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Hepatogenic Potential and Liver Regeneration Effect of Human Liver-derived Mesenchymal-Like Stem Cells. Cells 2020; 9:cells9061521. [PMID: 32580448 PMCID: PMC7348751 DOI: 10.3390/cells9061521] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/18/2020] [Accepted: 06/20/2020] [Indexed: 12/22/2022] Open
Abstract
Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not known whether liver resident hLD-SCs can differentiate toward a hepatic fate better than mesenchymal stem cells (MSCs) obtained from other origins. In this study, we compared the differentiation ability and regeneration potency of hLD-SCs with those of human umbilical cord matrix-derived stem cells (hUC-MSCs) by inducing hepatic differentiation. Undifferentiated hLD-SCs expressed relatively high levels of endoderm-related markers (GATA4 and FOXA1). During directed hepatic differentiation supported by two small molecules (Fasudil and 5-azacytidine), hLD-SCs presented more advanced mitochondrial respiration compared to hUC-MSCs. Moreover, hLD-SCs featured higher numbers of hepatic progenitor cell markers on day 14 of differentiation (CPM and CD133) and matured into hepatocyte-like cells by day 7 through 21 with increased hepatocyte markers (ALB, HNF4A, and AFP). During in vivo cell transplantation, hLD-SCs migrated into the liver of ischemia-reperfusion injury-induced mice within 2 h and relieved liver injury. In the thioacetamide (TAA)-induced liver injury mouse model, transplanted hLD-SCs trafficked into the liver and spontaneously matured into hepatocyte-like cells within 14 days. These results collectively suggest that hLD-SCs hold greater hepatogenic potential, and hepatic differentiation-induced hLD-SCs may be a promising source of stem cells for liver regeneration.
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Lu S, Shi G, Xu X, Wang G, Lan X, Sun P, Li X, Zhang B, Gu X, Ichim TE, Wang H. Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice. J Transl Med 2016; 14:300. [PMID: 27770815 PMCID: PMC5075169 DOI: 10.1186/s12967-016-1051-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 10/05/2016] [Indexed: 01/08/2023] Open
Abstract
Background The endometrial regenerative cell (ERC) is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4)–induced acute liver injury (ALI). Methods An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse) into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. Results ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G) was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA) was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs) was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. Conclusions Human ERCs protect the liver from acute injury in mice through hepatocyte proliferation promotion, as well as through anti-inflammatory and immunoregulatory effects.
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Affiliation(s)
- Shanzheng Lu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Ganggang Shi
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Xiaoxi Xu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Grace Wang
- Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Xu Lan
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Peng Sun
- Department of General Surgery, Affiliated Hospital of Weifang Medical University, Shandong, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Baoren Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Xiangying Gu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | | | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin General Surgery Institute, Tianjin, China.
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Burra P, Arcidiacono D, Bizzaro D, Chioato T, Di Liddo R, Banerjee A, Cappon A, Bo P, Conconi MT, Parnigotto PP, Mirandola S, Gringeri E, Carraro A, Cillo U, Russo FP. Systemic administration of a novel human umbilical cord mesenchymal stem cells population accelerates the resolution of acute liver injury. BMC Gastroenterol 2012; 12:88. [PMID: 22788801 PMCID: PMC3458924 DOI: 10.1186/1471-230x-12-88] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 07/12/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease. We aimed to evaluate the therapeutic potential of mesenchymal stem cells from human umbilical cord (UCMSCs), a readily available source of mesenchymal stem cells, in the CCl4-induced acute liver injury model. METHODS Mesenchymal stem cells profile was analyzed by flow cytometry. In order to evaluate the capability of our UCMSCs to differentiate in hepatocytes, cells were seeded on three different supports, untreated plastic support, MatrigelTM and human liver acellular matrix. Cells were analyzed by immunocitochemistry for alpha-fetoprotein and albumin expression, qPCR for hepatocyte markers gene expression, Periodic Acid-Schiff staining for glycogen storage, ELISA for albumin detection and colorimetric assay for urea secretion.To assess the effects of undifferentiated UCMSCs in hepatic regeneration after an acute liver injury, we transplanted them via tail vein in mice injected intraperitoneally with a single dose of CCl4. Livers were analyzed by histological evaluation for damage quantification, immunostaining for Kupffer and stellate cells/liver myofibroblasts activation and for UCMSCs homing. Pro- and anti-inflammatory cytokines gene expression was evaluated by qPCR analysis and antioxidant enzyme activity was measured by catalase quantification.Data were analyzed by Mann-Whitney U-test, Kruskal-Wallis test and Cuzick's test followed by Bonferroni correction for multiple comparisons. RESULTS We have standardized the isolation procedure to obtain a cell population with hepatogenic properties prior to in vivo transplantation. When subjected to hepatogenic differentiation on untreated plastic support, UCMSCs differentiated in hepatocyte-like cells as demonstrated by their morphology, progressive up-regulation of mature hepatocyte markers, glycogen storage, albumin and urea secretion. However, cells seeded on 3D-supports showed a minor or negligible differentiation capacity.UCMSCs-transplanted mice showed a more rapid damage resolution, as shown by histological analysis, with a lower inflammation level and an increased catalase activity compared to CCl4-treated mice. CONCLUSIONS Our findings show that UCMSCs can be reliably isolated, have hepatogenic properties and following systemic administration are able to accelerate the resolution of an acute liver injury without any differentiation and manipulation. These features make UCMSCs strong candidates for future application in regenerative medicine for human acute liver disease.
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Affiliation(s)
- Patrizia Burra
- Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, Padova University Hospital, Via Giustiniani 2, Padova, 35128, Italy.
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Burra P, Bizzaro D, Ciccocioppo R, Marra F, Piscaglia AC, Porretti L, Gasbarrini A, Russo FP. Therapeutic application of stem cells in gastroenterology: An up-date. World J Gastroenterol 2011; 17:3870-80. [PMID: 22025875 PMCID: PMC3198016 DOI: 10.3748/wjg.v17.i34.3870] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 03/07/2011] [Accepted: 03/14/2011] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells represent the self-renewing progenitors of numerous body tissues, and they are currently classified according to their origin and differentiation ability. In recent years, the research on stem cells has expanded enormously and holds therapeutic promises for many patients suffering from currently disabling diseases. This paper focuses on the possible use of stem cells in the two main clinical settings in gastroenterology, i.e., hepatic and intestinal diseases, which have a strong impact on public health worldwide. Despite encouraging results obtained in both regenerative medicine and immune-mediated conditions, further studies are needed to fully understand the biology of stem cells and carefully assess their putative oncogenic properties. Moreover, the research on stem cells arouses fervent ethical, social and political debate. The Italian Society of Gastroenterology sponsored a workshop on stem cells held in Verona during the XVI Congress of the Federation of Italian Societies of Digestive Diseases (March 6-9, 2010). Here, we report on the issues discussed, including liver and intestinal diseases that may benefit from stem cell therapy, the biology of hepatic and intestinal tissue repair, and stem cell usage in clinical trials.
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Darwiche H, Petersen BE. Biology of the adult hepatic progenitor cell: "ghosts in the machine". PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2010; 97:229-49. [PMID: 21074735 PMCID: PMC3122078 DOI: 10.1016/b978-0-12-385233-5.00008-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
This chapter reviews some of the basic biological principles governing adult progenitor cells of the liver and the mechanisms by which they operate. If scientists were better able to understand the conditions that govern stem cell mechanics in the liver, it may be possible to apply that understanding in a clinical setting for use in the treatment or cure of human pathologies. This chapter gives a basic introduction to hepatic progenitor cell biology and explores what is known about progenitor cell-mediated liver regeneration. We also discuss the putative stem cell niche in the liver, as well as the signaling pathways involved in stem cell regulation. Finally, the isolation and clinical application of stem cells to human diseases is reviewed, along with the current thoughts on the relationship between stem cells and cancer.
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Affiliation(s)
- Houda Darwiche
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
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Gaudio E, Carpino G, Cardinale V, Franchitto A, Onori P, Alvaro D. New insights into liver stem cells. Dig Liver Dis 2009; 41:455-62. [PMID: 19403350 DOI: 10.1016/j.dld.2009.03.009] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Accepted: 03/22/2009] [Indexed: 12/11/2022]
Abstract
Hepatic progenitor cells are bi-potential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic and the cholangiocytic lineages. In adult livers, hepatic progenitor cells are quiescent stem cells with a low proliferating rate, representing a reserve compartment that is activated only when the mature epithelial cells of the liver are continuously damaged or inhibited in their replication, or in cases of severe cell loss. Hepatic progenitor cell activation has been described in various acute and chronic liver diseases. Their niche is composed by numerous cells such as Hepatic Stellate Cells, endothelial cells, hepatocytes, cholangiocytes, Kupffer cells, pit cells and inflammatory cells. All these cells, numerous hormones and growth factors could interact and cross-talk with progenitor cells influencing their proliferative and differentiative processes. Hepatic progenitor cells and their niche could represent, in the near future, a target for therapeutic approaches to liver disease based on cell-specific drug delivery systems. Isolation and transplantation of hepatic progenitor cells could represent a new approach for therapy of end-stage chronic liver diseases, as they offer many advantages to transplantation of mature hepatocytes. The possibility of applying stem cell therapy to liver diseases will represent a major goal in this field.
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Affiliation(s)
- E Gaudio
- Department of Human Anatomy, Sapienza University of Rome, Rome, Italy.
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Abstract
Liver transplantation is the only established treatment for acute liver failure (ALF), one of the most challenging clinical syndromes; however, donor shortages remain problematic. Artificial livers as a bridge to liver transplantation are being considered worldwide. Non-bioarticifical liver (NBAL) have limitations in improving the survival rates. Therefore, a biological artificial liver (BAL) that has metabolic, detoxic,and synthetic function of hepatocytes is anticipated. Biological artificial livers are classified by cell source, types of culture system for hepatocytes, and types of bioreactor. This paper reviews the bioartificial liver devices that have been clinically tested to support ALF patients. Finally, we identify several improvements critical to bioartificial liver replacement therapy in the future.
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