reaching the desired region but require image guidance to be performed safely and precisely. In this context, interventional radiology becomes pivotal for providing different cell delivery possibilities in every case. In this review, we analyze different basic stem cell therapy concepts and the current and future role of interventional radiology with a focus on trans-arterial delivery.
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Affiliation(s)
- Makoto Taninokuchi Tomassoni
- Department of Radiology, IRRCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (L.B.)
| | - Yinghui Zhou
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Kanagawa, Japan (J.F.)
| | - Lorenzo Braccischi
- Department of Radiology, IRRCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (L.B.)
| | - Francesco Modestino
- Department of Radiology, IRRCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (L.B.)
| | - Junji Fukuda
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Kanagawa, Japan (J.F.)
| | - Cristina Mosconi
- Department of Radiology, IRRCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (L.B.)
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23
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Paresishvili T, Kakabadze Z. Freeze-Dried Mesenchymal Stem Cells: From Bench to Bedside. Review. Adv Biol (Weinh) 2024; 8:e2300155. [PMID: 37990389 DOI: 10.1002/adbi.202300155] [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: 04/21/2023] [Revised: 06/09/2023] [Indexed: 11/23/2023]
Abstract
This review describes the freeze-dried mesenchymal stem cells (MSCs) and their ability to restore damaged tissues and organs. An analysis of the literature shows that after the lyophilization MSCs retain >80% of paracrine factors and that the mechanism of their action on the restoration of damaged tissues and organs is similar to the mechanism of action of paracrine factors in fresh and cryopreserved mesenchymal stem cells. Based on the own materials, the use of paracrine factors of freeze-dried MSCs in vivo and in vitro for the treatment of various diseases of organs and tissues has shown to be effective. The study also discusses about the advantages and disadvantages of freeze-dried MSCs versus cryopreserved MSCs. However, for the effective use of freeze-dried MSCs in clinical practice, a more detailed study of the mechanism of interaction of paracrine factors of freeze-dried MSCs with target cells and tissues is required. It is also necessary to identify possible other specific paracrine factors of freeze-dried MSCs. In addition, develop new therapeutic strategies for the use of freeze-dried MSCs in regenerative medicine and tissue bioengineering.
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Affiliation(s)
- Teona Paresishvili
- Department of Clinical Anatomy, Tbilisi State Medical University, Tbilisi, 0186, Georgia
| | - Zurab Kakabadze
- Department of Clinical Anatomy, Tbilisi State Medical University, Tbilisi, 0186, Georgia
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24
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Zhang H, Chen Q, Hu D, Lai J, Yan M, Wu Z, Yang Z, Zheng S, Liu W, Zhang L, Bai L. Manipulating HGF signaling reshapes the cirrhotic liver niche and fills a therapeutic gap in regeneration mediated by transplanted stem cells. Exp Cell Res 2024; 434:113867. [PMID: 38043723 DOI: 10.1016/j.yexcr.2023.113867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/05/2023]
Abstract
Long-term stem cell survival in the cirrhotic liver niche to maintain therapeutic efficacy has not been achieved. In a well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis animal model, we previously showed that liver-resident stem/progenitor cells (MLpvNG2+ cells) or immune cells have improved survival in the fibrotic liver environment but died via apoptosis in the cirrhotic liver environment, and increased levels of hepatocyte growth factor (HGF) mediated this cell death. We tested the hypothesis that inhibiting HGF signaling during the cirrhotic phase could keep the cells alive. We used adeno-associated virus (AAV) vectors designed to silence the c-Met (HGF-only receptor) gene or a neutralizing antibody (anti-cMet-Ab) to block the c-Met protein in the DEN-induced liver cirrhosis mouse model transplanted with MLpvNG2+ cells between weeks 6 and 7 after DEN administration, which is the junction of liver fibrosis and cirrhosis at the site where most intrahepatic stem cells move toward apoptosis. After 4 weeks of treatment, the transplanted MLpvNG2+ cells survived better in c-Met-deficient mice than in wild-type mice, and cell activity was similar to that of the mice that received MLpvNG2+ cells at 5 weeks after DEN administration (liver fibrosis phase when most of these cells proliferated). Mechanistically, a lack of c-Met signaling remodeled the cirrhotic environment, which favored transplanted MLpvNG2+ cell expansion to differentiation into mature hepatocytes and initiate endogenous regeneration by promoting mature host hepatocyte generation and mediating functional improvements. Therapeutically, c-Met-mediated regeneration can be mimicked by anti-cMet-Ab to interfere functions, which is a potential drug for cell-based treatment of liver fibrosis/cirrhosis.
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Affiliation(s)
- Hongyu Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Quanyu Chen
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Deyu Hu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Bioengineering College, Chongqing University, No. 175 Gaotan, ShapingBa Distract, Chongqing 400044, China
| | - Jiejuan Lai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Min Yan
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Zhifang Wu
- Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Zhiqing Yang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Shuguo Zheng
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Wei Liu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Leida Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Bioengineering College, Chongqing University, No. 175 Gaotan, ShapingBa Distract, Chongqing 400044, China; Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China.
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25
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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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26
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Wang Z, Li T, Zhang Z, Yuan M, Shi M, Wang FS, Linghu EQ, Shi L. Human umbilical cord-derived mesenchymal stem cells for the treatment of decompensated cirrhosis (MSC-DLC-1): a dose-escalation, phase I trial protocol. BMJ Open 2023; 13:e078362. [PMID: 38159943 PMCID: PMC10759077 DOI: 10.1136/bmjopen-2023-078362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/11/2023] [Indexed: 01/03/2024] Open
Abstract
INTRODUCTION There are limited therapeutic options to efficiently treat patients with decompensated liver cirrhosis. This trial aims to explore the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for the treatment of patients with decompensated liver cirrhosis. METHODS AND ANALYSIS This study is an open-label, dose-escalation, one-armed phase I trial. A single injection of UC-MSCs will be administered in a predetermined dose in each cohort (5.0×107, 1.0×108, 1.5×108 or 2.0×108 cells) according to the '3+3' rule. The primary evaluation measures will include the incidence of adverse events and the change in the Model for End-stage Liver Disease (MELD) score from baseline to the 28th day. Secondary evaluation measures will be evaluated at baseline and at each follow-up point. These measures will include the change in the MELD score from baseline to each follow-up point, the incidence of each complication associated with decompensated cirrhosis, liver transplant-free survival and the incidence of liver failure, among other relevant measures. All patients will be followed up for 24 months. This study will evaluate whether the use of UC-MSCs to treat patients with decompensated liver cirrhosis is safe and tolerable. ETHICS AND DISSEMINATION The study has been approved by the Chinese People's Liberation Army General Hospital (Approval#: 2018-107-D-4). Once conducted, the results from the study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT05227846.
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Affiliation(s)
- Zerui Wang
- Chinese PLA Medical School, Beijing, People's Republic of China
- Senior Department of Gastroenterology, the First Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Tiantian Li
- Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People's Republic of China
| | - Ziying Zhang
- Chinese PLA Medical School, Beijing, People's Republic of China
- Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People's Republic of China
| | - Mengqi Yuan
- Chinese PLA Medical School, Beijing, People's Republic of China
- Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People's Republic of China
| | - Ming Shi
- Chinese PLA Medical School, Beijing, People's Republic of China
- Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People's Republic of China
| | - Fu-Sheng Wang
- Chinese PLA Medical School, Beijing, People's Republic of China
- Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People's Republic of China
| | - En-Qiang Linghu
- Chinese PLA Medical School, Beijing, People's Republic of China
- Senior Department of Gastroenterology, the First Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Lei Shi
- Chinese PLA Medical School, Beijing, People's Republic of China
- Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, People's Republic of China
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27
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Abdellateif MS, Zekri ARN. Stem cell therapy for hepatocellular carcinoma and end-stage liver disease. J Egypt Natl Canc Inst 2023; 35:35. [PMID: 37926787 DOI: 10.1186/s43046-023-00194-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 10/20/2023] [Indexed: 11/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide, especially for patients who are suffering from end-stage liver disease (ESLD). The ESLD is considered a great challenge for clinicians due to the limited chance for liver transplantation, which is the only curative treatment for those patients. Stem cell-based therapy as a part of regenerative medicine represents a promising application for ESLD patients. Many clinical trials were performed to assess the utility of bone marrow-derived stem cells as a potential therapy for patients with liver diseases. The aim of the present study is to present and review the various types of stem cell-based therapy, including the mesenchymal stem cells (MSCs), BM-derived mononuclear cells (BM-MNCs), CD34 + hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and cancer stem cells.Though this type of therapy achieved promising results for the treatment of ESLD, however still there is a confounding data regarding its clinical application. A large body of evidence is highly required to evaluate the stem cell-based therapy after long-term follow-up, with respect to the incidence of toxicity, immunogenicity, and tumorigenesis that developed in many patients.
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Affiliation(s)
- Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt.
| | - Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, NCI, Cairo University, Cairo, 11976, Egypt
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28
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Chang Z, Zhang L, Hang JT, Liu W, Xu GK. Viscoelastic Multiscale Mechanical Indexes for Assessing Liver Fibrosis and Treatment Outcomes. NANO LETTERS 2023; 23:9618-9625. [PMID: 37793647 PMCID: PMC10603793 DOI: 10.1021/acs.nanolett.3c03341] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/28/2023] [Indexed: 10/06/2023]
Abstract
Understanding liver tissue mechanics, particularly in the context of liver pathologies like fibrosis, cirrhosis, and carcinoma, holds pivotal significance for assessing disease severity and prognosis. Although the static mechanical properties of livers have been gradually studied, the intricacies of their dynamic mechanics remain enigmatic. Here, we characterize the dynamic creep responses of healthy, fibrotic, and mesenchymal stem cells (MSCs)-treated fibrotic lives. Strikingly, we unearth a ubiquitous two-stage power-law rheology of livers across different time scales with the exponents and their distribution profiles highly correlated to liver status. Moreover, our self-similar hierarchical theory effectively captures the delicate changes in the dynamical mechanics of livers. Notably, the viscoelastic multiscale mechanical indexes (i.e., power-law exponents and elastic stiffnesses of different hierarchies) and their distribution characteristics prominently vary with liver fibrosis and MSCs therapy. This study unveils the viscoelastic characteristics of livers and underscores the potential of proposed mechanical criteria for assessing disease evolution and prognosis.
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Affiliation(s)
- Zhuo Chang
- Laboratory
for Multiscale Mechanics and Medical Science, Department of Engineering
Mechanics, State Key Laboratory for Strength and Vibration of Mechanical
Structures, School of Aerospace Engineering, Xi’an Jiaotong University, Xi’an 710049, China
| | - Liqiang Zhang
- Institute
for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Jiu-Tao Hang
- Laboratory
for Multiscale Mechanics and Medical Science, Department of Engineering
Mechanics, State Key Laboratory for Strength and Vibration of Mechanical
Structures, School of Aerospace Engineering, Xi’an Jiaotong University, Xi’an 710049, China
| | - Wenjia Liu
- Institute
for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Guang-Kui Xu
- Laboratory
for Multiscale Mechanics and Medical Science, Department of Engineering
Mechanics, State Key Laboratory for Strength and Vibration of Mechanical
Structures, School of Aerospace Engineering, Xi’an Jiaotong University, Xi’an 710049, China
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29
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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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Xie Y, Li Y, Yao J, Song X, Wang H, Zhang J, Li X. Protein Lactylation Modification and Proteomics Features in Cirrhosis Patients after UC-MSC Treatment. Curr Issues Mol Biol 2023; 45:8444-8460. [PMID: 37886975 PMCID: PMC10605309 DOI: 10.3390/cimb45100532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/10/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023] Open
Abstract
Umbilical cord mesenchymal stem cell (UC-MSC) therapy improves liver function in liver cirrhosis patients. This study aimed to elucidate the therapeutic mechanism underlying cell therapy by analyzing changes in the modification and expression of proteins 1 month post-treatment with UC-MSCs. This prospective study included 11 cirrhosis patients who received MSC injection. The laboratory indexes before and after treatment were collected to evaluate the clinical treatment effect of UC-MSCs, and the protein expression and lactylation modification in the liver were comprehensively revealed. Meanwhile, weighted gene co-expression network analysis was used to analyze the co-expression protein modules and their relationship with clinical features. The patients with liver cirrhosis showed an improvement trend after receiving UC-MSC treatment; specifically, the liver protein synthesis function was significantly improved and the coagulation function was also significantly improved. Proteomics combined with lactic acid proteomics revealed 160 lysine lactylation (Kla) sites of 119 proteins. Functional analysis showed that the lactylation-modified proteins were enriched in the pathway of glucose and other substances' metabolism, and many key enzymes of glycolysis and gluconeogenesis were lactated. UC-MSC therapy has a certain clinical effect in the treatment of liver cirrhosis and may act by regulating material metabolism, because the lactylation protein points to energy metabolism.
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Affiliation(s)
- Ye Xie
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Ying Li
- General Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Jia Yao
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, China
| | - Xiaojing Song
- General Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Haiping Wang
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, China
| | - Jianjun Zhang
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, China
| | - Xun Li
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
- General Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, China
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31
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Yao L, Hu X, Yuan M, Liu P, Zhang Q, Wang Z, Chen P, Xiong Z, Wu L, Dai K, Jiang Y. Human umbilical cord-derived mesenchymal stromal cells alleviate liver cirrhosis through the Hippo/YAP/Id1 pathway and macrophage-dependent mechanism. Int Immunopharmacol 2023; 123:110456. [PMID: 37494836 DOI: 10.1016/j.intimp.2023.110456] [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: 04/13/2023] [Revised: 05/28/2023] [Accepted: 06/02/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Few effective anti-fibrotic therapies are currently available for liver cirrhosis. Mesenchymal stromal cells (MSCs) ameliorate liver fibrosis and contribute to liver regeneration after cirrhosis, attracting much attention as a potential therapeutic strategy for the disease. However, the underlying molecular mechanism of their therapeutic effect is still unclear. Here, we investigated the effect of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in treating liver cirrhosis and their underlying mechanisms. METHODS We used carbon tetrachloride (CCl4)-induced mice as liver cirrhosis models and treated them with hUC-MSCs via tail vein injection. We assessed the changes in liver function, inflammation, and fibrosis by histopathology and serum biochemistry and explored the mechanism of hUC-MSCs by RNA sequencing (RNA-seq) using liver tissues. In addition, we investigated the effects of hUC-MSCs on hepatic stellate cells (HSC) and macrophages by in vitro co-culture experiments. RESULTS We found that hUC-MSCs considerably improved liver function and attenuated liver inflammation and fibrosis in CCl4-injured mice. We also showed that these cells exerted therapeutic effects by regulating the Hippo/YAP/Id1 axis in vivo. Our in vitro experiments demonstrated that hUC-MSCs inhibit HSC activation by regulating the Hippo/YAP signaling pathway and targeting Id1. Moreover, hUC-MSCs also alleviated liver inflammation by promoting the transformation of macrophages to an anti-inflammatory phenotype. CONCLUSIONS Our study reveals that hUC-MSCs relieve liver cirrhosis in mice through the Hippo/YAP/Id1 pathway and macrophage-dependent mechanisms, providing a theoretical basis for the future use of these cells as a potential therapeutic strategy for patients with liver cirrhosis.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - Zheng Wang
- 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
| | - Zhiyu Xiong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China
| | - Lun Wu
- Experiment Center of Medicine, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan 442008, 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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32
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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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Lee T, Hwang S, Seo D, Cho S, Yang S, Kim H, Kim J, Uh Y. Comparative Analysis of Biological Signatures between Freshly Preserved and Cryo-Preserved Bone Marrow Mesenchymal Stem Cells. Cells 2023; 12:2355. [PMID: 37830568 PMCID: PMC10571833 DOI: 10.3390/cells12192355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into multiple connective tissue lineages, including osteoblasts, chondrocytes, and adipocytes. MSCs secrete paracrine molecules that are associated with immunomodulation, anti-fibrotic effects, and angiogenesis. Due to their orchestrative potential, MSCs have been therapeutically applied for several diseases. An important aspect of this process is the delivery of high-quality MSCs to patients at the right time, and cryo-biology and cryo-preservation facilitate the advancement of the logistics thereof. This study aimed to compare the biological signatures between freshly preserved and cryo-preserved MSCs by using big data sourced from the Pharmicell database. From 2011 to 2022, data on approximately 2300 stem cell manufacturing cases were collected. The dataset included approximately 60 variables, including viability, population doubling time (PDT), immunophenotype, and soluble paracrine molecules. In the dataset, 671 cases with no missing data were able to receive approval from an Institutional Review Board and were analyzed. Among the 60 features included in the final dataset, 20 were selected by experts and abstracted into two features by using a principal component analysis. Circular clustering did not introduce any differences between the two MSC preservation methods. This pattern was also observed when using viability, cluster of differentiation (CD) markers, and paracrine molecular indices as inputs for unsupervised analysis. The individual average PDT and cell viability at most passages did not differ according to the preservation method. Most immunophenotypes (except for the CD14 marker) and paracrine molecules did not exhibit different mean levels or concentrations between the frozen and unfrozen MSC groups. Collectively, the biochemical signatures of the cryo-preserved and unfrozen bone marrow MSCs were comparable.
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Affiliation(s)
- Taesic Lee
- Division of Data Mining and Computational Biology, Regenerative Medicine Research Center, Wonju Severance Christian Hospital, Wonju 26426, Republic of Korea;
- Department of Family Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Sangwon Hwang
- Department of Precision Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Dongmin Seo
- Department of Medical Information, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Sungyoon Cho
- Pharmicell Co., Ltd., Seongnam 13229, Republic of Korea; (S.C.); (S.Y.); (H.K.)
| | - Sunja Yang
- Pharmicell Co., Ltd., Seongnam 13229, Republic of Korea; (S.C.); (S.Y.); (H.K.)
| | - Hyunsoo Kim
- Pharmicell Co., Ltd., Seongnam 13229, Republic of Korea; (S.C.); (S.Y.); (H.K.)
| | - Jangyoung Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Young Uh
- Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
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Li H, Yu S, Chen L, Liu H, Shen C. Immunomodulatory Role of Mesenchymal Stem Cells in Liver Transplantation: Status and Prospects. Dig Dis 2023; 42:41-52. [PMID: 37729883 DOI: 10.1159/000534003] [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: 05/05/2023] [Accepted: 09/03/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Liver transplantation (LT) is the only effective therapy for end-stage liver diseases, but some patients usually present with serious infection and immune rejection. Those with immune rejection require long-term administration of immunosuppressants, leading to serious adverse effects. Mesenchymal stem cells (MSCs) have various advantages in immune regulation and are promising drugs most likely to replace immunosuppressants. SUMMARY This study summarized the application of MSCs monotherapy, its combination with immunosuppressants, MSCs genetic modification, and MSCs derivative therapy (cell-free therapy) in LT. This may deepen the understanding of immunomodulatory role of MSCs and promote the application of MSCs in immune rejection treatment after LT. KEY MESSAGES MSCs could attenuate ischemia-reperfusion injury and immune rejection. There is no consensus on the effects of types and concentrations of immunosuppressants on MSCs. Although genetically modified MSCs have contributed to better outcomes to some extent, the best modification is still unclear. Besides, multiple clinical complications developed frequently after LT. Unfortunately, there are still few studies on the polygenic modification of MSCs for the simultaneous treatment of these complications. Therefore, more studies should be performed to investigate the potency of multi-gene modified MSCs in treating complications after LT. Additionally, MSC derivatives mainly include exosomes, extracellular vesicles, and conditioned medium. Despite therapeutic effects, these three therapies still have some limitations such as heterogeneity between generations and that they cannot be quantified accurately.
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Affiliation(s)
- Haitao Li
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Saihua Yu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Lihong Chen
- Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Hongzhi Liu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Conglong Shen
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
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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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37
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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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Li K, Zhu Z, Sun X, Zhao L, Liu Z, Xing J. Harnessing the therapeutic potential of mesenchymal stem cell-derived exosomes in cardiac arrest: Current advances and future perspectives. Biomed Pharmacother 2023; 165:115201. [PMID: 37480828 DOI: 10.1016/j.biopha.2023.115201] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Cardiac arrest (CA), characterized by sudden onset and high mortality rates, is one of the leading causes of death globally, with a survival rate of approximately 6-24%. Studies suggest that the restoration of spontaneous circulation (ROSC) hardly improved the mortality rate and prognosis of patients diagnosed with CA, largely due to ischemia-reperfusion injury. MAIN BODY Mesenchymal stem cells (MSCs) exhibit self-renewal and strong potential for multilineage differentiation. Their effects are largely mediated by extracellular vesicles (EVs). Exosomes are the most extensively studied subgroup of EVs. EVs mainly mediate intercellular communication by transferring vesicular proteins, lipids, nucleic acids, and other substances to regulate multiple processes, such as cytokine production, cell proliferation, apoptosis, and metabolism. Thus, exosomes exhibit significant potential for therapeutic application in wound repair, tissue reconstruction, inflammatory reaction, and ischemic diseases. CONCLUSION Based on similar pathological mechanisms underlying post-cardiac arrest syndrome involving various tissues and organs in many diseases, the review summarizes the therapeutic effects of MSC-derived exosomes and explores the prospects for their application in the treatment of CA.
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Affiliation(s)
- Ke Li
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
| | - Zhu Zhu
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, China.
| | - Xiumei Sun
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
| | - Linhong Zhao
- Northeast Normal University, Changchun 130022, China.
| | - Zuolong Liu
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
| | - Jihong Xing
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
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39
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Lu D, Jiao X, Jiang W, Yang L, Gong Q, Wang X, Wei M, Gong S. Mesenchymal stem cells influence monocyte/macrophage phenotype: Regulatory mode and potential clinical applications. Biomed Pharmacother 2023; 165:115042. [PMID: 37379639 DOI: 10.1016/j.biopha.2023.115042] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 06/30/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from a variety of tissues, such as umbilical cord, fat, and bone marrow. Today, MSCs are widely recognized for their prominent anti-inflammatory properties in a variety of acute and chronic inflammatory diseases. In inflammatory diseases, monocytes/macrophages are an important part of the innate immune response in the body, and the alteration of the inflammatory phenotype plays a crucial role in the secretion of pro-inflammatory/anti-inflammatory factors, the repair of injured sites, and the infiltration of inflammatory cells. In this review, starting from the effect of MSCs on the monocyte/macrophage phenotype, we have outlined in detail the process by which MSCs influence the transformation of the monocyte/macrophage inflammatory phenotype, emphasizing the central role of monocytes/macrophages in MSC-mediated anti-inflammatory and damage site repair. MSCs are phagocytosed by monocytes/macrophages in various physiological states, the paracrine effect of MSCs and mitochondrial transfer of MSCs to macrophages to promote the transformation of monocytes/macrophages into anti-inflammatory phenotypes. We also review the clinical applications of the MSCs-monocytes/macrophages system and describe novel pathways between MSCs and tissue repair, the effects of MSCs on the adaptive immune system, and the effects of energy metabolism levels on monocyte/macrophage phenotypic changes.
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Affiliation(s)
- Dejin Lu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Xue Jiao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Wenjian Jiang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Li Yang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Qian Gong
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Xiaobin Wang
- Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
| | - Shiqiang Gong
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
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40
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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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Yao Y, Zhang L, Cheng F, Jiang Q, Ye Y, Ren Y, He Y, Su D, Cheng L, Shi G, Dai L, Deng H. PPARγ-dependent hepatic macrophage switching acts as a central hub for hUCMSC-mediated alleviation of decompensated liver cirrhosis in rats. Stem Cell Res Ther 2023; 14:184. [PMID: 37501214 PMCID: PMC10375757 DOI: 10.1186/s13287-023-03416-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 07/17/2023] [Indexed: 07/29/2023] Open
Abstract
BACKGROUND Decompensated liver cirrhosis (DLC), a terminal-stage complication of liver disease, is a major cause of morbidity and mortality in patients with hepatopathies. Human umbilical cord mesenchymal stem cell (hUCMSC) therapy has emerged as a novel treatment alternative for the treatment of DLC. However, optimized therapy protocols and the associated mechanisms are not entirely understood. METHODS We constructed a DLC rat model consistent with the typical clinical characteristics combined use of PB and CCL4. Performing dynamic detection of liver morphology and function in rats for 11 weeks, various disease characteristics of DLC and the therapeutic effect of hUCMSCs on DLC in experimental rats were thoroughly investigated, according to ascites examination, histopathological, and related blood biochemical analyses. Flow cytometry analysis of rat liver, immunofluorescence, and RT-qPCR was performed to examine the changes in the liver immune microenvironment after hucMSCs treatment. We performed RNA-seq analysis of liver and primary macrophages and hUCMSCs co-culture system in vitro to explore possible signaling pathways. PPARγ antagonist, GW9662, and clodronate liposomes were used to inhibit PPAR activation and pre-exhaustion of macrophages in DLC rats' livers, respectively. RESULTS We found that changing the two key issues, the frequency and initial phase of hUCMSCs infusion, can affect the efficacy of hUCMSCs, and the optimal hUCMSCs treatment schedule is once every week for three weeks at the early stage of DLC progression, providing the best therapeutic effect in reducing mortality and ascites, and improving liver function in DLC rats. hUCMSCs treatment skewed the macrophage phenotype from M1-type to M2-type by activating the PPARγ signaling pathway in the liver, which was approved by primary macrophages and hUCMSCs co-culture system in vitro. Both inhibition of PPARγ activation with GW9662 and pre-exhaustion of macrophages in DLC rats' liver abolished the regulation of hUCMSCs on macrophage polarization, thus attenuating the beneficial effect of hUCMSCs treatment in DLC rats. CONCLUSIONS These data demonstrated that the optimal hUCMSCs treatment effectively inhibits the ascites formation, prolongs survival and significantly improves liver structure and function in DLC rats through the activation of the PPARγ signaling pathway within liver macrophages. Our study compared the efficacy of different hUCMSCs infusion regimens for DLC, providing new insights on cell-based therapies for regenerative medicine.
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Affiliation(s)
- Yunqi Yao
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Lin Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Fuyi Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Qingyuan Jiang
- Department of Obstetrics, Sichuan Provincial Hospital for Women and Children, Chengdu, People's Republic of China
| | - Yixin Ye
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Yushuang Ren
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Yuting He
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Dongsheng Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Lin Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No.1, Gao-peng Street, Chengdu, 610041, People's Republic of China.
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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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Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023; 20:583-599. [PMID: 36823236 PMCID: PMC10229624 DOI: 10.1038/s41423-023-00983-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/29/2023] [Indexed: 02/25/2023] Open
Abstract
Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.
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Affiliation(s)
- Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Zhipeng Han
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China.
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Hu XH, Chen L, Wu H, Tang YB, Zheng QM, Wei XY, Wei Q, Huang Q, Chen J, Xu X. Cell therapy in end-stage liver disease: replace and remodel. Stem Cell Res Ther 2023; 14:141. [PMID: 37231461 DOI: 10.1186/s13287-023-03370-z] [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] [Received: 09/30/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.
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Affiliation(s)
- Xin-Hao Hu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Lan Chen
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Wu
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Yang-Bo Tang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Qiu-Min Zheng
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xu-Yong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qiang Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qi Huang
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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Wu HW, Chen HD, Chen YH, Mao XL, Feng YY, Li SW, Zhou XB. The Effects of Programmed Cell Death of Mesenchymal Stem Cells on the Development of Liver Fibrosis. Stem Cells Int 2023; 2023:4586398. [PMID: 37214784 PMCID: PMC10195177 DOI: 10.1155/2023/4586398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/06/2023] [Accepted: 04/02/2023] [Indexed: 05/24/2023] Open
Abstract
Mesenchymal stem cells have shown noticeable potential for unlimited self-renewal. They can differentiate into specific somatic cells, integrate into target tissues via cell-cell contact, paracrine effects, exosomes, and other processes and then regulate the target cells and tissues. Studies have demonstrated that transplantation of MSCs could decrease the expression and concentration of collagen in the liver, thereby reducing liver fibrosis. A growing body of evidence indicates that apoptotic MSCs could inhibit harmful immune responses and reduce inflammatory responses more effectively than viable MSCs. Accumulating evidence suggests that mitochondrial transfer from MSCs is a novel strategy for the regeneration of various damaged cells via the rescue of their respiratory activities. This study is aimed at reviewing the functions of MSCs and the related roles of the programmed cell death of MSCs, including autophagy, apoptosis, pyroptosis, and ferroptosis, as well as the regulatory pathogenic mechanisms of MSCs in liver fibrosis. Research has demonstrated that the miR-200B-3p gene is differentially expressed gene between LF and normal liver samples, and that the miR-200B-3p gene expression is positively correlated with the degree of liver fibrosis, suggesting that MSCs could inhibit liver fibrosis through pyroptosis. It was confirmed that circulating monocytes could deliver MSC-derived immunomodulatory molecules to different sites by phagocytosis of apoptotic MSCs, thereby achieving systemic immunosuppression. Accordingly, it was suggested that characterization of the programmed cell death-mediated immunomodulatory signaling pathways in MSCs should be a focus of research.
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Affiliation(s)
- Hong-wei Wu
- Department of Infectious Diseases, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, Zhejiang, China
| | - He-dan Chen
- Department of Infectious Diseases, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Ya-hong Chen
- Health Management Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xin-li Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu-yi Feng
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xian-bin Zhou
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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Giuli L, Santopaolo F, Pallozzi M, Pellegrino A, Coppola G, Gasbarrini A, Ponziani FR. Cellular therapies in liver and pancreatic diseases. Dig Liver Dis 2023; 55:563-579. [PMID: 36543708 DOI: 10.1016/j.dld.2022.11.013] [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: 08/11/2022] [Revised: 10/21/2022] [Accepted: 11/22/2022] [Indexed: 04/29/2023]
Abstract
Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine.
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Affiliation(s)
- Lucia Giuli
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Pallozzi
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Pellegrino
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
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Xu YN, Xu W, Zhang X, Wang DY, Zheng XR, Liu W, Chen JM, Chen GF, Liu CH, Liu P, Mu YP. BM-MSCs overexpressing the Numb enhance the therapeutic effect on cholestatic liver fibrosis by inhibiting the ductular reaction. Stem Cell Res Ther 2023; 14:45. [PMID: 36941658 PMCID: PMC10029310 DOI: 10.1186/s13287-023-03276-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 03/09/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Cholestatic liver fibrosis (CLF) is caused by inflammatory destruction of the intrahepatic bile duct and abnormal proliferation of the small bile duct after cholestasis. Activation of the Notch signaling pathway is required for hepatic stem cells to differentiate into cholangiocytes during the pathogenesis of CLF. Our previous research found that the expression of the Numb protein, a negative regulator of Notch signaling, was significantly reduced in the livers of patients with primary biliary cholangitis and CLF rats. However, the relationship between the Numb gene and CLF is largely unclear. In this study, we investigated the role of the Numb gene in the treatment of bile duct ligation (BDL)-induced CLF. METHODS In vivo, bone marrow-derived mesenchymal stem cells (BM-MSCs) with Numb gene overexpression or knockdown obtained using lentivirus transfection were transplanted into the livers of rats with BDL-induced CLF. The effects of the Numb gene on stem cell differentiation and CLF were evaluated by performing histology, tests of liver function, and measurements of liver hydroxyproline, cytokine gene and protein levels. In vitro, the Numb gene was overexpressed or knocked down in the WB-F344 cell line by lentivirus transfection, Then, cells were subjected immunofluorescence staining and the detection of mRNA levels of related factors, which provided further evidence supporting the results from in vivo experiments. RESULTS BM-MSCs overexpressing the Numb gene differentiated into hepatocytes, thereby inhibiting CLF progression. Conversely, BM-MSCs with Numb knockdown differentiated into biliary epithelial cells (BECs), thereby promoting the ductular reaction (DR) and the progression of CLF. In addition, we confirmed that knockdown of Numb in sodium butyrate-treated WB-F344 cells aggravated WB-F344 cell differentiation into BECs, while overexpression of Numb inhibited this process. CONCLUSIONS The transplantation of BM-MSCs overexpressing Numb may be a useful new treatment strategy for CLF.
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Affiliation(s)
- Yan-Nan Xu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Wen Xu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Xu Zhang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Dan-Yang Wang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Xin-Rui Zheng
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Wei Liu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Jia-Mei Chen
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Gao-Feng Chen
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Cheng-Hai Liu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China
| | - Ping Liu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China.
| | - Yong-Ping Mu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, 528, Zhangheng Road, Pudong District, Shanghai, 201203, China.
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Kim JY, Kim SH, Seok J, Bae SH, Hwang SG, Kim GJ. Increased PRL-1 in BM-derived MSCs triggers anaerobic metabolism via mitochondria in a cholestatic rat model. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 31:512-524. [PMID: 36865088 PMCID: PMC9970868 DOI: 10.1016/j.omtn.2023.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 01/31/2023] [Indexed: 02/09/2023]
Abstract
Mesenchymal stem cell (MSC) therapy in chronic liver disease is associated with mitochondrial anaerobic metabolism. Phosphatase of regenerating liver-1 (PRL-1), known as protein tyrosine phosphatase type 4A, member 1 (PTP4A1), plays a critical role in liver regeneration. However, its therapeutic mechanism remains obscure. The aim of this study was to establish genetically modified bone marrow (BM)-MSCs overexpressing PRL-1 (BM-MSCsPRL-1) and to investigate their therapeutic effects on mitochondrial anaerobic metabolism in a bile duct ligation (BDL)-injured cholestatic rat model. BM-MSCsPRL-1 were generated with lentiviral and nonviral gene delivery systems and characterized. Compared with naive cells, BM-MSCsPRL-1 showed an improved antioxidant capacity and mitochondrial dynamics and decreased cellular senescence. In particular, mitochondrial respiration in BM-MSCsPRL-1 generated using the nonviral system was significantly increased as well as mtDNA copy number and total ATP production. Moreover, transplantation of BM-MSCsPRL-1 generated using the nonviral system had predominantly antifibrotic effects and restored hepatic function in a BDL rat model. Decreased cytoplasmic lactate and increased mitochondrial lactate upon the administration of BM-MSCsPRL-1 indicated significant alterations in mtDNA copy number and ATP production, activating anaerobic metabolism. In conclusion, BM-MSCsPRL-1 generated by a nonviral gene delivery system enhanced anaerobic mitochondrial metabolism in a cholestatic rat model, improving hepatic function.
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Affiliation(s)
- Jae Yeon Kim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si 13488, Republic of Korea,Research Institute of Placental Science, CHA University, Seongnam 13488, Republic of Korea
| | - Se Ho Kim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si 13488, Republic of Korea
| | - Jin Seok
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si 13488, Republic of Korea,Research Institute of Placental Science, CHA University, Seongnam 13488, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Catholic University Medical College, Seoul 03312, Republic of Korea
| | - Seong-Gyu Hwang
- Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si 13488, Republic of Korea,Research Institute of Placental Science, CHA University, Seongnam 13488, Republic of Korea,Corresponding author Gi Jin Kim, Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si 13488, Republic of Korea.
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Human Umbilical Cord Blood-Derived Mesenchymal Stem Cell Transplantation for Patients with Decompensated Liver Cirrhosis. J Gastrointest Surg 2023; 27:926-931. [PMID: 36703021 PMCID: PMC10133084 DOI: 10.1007/s11605-022-05528-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/04/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND OR PURPOSE Although human umbilical cord blood-derived mesenchymal stem cell transplantation (HUCB-MSCT) resulted in a good short-term therapeutic effect on patients with decompensated liver cirrhosis (DLC), the long-term survival remained unclear. This study aimed to evaluate the impact of HUCB-MSCT on long-term outcomes in patients with DLC. METHODS This retrospective cohort study included hospitalized patients with decompensated cirrhosis in Liuzhou Hospital of Traditional Chinese Medicine between November 2010 and February 2013. The primary outcome was overall survival (OS). The secondary outcomes were 3-year and 5-year survival rates and the occurrence rate of hepatocellular carcinoma (HCC). RESULTS A total of 201 subjects were enrolled, including 36 patients who underwent HUCB-MSCT (SCT group) and 165 patients who did not (non-SCT group). After PSM (1:2), there were 36 patients in the SCT group and 72 patients in non-SCT group. The 3-year and 5-year survival rates of the two groups were 83.3% vs. 61.8% and 63.9% vs. 43.6%, and median OS time was 92.50 and 50.80 months, respectively. HUCB-MSCT treatment was found to be an independent beneficial factor for patient OS (hazard ratio = 0.47; 95% CI: 0.29-0.76; P = 0.002). There was no significant difference in the occurrence rate of HCC between the two groups (P = 0.410). DISCUSSION OR CONCLUSIONS HUCB-MSCT may improve long-term OS without increasing the occurrence of HCC in patients with DLC. TRIAL REGISTRATION The Chinese Clinical Trial Registry (ChiCTR2100047550).
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50
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Felli E, Nulan Y, Selicean S, Wang C, Gracia-Sancho J, Bosch J. Emerging Therapeutic Targets for Portal Hypertension. CURRENT HEPATOLOGY REPORTS 2023; 22:51-66. [PMID: 36908849 PMCID: PMC9988810 DOI: 10.1007/s11901-023-00598-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/18/2023] [Indexed: 02/13/2023]
Abstract
Purpose of Review Portal hypertension is responsible of the main complications of cirrhosis, which carries a high mortality. Recent treatments have improved prognosis, but this is still far from ideal. This paper reviews new potential therapeutic targets unveiled by advances of key pathophysiologic processes. Recent Findings Recent research highlighted the importance of suppressing etiologic factors and a safe lifestyle and outlined new mechanisms modulating portal pressure. These include intrahepatic abnormalities linked to inflammation, fibrogenesis, vascular occlusion, parenchymal extinction, and angiogenesis; impaired regeneration; increased hepatic vascular tone due to sinusoidal endothelial dysfunction with insufficient NO availability; and paracrine liver cell crosstalk. Moreover, pathways such as the gut-liver axis modulate splanchnic vasodilatation and systemic inflammation, exacerbate liver fibrosis, and are being targeted by therapy. We have summarized studies of new agents addressing these targets. Summary New agents, alone or in combination, allow acting in complementary mechanisms offering a more profound effect on portal hypertension while simultaneously limiting disease progression and favoring regression of fibrosis and of cirrhosis. Major changes in treatment paradigms are anticipated.
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Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Yelidousi Nulan
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Sonia Selicean
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Cong Wang
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
- Liver Vascular Biology Research Group, CIBEREHD, IDIBAPS Research Institute, 08036 Barcelona, Spain
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
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