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Li X, Feng J, Cheng H, Jin N, Jin S, Liu Z, Xu J, Xie J. Human umbilical cord mesenchymal stem cells enhance liver regeneration and decrease collagen content in fibrosis mice after partial hepatectomy by activating Wnt/β-catenin signaling. Acta Biochim Biophys Sin (Shanghai) 2024. [PMID: 39716885 DOI: 10.3724/abbs.2024207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024] Open
Abstract
Liver fibrosis is a critical stage in the progression of various chronic liver diseases to cirrhosis and liver cancer. Early inhibition of liver fibrosis is crucial for the treatment of liver disease. Hepatectomy, a common treatment for liver-related diseases, promotes liver regeneration. However, in the context of liver fibrosis, liver regeneration is hindered. Many studies have shown that mesenchymal stem cells (MSCs) can promote liver regeneration after partial hepatectomy (PH). However, there are few reports on the impact of MSC therapy on liver regeneration post-PH in the context of hepatic fibrosis. The objective of this study is to examine the impact of MSCs on liver regeneration following PH in the fibrotic liver and uncover the related molecular mechanisms. This study reveals that MSC therapy significantly enhances liver function and mitigates liver inflammation after PH in the context of hepatic fibrosis. MSCs also significantly promote liver regeneration and alleviate liver fibrosis. In addition, this study identifies the role of MSCs in promoting liver regeneration and alleviating liver fibrosis via the activation of Wnt/β-catenin signaling. The combination of MSCs with hepatectomy may offer a novel approach for the treatment of liver fibrotic diseases.
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Affiliation(s)
- Xuewei Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jinghui Feng
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Haiqin Cheng
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Ning Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Shanshan Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xu
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplant Center, the First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
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Elzainy A, El Sadik A, Altowayan WM. Comparison between the Regenerative and Therapeutic Impacts of Bone Marrow Mesenchymal Stem Cells and Adipose Mesenchymal Stem Cells Pre-Treated with Melatonin on Liver Fibrosis. Biomolecules 2024; 14:297. [PMID: 38540717 PMCID: PMC10968153 DOI: 10.3390/biom14030297] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/14/2024] [Accepted: 02/28/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND The distinctive feature of liver fibrosis is the progressive replacement of healthy hepatic cells by the extracellular matrix protein, which is abundant in collagen I and III, with impaired matrix remodeling. The activation of myofibroblastic cells enhances the fibrogenic response of complex interactions of hepatic stellate cells, fibroblasts, and inflammatory cells to produce the excessive deposition of the extracellular protein matrix. This process is activated by multiple fibrogenic mediators and cytokines, such as TNF-α and IL-1β, accompanied with a decrease in the anti-fibrogenic factor NF-κβ. Mesenchymal stem cells (MSCs) represent a promising therapy for liver fibrosis, allowing for a more advanced regenerative influence when cultured with extrinsic or intrinsic proliferative factors, cytokines, antioxidants, growth factors, and hormones such as melatonin (MT). However, previous studies showed conflicting findings concerning the therapeutic effects of adipose (AD) and bone marrow (BM) MSCs; therefore, the present work aimed to conduct a comparative and comprehensive study investigating the impact of MT pre-treatment on the immunomodulatory, anti-inflammatory, and anti-apoptotic effects of AD- and BM-MSCs and to critically analyze whether MT-pre-treated AD-MSCs and BM-MSCs reveal equal or different therapeutic and regenerative potentials in a CCl4-injured liver experimental rat model. MATERIALS AND METHODS Six groups of experimental rats were used, with ten rats in each group: group I (control group), group II (CCl4-treated group), group III (CCl4- and BM-MSC-treated group), group IV (CCl4 and MT-pre-treated BM-MSC group), group V (CCl4- and AD-MSC-treated group), and group VI (CCl4 and MT-pre-treated AD-MSC group). Liver function tests and the gene expression of inflammatory, fibrogenic, apoptotic, and proliferative factors were analyzed. Histological and immunohistochemical changes were assessed. RESULTS The present study compared the ability of AD- and BM-MSCs, with and without MT pre-treatment, to reduce hepatic fibrosis. Both types of MSCs improved hepatocyte function by reducing the serum levels of ALT, aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL). In addition, the changes in the hepatocellular architecture, including the hepatocytes, liver sinusoids, central veins, portal veins, biliary ducts, and hepatic arteries, showed a decrease in hepatocyte injury and cholestasis with a reduction in inflammation, apoptosis, and necrosis of the hepatic cells, together with an inhibition of liver tissue fibrosis. These results were augmented by an analysis of the expression of the pro-inflammatory cytokines TNFα and IL-1β, the anti-fibrogenic factor NF-κβ, the apoptotic factor caspase-3, and the proliferative indicators antigen Ki-67 and proliferating cell nuclear antigen (PCNA). These findings were found to be statistically significant, with the restoration of normal parameters in the rats that received AD-MSCs pre-treated with MT, denoting optimal regenerative and therapeutic effects. CONCLUSIONS AD-MSCs pre-treated with MT are the preferred choice in improving hepatic fibrosis and promoting the therapeutic and regenerative ability of liver tissue. They represent a very significant tool for future stem cell use in the tissue regeneration strategy for the treatment of liver diseases.
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Affiliation(s)
- Ahmed Elzainy
- Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia; (A.E.); (A.E.S.)
- Department of Anatomy and Embryology, College of Medicine, Cairo University, Cairo 11956, Egypt
| | - Abir El Sadik
- Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia; (A.E.); (A.E.S.)
- Department of Anatomy and Embryology, College of Medicine, Cairo University, Cairo 11956, Egypt
| | - Waleed Mohammad Altowayan
- Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
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Mohamed SR, El-Mahroky SM, Abdel Aal SM. Comparative study between the effect of mesenchymal stem cells microvesicles versus ozone on induced liver injury in adult male albino rats (Histological & Immunohistochemical study). Ultrastruct Pathol 2024; 48:16-28. [PMID: 37997442 DOI: 10.1080/01913123.2023.2278627] [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: 06/28/2023] [Accepted: 10/30/2023] [Indexed: 11/25/2023]
Abstract
Liver disease accounts for approximately 2 million deaths er year worldwide. Liver fibrisis results from chronic injury to the liver. If not effectively treated in time, liver fibrosis may transform into liver cirrhosis. MVs are recognized as potential biomarkers and important theraputic tools for a wide sectrum of diseases. Medical ozone has the ability to protect the body against pathological conditions caused by oxidative stress. The influence of ozone and MVs on CCL4 induced liver fibrosis was investigated in this study. Forty-eight adult male albino rats were divided into four equal groups. I control, II CCL4 group, III ozone and IV microvesicles groups. Liver fibrosis was induced in group II, III & IV using 12 SC injections (0.5 ml/kg body weight) of CCL4 dissolved in olive oil twice ber week for weeks. Blood samples were obtained to estimate serum ALT & AST. Liver tissues were processed for measurment of GSH & SOD, light and electron microscopic examination. H&E staine sections og group II showed dilated congested sinusoids and centralveins, mononuclear infiltrations, vacuolations and dark nuclei. Ultrastructurally, group II revealed irregular heterochromatic nuclei of hepatocytes, small scanty mitochondria & vacuolations. Morphometric & statistical analyses were performed. Group III showed some improvement, however, group IV showed more imrovement. The results indicates that MVs caused marked improvement than ozone against CCL4 induced liver damage via antioxidant & antiinflammatory properties.
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Affiliation(s)
- Samar R Mohamed
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Samaa M El-Mahroky
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sara Mohamed Abdel Aal
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Mik P, Barannikava K, Surkova P. Biased Quantification of Rat Liver Fibrosis-Meta-Analysis with Practical Recommendations and Clinical Implications. J Clin Med 2023; 12:5072. [PMID: 37568474 PMCID: PMC10420125 DOI: 10.3390/jcm12155072] [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: 06/30/2023] [Revised: 07/21/2023] [Accepted: 07/29/2023] [Indexed: 08/13/2023] Open
Abstract
For liver fibrosis assessment, the liver biopsy is usually stained with Masson's trichrome (MT) or picrosirius red (PSR) to quantify liver connective tissue (LCT) for fibrosis scoring. However, several concerns of such semiquantitative assessments have been raised, and when searching for data on the amount of LCT in healthy rats, the results vastly differ. Regarding the ongoing reproducibility crisis in science, it is necessary to inspect the results and methods, and to design an unbiased and reproducible method of LCT assessment. We searched the Medline database using search terms related to liver fibrosis, LCT and collagen, rat strains, and staining methods. Our search identified 74 eligible rat groups in 57 studies. We found up to 170-fold differences in the amount of LCT among healthy Wistar and Sprague-Dawley rats, with significant differences even within individual studies. Biased sampling and quantification probably caused the observed differences. In addition, we also found incorrect handling of liver fibrosis scoring. Assessment of LCT using stereological sampling methods (such as systematic uniform sampling) would provide us with unbiased data. Such data could eventually be used not only for the objective assessment of liver fibrosis but also for validation of noninvasive methods of the assessment of early stages of liver fibrosis.
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Affiliation(s)
- Patrik Mik
- Department of Anatomy, Faculty of Medicine in Pilsen, Charles University, alej Svobody 76, 323 00 Pilsen, Czech Republic
- Biomedical Center and Department of Histology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Katsiaryna Barannikava
- Department of Anatomy, Faculty of Medicine in Pilsen, Charles University, alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Polina Surkova
- Department of Anatomy, Faculty of Medicine in Pilsen, Charles University, alej Svobody 76, 323 00 Pilsen, Czech Republic
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Drobiova H, Sindhu S, Ahmad R, Haddad D, Al-Mulla F, Al Madhoun A. Wharton's jelly mesenchymal stem cells: a concise review of their secretome and prospective clinical applications. Front Cell Dev Biol 2023; 11:1211217. [PMID: 37440921 PMCID: PMC10333601 DOI: 10.3389/fcell.2023.1211217] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
Accumulating evidence indicates that most primary Wharton's jelly mesenchymal stem cells (WJ-MSCs) therapeutic potential is due to their paracrine activity, i.e., their ability to modulate their microenvironment by releasing bioactive molecules and factors collectively known as secretome. These bioactive molecules and factors can either be released directly into the surrounding microenvironment or can be embedded within the membrane-bound extracellular bioactive nano-sized (usually 30-150 nm) messenger particles or vesicles of endosomal origin with specific route of biogenesis, known as exosomes or carried by relatively larger particles (100 nm-1 μm) formed by outward blebbing of plasma membrane called microvesicles (MVs); exosomes and MVs are collectively known as extracellular vesicles (EVs). The bioactive molecules and factors found in secretome are of various types, including cytokines, chemokines, cytoskeletal proteins, integrins, growth factors, angiogenic mediators, hormones, metabolites, and regulatory nucleic acid molecules. As expected, the secretome performs different biological functions, such as immunomodulation, tissue replenishment, cellular homeostasis, besides possessing anti-inflammatory and anti-fibrotic effects. This review highlights the current advances in research on the WJ-MSCs' secretome and its prospective clinical applications.
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Affiliation(s)
- Hana Drobiova
- Human Genetics Unit, Department of Pathology, College of Medicine, Kuwait University, Jabriya, Kuwait
| | - Sardar Sindhu
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman, Kuwait
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Rasheed Ahmad
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Dania Haddad
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
| | - Ashraf Al Madhoun
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman, Kuwait
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
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Huang YL, De Gregorio C, Silva V, Elorza ÁA, Léniz P, Aliaga-Tobar V, Maracaja-Coutinho V, Budini M, Ezquer F, Ezquer M. Administration of Secretome Derived from Human Mesenchymal Stem Cells Induces Hepatoprotective Effects in Models of Idiosyncratic Drug-Induced Liver Injury Caused by Amiodarone or Tamoxifen. Cells 2023; 12:cells12040636. [PMID: 36831304 PMCID: PMC9954258 DOI: 10.3390/cells12040636] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/19/2023] [Accepted: 02/07/2023] [Indexed: 02/18/2023] Open
Abstract
Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. While many factors may contribute to the susceptibility to DILI, obese patients with hepatic steatosis are particularly prone to suffer DILI. The secretome derived from mesenchymal stem cell has been shown to have hepatoprotective effects in diverse in vitro and in vivo models. In this study, we evaluate whether MSC secretome could improve DILI mediated by amiodarone (AMI) or tamoxifen (TMX). Hepatic HepG2 and HepaRG cells were incubated with AMI or TMX, alone or with the secretome of MSCs obtained from human adipose tissue. These studies demonstrate that coincubation of AMI or TMX with MSC secretome increases cell viability, prevents the activation of apoptosis pathways, and stimulates the expression of priming phase genes, leading to higher proliferation rates. As proof of concept, in a C57BL/6 mouse model of hepatic steatosis and chronic exposure to AMI, the MSC secretome was administered endovenously. In this study, liver injury was significantly attenuated, with a decrease in cell infiltration and stimulation of the regenerative response. The present results indicate that MSC secretome administration has the potential to be an adjunctive cell-free therapy to prevent liver failure derived from DILI caused by TMX or AMI.
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Affiliation(s)
- Ya-Lin Huang
- Centro de Medicina Regenerativa, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago 7610658, Chile
| | - Cristian De Gregorio
- Centro de Medicina Regenerativa, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago 7610658, Chile
| | - Verónica Silva
- Centro de Medicina Regenerativa, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago 7610658, Chile
| | - Álvaro A. Elorza
- Instituto de Ciencias Biomédicas, Facultad de Medicina y Ciencias de la Vida, Universidad Andres Bello, Santiago 7610658, Chile
| | - Patricio Léniz
- Unidad de Cirugía Plástica, Reparadora y Estética, Clínica Alemana, Santiago 7610658, Chile
| | - Víctor Aliaga-Tobar
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 7610658, Chile
- Centro de Modelamiento Molecular, Biofísica y Bioinformática (CM2B2), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 7610658, Chile
- Laboratorio de Bioingeniería, Instituto de Ciencias de la Ingeniería, Universidad de O’Higgins, Rancagua 7610658, Chile
| | - Vinicius Maracaja-Coutinho
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 7610658, Chile
- Centro de Modelamiento Molecular, Biofísica y Bioinformática (CM2B2), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 7610658, Chile
| | - Mauricio Budini
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago 7610658, Chile
| | - Fernando Ezquer
- Centro de Medicina Regenerativa, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago 7610658, Chile
- Correspondence: (F.E.); (M.E.); Tel.: +56-990-699-272 (F.E.); +56-976-629-880 (M.E.)
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago 7610658, Chile
- Correspondence: (F.E.); (M.E.); Tel.: +56-990-699-272 (F.E.); +56-976-629-880 (M.E.)
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Rashidi M, Matour E, Monjezi S, Asadi Zadeh S, Shakerian E, Sabahy S, Afarin R. Effects of exosomes of mesenchymal stem cells on cholesterol-induced hepatic fibrogenesis. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:695-700. [PMID: 37275763 PMCID: PMC10237171 DOI: 10.22038/ijbms.2023.68858.15003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 04/05/2023] [Indexed: 06/07/2023]
Abstract
Objectives Free cholesterol in the diet can cause liver fibrosis by accumulating in Hepatic stellate cells (HSCs). The rate of mortality of this disease is high worldwide and there is no definite remedy for it, but might be treated by anti-fibrotic therapies. MSCs-derived exosomes are known as the new mechanism of cell-to-cell communication, showing that exosomes can be used as a new treatment. In this study, we investigated the ability of exosomes of WJ-MSCs as a new remedy to reduce cholesterol-induced liver fibrosis in the LX2 cell line. Materials and Methods MSCs were isolated from Wharton's jelly of the umbilical cord and the exosomes were extracted. The LX2 cell line was cultured in DMEM medium with 10% FBS, then cells were treated with 75 and 100 μM concentrations of cholesterol for 24 hr. The mRNA expression of TGF-β, αSMA, and collagen1α genes, and the level of Smad3 protein were measured to assess liver fibrosis. Results Cholesterol increased the expression of TGF-β, αand -SMA, and collagen1α genes by increasing the phosphorylation of the Smad3 protein. Treatment with Exosomes significantly reduced the expression of TGF-β, α-SMA, and collagen1α genes (fibrosis genes). Treatment with exosomes prevented the activation of HSCs by inhibiting the phosphorylation of the Smad3 protein. Conclusion The exosomes of WJ-MSCs can inhibit the TGFβ/Smad3 signaling pathway preventing further activation of HSCs and progression of liver fibrosis. So, the exosomes of WJ-MSCs s could be introduced as a treatment for liver failure.
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Affiliation(s)
- Mojtaba Rashidi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Emad Matour
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sajad Monjezi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shahla Asadi Zadeh
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Elham Shakerian
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sahar Sabahy
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Afarin
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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8
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Abdelgwad M, Ewaiss M, Sabry D, Khalifa WA, Altaib ZM, Alhelf M. Comparative study on effect of mesenchymal stem cells and endothelial progenitor cells on treatment of experimental CCL4-induced liver fibrosis. Arch Physiol Biochem 2022; 128:1071-1080. [PMID: 32374186 DOI: 10.1080/13813455.2020.1752256] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND We speculated impacts of BM-MSCs and UC-EPCs on reversal of hepatic injury induced by carbon tetrachloride (CCl4). Fifty adult rats were divided into five groups: control group, CCl4A group, CCl4B group, CCl4/BM-MSCs group and CCl4/UC-EPCs group. Blood samples were driven to measure concentration of albumin and ALT. Quantitative expression of HGF, TGF-β, MMP-2, and VEGF were assessed by PCR. Histological and immunohistochemistry examination of the liver tissue were performed. RESULTS There was elevating albumin (p < .05) and reducing ALT (p < .05) concentrations in groups treated with BM-MSCs and UC-EPCs compared to untreated CCL4A&B groups. UC-EPCs treated group have significantly higher MMP-2 and VEGF (p < .01) genes expression than BM-MSCs treated group. Furthermore, UC-EPCs were more valuable than BMMSCs in increasing gene expression of HGF (p < .05) and immunohistochemistry of α-SMA and Ki-67 (p < .01). BM-MSCs have significantly lower TGF-β (p < .00) compared to UC-EPCs. CONCLUSION This study highlighted on liver regeneration role of both UC-EPCs and BM-MSCs in liver fibrosis.
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Affiliation(s)
- Marwa Abdelgwad
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Manal Ewaiss
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt
- Medical College, Al-Jouf University, Al-Jawf, Saudi Arabia
| | - Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Warda A Khalifa
- Department of Biotechnology, Faculty of Science, Sebha University, Sabha, Libya
| | - Zeinab M Altaib
- Department of Histology and Cell Biology, Helwan Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Maha Alhelf
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
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Xu Q, Xia W, Zhou L, Zou Z, Li Q, Deng L, Wu S, Wang T, Cui J, Liu Z, Sun T, Ye J, Li F. Determination of Hepatic Iron Deposition in Drug-Induced Liver Fibrosis in Rats by Confocal Micro-XRF Spectrometry. ACS OMEGA 2022; 7:3738-3745. [PMID: 35128282 PMCID: PMC8811927 DOI: 10.1021/acsomega.1c06476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/14/2022] [Indexed: 06/14/2023]
Abstract
Liver fibrosis is the intermediate process and inevitable stage of the development of chronic liver disease into cirrhosis. Reducing the degree of liver fibrosis plays an extremely important role in treating chronic liver disease and preventing liver cirrhosis and liver cancer. The formation of liver fibrosis is affected by iron deposition to a certain extent, and excessive iron deposition further induces liver cirrhosis and liver cancer. Herein, confocal microbeam X-ray fluorescence (μ-XRF) was used to determine the intensity and biodistribution of iron deposition at different time points in the process of liver fibrosis induced by thioacetamide (TAA) in rats. To our best knowledge, this is the first study using confocal μ-XRF to analyze hepatic iron deposition in hepatic fibrosis. The results showed that there are minor and trace elements such as iron, potassium, and zinc in the liver of rats. Continuous injection of TAA solution resulted in increasing liver iron deposition over time. The intensity of iron deposition in liver tissue was also significantly reduced after bone mesenchymal stem cells (BMSCs) were injected. These findings indicated that confocal μ-XRF can be used as a nondestructive and quantitative method of evaluating hepatic iron deposition in hepatic fibrosis, and iron deposition may play an important role in the progression of hepatic fibrosis induced by TAA.
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Affiliation(s)
- Qianqian Xu
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular
Diseases, Ministry of Education, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Biomaterials and Biofabrication in Tissue Engineering
of Jiangxi Province, Gannan Medical University, Ganzhou 341000, China
| | - Wenjing Xia
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular
Diseases, Ministry of Education, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Biomaterials and Biofabrication in Tissue Engineering
of Jiangxi Province, Gannan Medical University, Ganzhou 341000, China
| | - Lazhen Zhou
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular
Diseases, Ministry of Education, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Biomaterials and Biofabrication in Tissue Engineering
of Jiangxi Province, Gannan Medical University, Ganzhou 341000, China
| | - Zhengwei Zou
- Key
Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular
Diseases, Ministry of Education, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Biomaterials and Biofabrication in Tissue Engineering
of Jiangxi Province, Gannan Medical University, Ganzhou 341000, China
- Sub-center
for Stem Cell Clinical Translation, First
Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi, China
| | - Qiuxia Li
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
| | - Lijun Deng
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
| | - Sha Wu
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
| | - Tao Wang
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
| | - Jingduo Cui
- College
of Nuclear Science and Technology, Beijing
Normal University, Beijing 100875, China
| | - Zhiguo Liu
- College
of Nuclear Science and Technology, Beijing
Normal University, Beijing 100875, China
| | - Tianxi Sun
- College
of Nuclear Science and Technology, Beijing
Normal University, Beijing 100875, China
| | - Junsong Ye
- Key
Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular
Diseases, Ministry of Education, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Biomaterials and Biofabrication in Tissue Engineering
of Jiangxi Province, Gannan Medical University, Ganzhou 341000, China
- Sub-center
for Stem Cell Clinical Translation, First
Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi, China
| | - Fangzuo Li
- College
of Medical Information Engineering, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular
Diseases, Ministry of Education, Gannan
Medical University, Ganzhou 341000, China
- Key
Laboratory of Biomaterials and Biofabrication in Tissue Engineering
of Jiangxi Province, Gannan Medical University, Ganzhou 341000, China
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10
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Zhao Y, Li HX, Luo Y, Cui JG, Talukder M, Li JL. Lycopene mitigates DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and mitochondrial unfolded protein response. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 292:118390. [PMID: 34699919 DOI: 10.1016/j.envpol.2021.118390] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/25/2021] [Accepted: 10/18/2021] [Indexed: 06/13/2023]
Abstract
Di (2-ethylhexyl) phthalate (DEHP) is a hazardous chemical which is used as a plasticizer in the plastic products. Lycopene (LYC) is a carotenoid that has protective roles against cellular damage in different organs. The present study sought to explore the role of the interaction between mitophagy and mitochondrial unfolded protein response (UPRmt) in the LYC mitigating DEHP-induced hepatic mitochondrial quality control disorder. The mice were treated with LYC (5 mg/kg) and/or DEHP (500 or 1000 mg/kg). In our findings, LYC prevented DEHP-induced histopathological alterations including steatosis and fibrosis, and ultrastructural injuries including decreased mitochondrial membrane potential (ΔΨm) and mitochondria volume density. Furthermore, LYC alleviated DEHP-induced mitochondrial biogenesis disorder by suppressing SIRT1-PGC-1α axis, PINK1-mediated mitophagy and the activation of mitochondrial unfolded protein response (UPRmt). This research suggested that LYC could prevent DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and UPRmt. The present study provided a current understanding about the potential implication of the SIRT1/PINK1/mitophagy axis and UPRmt in LYC preventing DEHP-induced hepatic mitochondrial quality control disorder.
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Affiliation(s)
- Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Hui-Xin Li
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150086, PR China
| | - Yu Luo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; People's Government of Nierhe Township of Suiling County, Suihua, 152236, PR China
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
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11
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Gupta S, Pinky, Vishal, Sharma H, Soni N, Rao EP, Dalela M, Yadav A, Nautiyal N, Kumar A, Nayak B, Banerjee A, Dinda AK, Mohanty S. Comparative Evaluation of Anti-Fibrotic Effect of Tissue Specific Mesenchymal Stem Cells Derived Extracellular Vesicles for the Amelioration of CCl4 Induced Chronic Liver Injury. Stem Cell Rev Rep 2021; 18:1097-1112. [PMID: 34859376 DOI: 10.1007/s12015-021-10313-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 01/08/2023]
Abstract
Mesenchymal Stem Cells (MSCs) derived Extracellular Vesicles (EVs) have emerged as an effective candidate for amelioration of liver fibrosis. However, the effect and the mechanisms of MSC-EVs in liver repair remains elusive. In this study, we have evaluated the differential regenerative efficacy of EVs derived from two different human tissue-specific MSCs (Adipose tissue; AD-MSC and Wharton's Jelly; WJ-MSC), in a murine model of chronic liver fibrosis. Mouse model of chronic liver injury was induced by carbon tetrachloride (CCl4) injection, followed by administration of EVs via the tail vein. Both quantitative and qualitative assessment was done to evaluate the hepatic regenerative potential of tissue specific MSC-extracellular vesicles. EVs, regardless of their MSC source, were found to be effective in alleviating chronic liver fibrosis, as demonstrated by macroscopic alterations in the liver. According to the findings of the comprehensive study, there were subtle variations in the tissue specific MSCs-EVs mediated approaches. A greater anti-fibrotic impact was demonstrated by AD-MSC derived EVs through extracellular matrix alteration and hepatocyte proliferation. WJ-MSC EVs, on the other hand, have an anti-inflammatory effect, as evidenced by alterations in the expression of pro- and anti-inflammatory cytokines. Furthermore, cargo profiling of these EVs revealed differences in the miRNA and protein expression, as well as the pathways that they were associated. Comparative overview of regression of fibrosis using tissue specific MSC derived EVs (credits BioRender.com ).
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Affiliation(s)
- Suchi Gupta
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India
| | - Pinky
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India
| | - Vishal
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India
| | - Harshita Sharma
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India
| | - Naina Soni
- Regional Centre for Biotechnology, Faridabad, Haryana, India
| | - E Pranshu Rao
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India
| | - Manu Dalela
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India
| | - Alka Yadav
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India
| | - Nidhi Nautiyal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Anupam Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Arup Banerjee
- Regional Centre for Biotechnology, Faridabad, Haryana, India
| | - Amit Kumar Dinda
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, 1st Floor, ORBO Complex, New Delhi, Ansari Nagar, India.
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12
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Endria Gunadi E, Wisnu Prajoko Y, Putra A. Effectiveness of Mesenchymal Stem Cells and Bovine Colostrum on Decreasing Tumor Necrosis Factor-Α Levels and Enhancement of Macrophages M2 in Remnant Liver. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) and bovine colostrum are potential therapies for the treatment of various degenerative and immune diseases.
AIM: This study aimed to analyze the effect of MSCs on levels of tumor necrosis factor-Α (TNF-α) and macrophages M2 in the liver fibrosis of Wistar rats after 50% resection.
METHODS: This study is a quasi-experimental post-test-only control group design to analyze the effect of giving bovine colostrum and MSCs to test animals on the process of regeneration of the remaining 50% liver with fibrosis. The study was conducted at the Stem Cell and Cancer Research Universitas Sultan Agung. The number of samples used was 40 male Wistar rats. The independent variables included MSC 1.000.0000 cells and bovine colostrum at a dose of 15 μL/g. Dependent variables used were macrophages M2 and levels of TNF-α ELISA.
RESULTS: TNF-α levels on day 3 were (p = 0.001), day 7 were (p = 0.01), and day 10 were (p = 0.01) in liver tissue in various study groups analyzed using ELISA on day three*. The results showed differences which were significant between the control and treatment groups (p < 0.05). The expression of CD163 marked brown in liver tissue had more expression than the control group.
CONCLUSION: The combination of MSCs and bovine colostrum can reduce TNF-α levels and significantly increase macrophages expression in the liver fibrosis of Wistar rats after 50% resection on the 3th, 7th, and 10th days.
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13
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Zhao Y, Cui JG, Zhang H, Li XN, Li MZ, Talukder M, Li JL. Role of mitochondria-endoplasmic reticulum coupling in lycopene preventing DEHP-induced hepatotoxicity. Food Funct 2021; 12:10741-10749. [PMID: 34608470 DOI: 10.1039/d1fo00478f] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Di (2-ethylhexyl) phthalate (DEHP) is a hazardous compound used as a plasticizer in plastic products. As a natural carotenoid, lycopene (LYC) is considered an effective protective agent against various types of organ damage. The present study aimed to investigate the role of mitochondria-endoplasmic reticulum (ER) coupling in LYC preventing DEHP-induced hepatotoxicity. The mice were treated with LYC (5 mg kg-1) and/or DEHP (500 or 1000 mg kg-1). In the present study, LYC prevented DEHP-induced histopathological changes including fibrosis and glycogen storage in the liver. Additionally, LYC alleviated DEHP-induced ultrastructural injury of mitochondria and ER. LYC had the underlying preventability against DEHP-induced mitochondrial dynamics imbalance including an increase in fission and a decrease in fusion. Furthermore, DEHP induced mitochondria-associated endoplasmic reticulum membrane (MAM) disorder-induced ER stress through the ER unfolded protein response (UPRER), but LYC alleviated these alterations. Therefore, LYC prevented DEHP-induced hepatic mitochondrial dynamics and MAM disorder, leading to ER stress. The present study provides novel evidence of mitochondria-ER coupling as a target for LYC that prevents DEHP-induced hepatotoxicity.
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Affiliation(s)
- Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Mu-Zi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. .,Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Bangladesh
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. .,Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.,Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, P. R. China
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14
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Deng Y, Xia B, Chen Z, Wang F, Lv Y, Chen G. Stem Cell-based Therapy Strategy for Hepatic Fibrosis by Targeting Intrahepatic Cells. Stem Cell Rev Rep 2021; 18:77-93. [PMID: 34668120 DOI: 10.1007/s12015-021-10286-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2021] [Indexed: 12/11/2022]
Abstract
The whole liver transplantation is the most effective treatment for end-stage fibrosis. However, the lack of available donors, immune rejection and total cost of surgery remain as the key challenges in advancing liver fibrosis therapeutics. Due to the multi-differentiation and low immunogenicity of stem cells, treatment of liver fibrosis with stem cells has been considered as a valuable new therapeutic modality. The pathological progression of liver fibrosis is closely related to the changes in the activities of intrahepatic cells. Damaged hepatocytes, activated Kupffer cells and other inflammatory cells lead to hepatic stellate cells (HSCs) activation, further promoting apoptosis of damaged hepatocytes, while stem cells can work on fibrosis-related intrahepatic cells through relevant transduction pathways. Herein, this article elucidates the phenomena and the mechanisms of the crosstalk between various types of stem cells and intrahepatic cells including HSCs and hepatocytes in the treatment of liver fibrosis. Then, the important influences of chemical compositions, mechanical properties and blood flow on liver fibrosis models with stem cell treatment are emphasized. Clinical trials on stem cell-based therapy for liver fibrosis are also briefly summarized. Finally, continuing challenges and future directions of stem cell-based therapy for hepatic fibrosis are discussed. In short, stem cells play an important advantage and have a great potential in treating liver fibrosis by interacting with intrahepatic cells. Clarifying how stem cells interact with intrahepatic cells to change the progression of liver fibrosis is of great significance for a deeper understanding of liver fibrosis mechanisms and targeted therapy.
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Affiliation(s)
- Yaxin Deng
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Bin Xia
- Engineering Research Center for Waste Oil Recovery Technology and Equipment, Ministry of Education, Chongqing Technology and Business University, Chongqing, 400067, People's Republic of China
| | - Zhongmin Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Fuping Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Yonggang Lv
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, 400044, People's Republic of China.,State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Guobao Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China. .,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China.
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15
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Thej C, Balasubramanian S, Rengasamy M, Walvekar A, Swamynathan P, Raj SS, Shahani P, Siddikuzzaman, Kolkundkar U, Seetharam RN, Gupta PK, Majumdar AS. Human bone marrow-derived, pooled, allogeneic mesenchymal stromal cells manufactured from multiple donors at different times show comparable biological functions in vitro, and in vivo to repair limb ischemia. Stem Cell Res Ther 2021; 12:279. [PMID: 33971964 PMCID: PMC8108338 DOI: 10.1186/s13287-021-02330-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/07/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND We have previously demonstrated that a pooled population of bone marrow-derived, allogeneic mesenchymal stromal cells (BMMSC), Stempeucel®-1, produced under good manufacturing practices (GMP) conditions, showed clinical efficacy and safety in patients suffering from critical limb ischemia (CLI) due to Buerger's disease. While Stempeucel®-1 is currently used for CLI and other clinical indications, we wanted to ensure that the product's continuity is addressed by developing and characterizing a second generation of pooled product (Stempeucel®-1A), manufactured identically from second BM aspirates of the same three donors after a 2-year interval. METHODS The two versions of Stempeucel® were manufactured and subjected to gene and protein expression analysis. The nature of various growth factors/cytokines secreted and immunomodulatory activity of these two cell populations were compared directly by various in vitro assays. The preclinical efficacy of these two cell types was compared in an experimental model of hind limb ischemia (HLI) in BALB/c nude mice. The reversal of ischemia, blood flow, and muscle regeneration were determined by functional scoring, laser Doppler imaging, and immunohistochemical analyses. RESULTS Qualitative and quantitative analyses of genes and proteins involved in promoting angiogenic activity and immune regulatory functions revealed high levels of correlation between Stempeucel®-1 and Stempeucel®-1A cell populations. Moreover, intramuscular (i.m) administration of these two cell products in the ischemic limbs of BALB/c nude mice showed significant repair (≥ 70%) of toe and foot necrosis, leading to improved ambulatory function and limb salvage. Furthermore, a biodistribution kinetics study showed that Stempeucel®-1 was mostly localized in the ischemic muscles of mice for a significantly longer time compared to normal muscles, thus playing an essential role in modulating and reversing HLI damage. CONCLUSIONS This study shows that with a reproducible manufacturing procedure, it is possible to generate large numbers of pooled mesenchymal stromal cells from human bone marrow samples to establish product equivalence. We conclude from these results that, for the first time, two pooled, allogeneic BMMSC products can be repeatedly manufactured at different time intervals using a two-tier cell banking process with robust and comparable angiogenic properties to treat ischemic diseases.
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Affiliation(s)
- Charan Thej
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Sudha Balasubramanian
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Mathiyazhagan Rengasamy
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Ankita Walvekar
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Priyanka Swamynathan
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Swathi Sundar Raj
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Pradnya Shahani
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Siddikuzzaman
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Udaykumar Kolkundkar
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Raviraja N Seetharam
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Pawan Kumar Gupta
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India
| | - Anish S Majumdar
- Stempeutics Research Pvt Ltd, 3rd Floor, Manipal Hospitals Whitefield Pvt. Ltd., #143, EPIP Industrial Area, K R Puram Hobli, Bengaluru, India.
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16
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Al-Dhamin Z, Liu LD, Li DD, Zhang SY, Dong SM, Nan YM. Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies. World J Gastroenterol 2020; 26:7444-7469. [PMID: 33384547 PMCID: PMC7754546 DOI: 10.3748/wjg.v26.i47.7444] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/31/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.
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Affiliation(s)
- Zaid Al-Dhamin
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Ling-Di Liu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Dong-Dong Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Si-Yu Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Shi-Ming Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
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17
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Chiabotto G, Pasquino C, Camussi G, Bruno S. Molecular Pathways Modulated by Mesenchymal Stromal Cells and Their Extracellular Vesicles in Experimental Models of Liver Fibrosis. Front Cell Dev Biol 2020; 8:594794. [PMID: 33425900 PMCID: PMC7794013 DOI: 10.3389/fcell.2020.594794] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/06/2020] [Indexed: 12/18/2022] Open
Abstract
End-stage liver fibrosis is common to all chronic liver diseases. Since liver transplantation has several limitations, including lack of donors, immunological rejection, and high medical costs, therapeutic alternatives are needed. The administration of mesenchymal stromal cells (MSCs) has been proven effective in tissue regeneration after damage. However, the risk of uncontrolled side effects, such as cellular rejection and tumorigenesis, should be taken into consideration. A safer alternative to MSC transplantation is represented by the MSC secretome, which retains the same beneficial effect of the cell of origin, without showing any considerable side effect. The paracrine effect of MSCs is mainly carried out by secreted particles in the nanometer range, known as extracellular vesicles (EVs) that play a fundamental role in intercellular communication. In this review, we discuss the current literature on MSCs and MSC-EVs, focusing on their potential therapeutic action in liver fibrosis and on their molecular content (proteins and RNA), which contributes in reverting fibrosis and prompting tissue regeneration.
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Affiliation(s)
- Giulia Chiabotto
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Chiara Pasquino
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
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18
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Yin F, Wang WY, Mao LC, Cai QQ, Jiang WH. Effect of Human Umbilical Cord Mesenchymal Stem Cells Transfected with HGF on TGF-β1/Smad Signaling Pathway in Carbon Tetrachloride-Induced Liver Fibrosis Rats. Stem Cells Dev 2020; 29:1395-1406. [DOI: 10.1089/scd.2020.0060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Fei Yin
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Wen-Ying Wang
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Li-Cui Mao
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Qi-Qi Cai
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Wen-Hua Jiang
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
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19
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Magdy M, Fahmy A, Zaki NI, Mohamed AK. Prophylactic versus therapeutic role of the transplanted CD34 + Umbilical Cord Blood Stem Cells and Wharton Jelly Mesenchymal Stem Cells in early / acute hepatic S. mansoni granulomas reversal in mice; a novel approach. Exp Parasitol 2020; 217:107938. [PMID: 32768560 DOI: 10.1016/j.exppara.2020.107938] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 04/03/2020] [Accepted: 06/04/2020] [Indexed: 01/08/2023]
Abstract
PURPOSE Praziquantel (PZQ) is the conventional antibilharzial agent. Nevertheless, no antibilharzial prophylactic agents or 100% curable therapy approved and no reported data about use of human CD34+ Umbilical Cord Blood Stem Cells (CD34+UCBSCs) or Wharton Jelly Mesenchymal Stem Cells (WJMSCs) in prevention and/or complete eradication of acute S.mansoni granulomas in liver. We aimed to study possible prophylactic vs therapeutic role of human CD34+UCBSCs and WJMSCs in acute hepatic bilharzial granulomas in pre vs post-infected mice. METHODS Seventy mice were divided into 7 groups (10 mice each): Normal, S.mansoni-infected, post-infected PZQ-treated, CD34+UCBSCs pre and post-infected, WJMSCs pre and post-infected. Serological, parasitological, histopathological evaluation using OCT4 & TGFB immunohistochemistry and quantitative image analysis assessment of TGFB-stained fibrogenesis in liver granulomas performed. RESULTS Histopathologically, surprisingly and significantly, the prophylactic pre-infection stem cells (CD34+UCBSCs and WJMSCs) & similarly the post-infection CD34+UCBSCs treatment revealed eradication/reversal of the entire granulomas and no fibrosis. Moreover, post-infection PZQ treatment showed fewer and significantly smaller granulomas than post-infection WJMSCs treatment. Nevertheless, post-infection WJMSCs exhibited non-significant less TGFB-stained fibrogenesis. CONCLUSION CD34+UCBSCs exerted the best prophylactic and therapeutic roles in prevention and complete cure of acute hepatic S.mansoni granulomas over WJMSCs and PZQ. In contrast, only pre-infection WJMSCs exhibited similar preventive (prophylactic) effect. On the contrary, post-infection WJMSCs were the worst (incompletely reversed granulomas). Post-infection Praziquantel was overall better therapeutically than WJMSCs in this regard. Accordingly, when it comes to WJMSCs application, WJMSCs are better used as a pre-infection prophylactic and preventive tool rather than a post-infection therapy. Further studies are needed.
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Affiliation(s)
- Mona Magdy
- Department of Pathology, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza, Egypt.
| | - Azza Fahmy
- Departments of Parasitology, Immunology & Drug Evaluation, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza, Egypt
| | - Nashwa Ismail Zaki
- Physiology Department, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt
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20
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Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour AA, Yousefi M, Talebi M, Shamsasenjan K. Regenerative potential of Wharton's jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy. J Cell Physiol 2020; 235:9230-9240. [PMID: 32557631 DOI: 10.1002/jcp.29810] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 04/17/2020] [Indexed: 12/14/2022]
Abstract
Umbilical cord Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have recently gained considerable attention in the field of regenerative medicine. Their high proliferation rate, differentiation ability into various cell lineages, easy collection procedure, immuno-privileged status, nontumorigenic properties along with minor ethical issues make them an ideal approach for tissue repair. Besides, the number of WJ-MSCs in the umbilical cord samples is high as compared to other sources. Because of these properties, WJ-MSCs have rapidly advanced into clinical trials for the treatment of a wide range of disorders. Therefore, this paper summarized the current preclinical and clinical studies performed to investigate the regenerative potential of WJ-MSCs in neural, myocardial, skin, liver, kidney, cartilage, bone, muscle, and other tissue injuries.
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Affiliation(s)
- Hossein Abbaszadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Ghorbani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Derakhshani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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21
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Tricot T, De Boeck J, Verfaillie C. Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand? Cells 2020; 9:E566. [PMID: 32121068 PMCID: PMC7140465 DOI: 10.3390/cells9030566] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/20/2020] [Accepted: 02/22/2020] [Indexed: 12/28/2022] Open
Abstract
Acute and chronic liver failure is a highly prevalent medical condition with high morbidity and mortality. Currently, the therapy is orthotopic liver transplantation. However, in some instances, chiefly in the setting of metabolic diseases, transplantation of individual cells, specifically functional hepatocytes, can be an acceptable alternative. The gold standard for this therapy is the use of primary human hepatocytes, isolated from livers that are not suitable for whole organ transplantations. Unfortunately, primary human hepatocytes are scarcely available, which has led to the evaluation of alternative sources of functional hepatocytes. In this review, we will compare the ability of most of these candidate alternative cell sources to engraft and repopulate the liver of preclinical animal models with the repopulation ability found with primary human hepatocytes. We will discuss the current shortcomings of the different cell types, and some of the next steps that we believe need to be taken to create alternative hepatocyte progeny capable of regenerating the failing liver.
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22
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Sabry D, Mohamed A, Monir M, Ibrahim HA. The Effect of Mesenchymal Stem Cells Derived Microvesicles on the Treatment of Experimental CCL4 Induced Liver Fibrosis in Rats. Int J Stem Cells 2019; 12:400-409. [PMID: 31474025 PMCID: PMC6881047 DOI: 10.15283/ijsc18143] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 06/22/2019] [Accepted: 07/01/2019] [Indexed: 12/14/2022] Open
Abstract
Background and Objectives The release of microvesicles (MVs) from mesenchymal stem cells (MSCs) has been implicated in intercellular communication, and may contribute to beneficial paracrine effects of stem cell-based therapies. We investigated the effect of administration of MSC-MVs on the therapeutic potential of carbon tetrachloride (CCL4) induced liver fibrosis in rats. Methods Our work included: isolation and further identification of bone marrow MSC-MVs by transmission electron microscopy (TEM). Liver fibrosis was induced in rats by CCl4 followed by injection of prepared MSC-MVs in injured rats. The effects of MSC-MVs were evaluated by biochemical analysis of liver functions, RNA gene expression quantitation for collagen-1α, transforming growth factor β (TGF-β), interleukin-1β (IL-1β), vascular endothelial growth factor (VEGF) by real time reverse transcription PCR (RT-PCR) techniques. Finally histopathological examination of the liver tissues was assessed for all studied groups. Results BM-MSC-MVs treated group showed significant increase in serum albumin levels, VEGF quantitative gene expression (p<0.05), while it showed a significant decrease in serum alanine transaminase (ALT) enzyme levels, quantitative gene expression of TGF-β, collagen-1α, IL-1β compared to CCL4 fibrotic group (p<0.05). Additionally, the histopathological assessment of the liver tissues of BM-MSC-MVs treated group showed marked decrease in the collagen deposition & improvement of histopathological picture in comparison with CCL4 fibrotic group. Conclusions Our study demonstrates that BM-MSC-MVs possess anti-fibrotic, anti-inflammatory, and pro-angiogenic properties which can promote the resolution of CCL4 induced liver fibrosis in rats.
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Affiliation(s)
- Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Abbas Mohamed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Manar Monir
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Heba A Ibrahim
- Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
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He L, Ye X, Gao M, Yang J, Ma J, Xiao F, Wei H. Down-regulation of GLT25D1 inhibited collagen secretion and involved in liver fibrogenesis. Gene 2019; 729:144233. [PMID: 31759980 DOI: 10.1016/j.gene.2019.144233] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 07/28/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023]
Abstract
Collagen β (1-O) galactosyltransferase 1 (GLT25D1) has been reported to transfer galactose to hydroxylysine residues via β (1-O) linkages in collagen. However, the role of Glt25d1 in liver fibrogenesis is still unknow. Recently, we generated a Glt25d1 knockout mouse to elucidate the role of Glt25d1 in vivo. However, we found that complete deletion of the Glt25d1 gene resulted in embryonic lethality at E11.5. Histopathological analysis revealed that dysplasia in Glt25d1-/- labyrinth with defects of the vascular network. Immunohistochemical showed that the decrease in proliferation of Glt25d1-/- liver and the developing central nervous system (CNS). The role of Glt25d1 in liver fibrogenesis was explored by Glt25d1+/- mice. Glt25d1+/- mice and wild-type (WT) mice were injected intraperitoneally with the same dose of CCl4. The higher level of serum alanine aminotransferase was observed in Glt25d1+/- mice. Reverse transcription-quantitative polymerase chainreaction demonstrated that the mRNA expression levels of the inflammatory cytokines such as, Tnf-α, Cxcl-1 and Mcp-1, showed a significantly increase in CCl4-treated Glt25d1+/- mice. Collagen-I, collagen-III and α-SMA transcripts accumulation was markedly increased in the Glt25d1+/- mice. However, Masson's trichrome staining revealed a trend to decrease in the ECM proteins deposition of Glt25d1+/- liver. Immunohistochemistry and Western blots revealed that the protein expression of Collagen-III was reduced and a trend to a decrease in collagen-I was observed in the Glt25d1+/- liver compared with those of WT mice. Our results demonstrate that Glt25d1 knockout results in embryonic lethality and down-regulation of Glt25d1 may inhibit collagen secretion during liver fibrogenesis.
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Affiliation(s)
- Lingling He
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Xiaohui Ye
- Beijing Huaxin Hospital, The First Affiliated Hospital of Tsinghua Uinversity, Beijing, China.
| | - Meixin Gao
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Junru Yang
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Jiali Ma
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Fan Xiao
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Hongshan Wei
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
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Rockel JS, Rabani R, Viswanathan S. Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases. Semin Cell Dev Biol 2019; 101:87-103. [PMID: 31757583 DOI: 10.1016/j.semcdb.2019.10.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/11/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
Most chronic diseases involving inflammation have a fibrotic component that involves remodeling and excess accumulation of extracellular matrix components. Left unchecked, fibrosis leads to organ failure and death. Mesenchymal stromal cells (MSCs) are emerging as a potent cell-based therapy for a wide spectrum of fibrotic conditions due to their immunomodulatory, anti-inflammatory and anti-fibrotic properties. This review provides an overview of known mechanisms by which MSCs mediate their anti-fibrotic actions and in relation to animal models of pulmonary, liver, renal and cardiac fibrosis. Recent MSC clinical trials results in liver, lung, skin, kidney and hearts are discussed and next steps for future MSC-based therapies including pre-activated or genetically-modified cells, or extracellular vesicles are also considered.
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Affiliation(s)
- Jason S Rockel
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
| | - Razieh Rabani
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
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Zhang L, Zhou D, Li J, Yan X, Zhu J, Xiao P, Chen T, Xie X. Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Hypoxia and the Transforming Growth Factor beta 1 (TGFβ-1) and SMADs Pathway in a Mouse Model of Cirrhosis. Med Sci Monit 2019; 25:7182-7190. [PMID: 31550244 PMCID: PMC6775794 DOI: 10.12659/msm.916428] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background The role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in liver fibrosis remains poorly understood. This study aimed to use a mouse model of carbon tetrachloride (CCL4)-induced liver fibrosis to investigate the effects of BM-MSCs during liver hypoxia and the involvement of the transforming growth factor beta 1 (TGF-β1) and SMADs pathway. Material/Methods Thirty C57BL/6 mice were randomly divided into the control group (n=10), the model group (n=10), and the BM-MSC-treated model group (n=10). In the model group, liver fibrosis was induced by intraperitoneal injection of CCl4. BM-MSCs were transplanted after 12 weeks of CCl4 treatment. The serum biochemical parameters and histological changes in the liver, using histochemical stains, were investigated. The expression of collagen type I (collagen I), alpha-smooth muscle actin (α-SMA), TGF-β1, SMAD3, SMAD7, hypoxia-inducible factor 1 alpha (HIF-1α), and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and quantitative real-time polymerase chain (RT-qPCR) reaction. Results Treatment with BM-MSCs reduced the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with the model group, and reduced liver fibrosis determined histologically using hematoxylin and eosin (H&E) and Masson’s trichrome staining compared with the model group. The area of liver fibrosis decreased after BM-MSCs treatment (p<0.05). Protein expression of HIF-1α and VEGF were decreased after BM-MSCs treatment (p<0.05). Transplantation of BM-MSCs reduced the mRNA expression of TGF-β1, collagen I, α-SMA, and SMAD3 (p<0.05). Conclusions BM-MSC transplantation reduced CCl4-induced murine liver fibrosis, indicating that in a hypoxic microenvironment, BM-MSCs may inhibit the TGFβ-1/SMADs pathway.
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Affiliation(s)
- Liting Zhang
- State Key Laboratory of Cryospheric Science, Northwest Institute of Eco-Environmental and Resources, Chinese Academy of Sciences, Lanzhou, Gansu, China (mainland).,Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China (mainland)
| | - Dan Zhou
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China (mainland)
| | - Junfeng Li
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China (mainland)
| | - Xiaoming Yan
- The 4th People's Hospital of Qinghai Province, Xining, Qinghai, China (mainland)
| | - Jun Zhu
- Department of Pathology of Donggang Branch, The First Hospital of Lanzhou University, Lanzhou, Gansu, China (mainland)
| | - Ping Xiao
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China (mainland)
| | - Tuo Chen
- State Key Laboratory of Cryospheric Science, Northwest Institute of Eco-Environmental and Resources, Chinese Academy of Sciences, Lanzhou, Gansu, China (mainland)
| | - Xiaodong Xie
- Institute of Medical Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China (mainland)
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26
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Human Liver-Derived Stem Cells Improve Fibrosis and Inflammation Associated with Nonalcoholic Steatohepatitis. Stem Cells Int 2019; 2019:6351091. [PMID: 31281379 PMCID: PMC6589210 DOI: 10.1155/2019/6351091] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/19/2019] [Accepted: 04/04/2019] [Indexed: 12/17/2022] Open
Abstract
Cell therapy may be regarded as a feasible alternative to whole organ transplantation to treat end-stage liver diseases. Human liver stem cells (HLSCs) are a population of cells easily obtainable and expandable from a human adult liver biopsy. HLSCs share with mesenchymal stromal cells the same phenotype, gene expression profile, and differentiation capabilities. In addition, HLSCs show a specific commitment to the hepatic phenotype. Injection of HLSCs into immunodeficient mice fed with a methionine-choline-deficient diet to induce nonalcoholic steatohepatitis ameliorates liver function and morphology. In particular, HLSC treatment induced a reduction of liver fibrosis and inflammation at morphological and molecular levels. Moreover, HLSCs were able to persist for up to 3 weeks after the injection. In conclusion, HLSCs have healing effects in a model of chronic liver disease.
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27
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Rong X, Liu J, Yao X, Jiang T, Wang Y, Xie F. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway. Stem Cell Res Ther 2019; 10:98. [PMID: 30885249 PMCID: PMC6421647 DOI: 10.1186/s13287-019-1204-2] [Citation(s) in RCA: 222] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 02/12/2019] [Accepted: 03/01/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are increasingly being applied as a therapy for liver fibrosis. Exosomes possess similar functions to their parent cells; however, they are safe and effective cell-free reagents with controllable and predictable outcomes. In this study, we investigated the therapeutic potential and underlying molecular mechanism for human bone mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) in the treatment of liver fibrosis. METHODS We established an 8-week CCl4-induced rat liver fibrosis model, after which, we administered hBM-MSCs-Ex in vivo for 4 weeks. The resulting histopathology, liver function, and inflammatory cytokines were analyzed. In addition, we investigated the anti-fibrotic mechanism of hBM-MSCs-Ex in hepatic stellate cells (HSCs) and liver fibrosis tissue, by western blotting for the expression of Wnt/β-catenin signaling pathway-related genes. RESULTS In vivo administration of hBM-MSCs-Ex effectively alleviated liver fibrosis, including a reduction in collagen accumulation, enhanced liver functionality, inhibition of inflammation, and increased hepatocyte regeneration. Moreover, based on measurement of the collagen area, Ishak fibrosis score, MDA levels, IL-1, and IL-6, the therapeutic effect of hBM-MSCs-Ex against liver fibrosis was significantly greater than that of hBM-MSCs. In addition, we found that hBM-MSCs-Ex inhibited the expression of Wnt/β-catenin pathway components (PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, Cyclin D1), α-SMA, and Collagen I, in both HSCs and liver fibrosis tissue. CONCLUSIONS These results suggest that hBM-MSCs-Ex treatment could ameliorate CCl4-induced liver fibrosis via inhibition of HSC activation through the Wnt/β-catenin pathway.
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Affiliation(s)
- Xiaoli Rong
- Department of Clinical Laboratory, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, 130033, Jilin, China.,The Scientific Research Center, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, 130033, Jilin, China
| | - Junzhi Liu
- Department of Quality Control, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, 130033, Jilin, China
| | - Xia Yao
- Department of Anesthesiology, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, 1478 Gongnong Road, Changchun, 130117, Jilin, China
| | - Tiechao Jiang
- Department of Cardiology, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, 130033, Jilin, China
| | - Yimin Wang
- The Scientific Research Center, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, 130033, Jilin, China.
| | - Feng Xie
- Department of Clinical Laboratory, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, 130033, Jilin, China.
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28
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Luo XY, Meng XJ, Cao DC, Wang W, Zhou K, Li L, Guo M, Wang P. Transplantation of bone marrow mesenchymal stromal cells attenuates liver fibrosis in mice by regulating macrophage subtypes. Stem Cell Res Ther 2019; 10:16. [PMID: 30635047 PMCID: PMC6329168 DOI: 10.1186/s13287-018-1122-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 12/11/2018] [Accepted: 12/25/2018] [Indexed: 12/31/2022] Open
Abstract
Background Liver fibrosis is a key phase that will progress to further injuries such as liver cirrhosis or carcinoma. This study aimed to investigate whether transplantation of bone marrow mesenchymal stromal cells (BM-MSCs) can attenuate liver fibrosis in mice and the underlying mechanisms based on the regulation of macrophage subtypes. Methods A liver fibrosis model was induced by intraperitoneal (i.p.) injection of CCl4 twice per week for 70 days, and BM-MSCs were intravenously transplanted twice on the 60th and 70th days. Immunohistology and gene expression of liver fibrosis and macrophage subtypes were analyzed. Mouse RAW264.7 cells and JS1 cells (hepatic stellate cell strain) were also used to explore the underlying mechanisms of the effects of BM-MSCs on liver fibrosis. Results After transplantation of BM-MSCs, F4/80+CD206+-activated M2 macrophages and matrix metalloproteinase 13 (MMP 13) expression were significantly increased while F4/80+iNOS+-activated M1 macrophages were inhibited in liver tissue. Gene expression of IL-10 was elevated while IL12b, IFN-γ, TNF-α, and IL-6 gene expression were decreased. ΤGF-β1 and collagen-1 secretions were reduced while caspase-3 was increased in JS1 cells treated with BM-MSC-conditioned media. BM-MSCs effectively suppressed the expression of α-SMA, Sirius red, and collagen-1 in the liver, which are positively correlated with fibrosis and induced by CCl4 injection. Conclusions Taken together, we have provided the first demonstration that BM-MSC transplantation can promote the activation of M2 macrophages expressing MMP13 and inhibition of M1 macrophages to further inhibit hepatic stellate cells (HSCs), which play synergistic roles in attenuating liver fibrosis.
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Affiliation(s)
- Xiao-Yu Luo
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China
| | - Xiang-Jun Meng
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China.
| | - Da-Chun Cao
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China.
| | - Wei Wang
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China.,Department of Pathology, Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu province, China
| | - Kun Zhou
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China
| | - Lei Li
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China
| | - Mei Guo
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China
| | - Ping Wang
- Department of Pathology, Traditional Chinese Medicine Hospital of Kunshan, Kunshan, Jiangsu province, China
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Hu C, Zhao L, Duan J, Li L. Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis. J Cell Mol Med 2019; 23:1657-1670. [PMID: 30635966 PMCID: PMC6378173 DOI: 10.1111/jcmm.14115] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 12/06/2018] [Accepted: 12/06/2018] [Indexed: 12/12/2022] Open
Abstract
End‐stage liver fibrosis frequently progresses to portal vein thrombosis, formation of oesophageal varices, hepatic encephalopathy, ascites, hepatocellular carcinoma and liver failure. Mesenchymal stem cells (MSCs), when transplanted in vivo, migrate into fibrogenic livers and then differentiate into hepatocyte‐like cells or fuse with hepatocytes to protect liver function. Moreover, they can produce various growth factors and cytokines with anti‐inflammatory effects to reverse the fibrotic state of the liver. In addition, only a small number of MSCs migrate to the injured tissue after cell transplantation; consequently, multiple studies have investigated effective strategies to improve the survival rate and activity of MSCs for the treatment of liver fibrosis. In this review, we intend to arrange and analyse the current evidence related to MSC transplantation in liver fibrosis, to summarize the detailed mechanisms of MSC transplantation for the reversal of liver fibrosis and to discuss new strategies for this treatment. Finally, and most importantly, we will identify the current problems with MSC‐based therapies to repair liver fibrosis that must be addressed in order to develop safer and more effective routes for MSC transplantation. In this way, it will soon be possible to significantly improve the therapeutic effects of MSC transplantation for liver regeneration, as well as enhance the quality of life and prolong the survival time of patients with liver fibrosis.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Lingfei Zhao
- Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang, PR China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Jinfeng Duan
- The Key Laboratory of Mental Disorder Management of Zhejiang Province, Department of Psychiatry, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, PR China
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Fakiruddin KS, Ghazalli N, Lim MN, Zakaria Z, Abdullah S. Mesenchymal Stem Cell Expressing TRAIL as Targeted Therapy against Sensitised Tumour. Int J Mol Sci 2018; 19:ijms19082188. [PMID: 30060445 PMCID: PMC6121609 DOI: 10.3390/ijms19082188] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 06/30/2018] [Accepted: 07/02/2018] [Indexed: 02/06/2023] Open
Abstract
Tapping into the ability of engineered mesenchymal stem cells (MSCs) to mobilise into the tumour has expanded the scope of cancer treatment. Engineered MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) could serve as a platform for an efficient and targeted form of therapy. However, the presence of cancer stem cells (CSCs) that are resistant to TRAIL and apoptosis may represent a challenge for effective treatment. Nonetheless, with the discovery of small molecular inhibitors that could target CSCs and tumour signalling pathways, a higher efficacy of MSC-TRAIL mediated tumour inhibition can be achieved. This might pave the way for a more effective form of combined therapy, which leads to a better treatment outcome. In this review, we first discuss the tumour-homing capacity of MSCs, its effect in tumour tropism, the different approach behind genetically-engineered MSCs, and the efficacy and safety of each agent delivered by these MSCs. Then, we focus on how sensitisation of CSCs and tumours using small molecular inhibitors can increase the effect of these cells to either TRAIL or MSC-TRAIL mediated inhibition. In the conclusion, we address a few questions and safety concerns regarding the utilization of engineered MSCs for future treatment in patients.
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Affiliation(s)
- Kamal Shaik Fakiruddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
| | - Nadiah Ghazalli
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
| | - Moon Nian Lim
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
| | - Zubaidah Zakaria
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
| | - Syahril Abdullah
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
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Matrix metalloproteinases and liver fibrosis (translational aspects). Matrix Biol 2017; 68-69:463-473. [PMID: 29289644 DOI: 10.1016/j.matbio.2017.12.012] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/18/2017] [Accepted: 12/20/2017] [Indexed: 02/07/2023]
Abstract
Liver fibrosis, a reversible wound-healing response to chronic cellular injury, reflects a balance between liver repair and progressive substitution of the liver parenchyma by scar tissue. Complex mechanisms that underlie liver fibrogenesis are summarized to provide the basis for generating targeted therapies to reverse fibrogenesis and improve the outcomes of patients with chronic liver disease. This minireview presents some pathophysiological aspects of liver fibrosis as a dynamic process and elucidates matrix metalloproteinases (MMPs) and their role within as well as beyond matrix degradation. Open questions remain, whether inhibition of fibrogenesis or induction of fibrolysis is the key mechanism to resolve fibrosis. And a point of principle might be whether regeneration of liver cirrhosis is possible. Will we ever cure fibrosis?
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