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Title: Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

Abstract

Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced.more » Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.« less

Authors:
 [1];  [2];  [1];  [1];  [3];  [2];  [1];  [4]
  1. Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany)
  2. Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany)
  3. Department for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany)
  4. (TRM), University of Leipzig, Leipzig (Germany)
Publication Date:
OSTI Identifier:
22416918
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 326; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL RECOVERY; BONE MARROW; FIBROSIS; HEPATOMAS; HOMEOSTASIS; INFLAMMATION; LIVER; LIVER CELLS; LIVER CIRRHOSIS; MICE; STEM CELLS; THERAPY; TRIGLYCERIDES

Citation Formats

Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de, Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de, Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de, Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de, Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de, Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de, Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de, and Translational Centre for Regenerative Medicine. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model. United States: N. p., 2014. Web. doi:10.1016/J.YEXCR.2014.04.017.
Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de, Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de, Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de, Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de, Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de, Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de, Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de, & Translational Centre for Regenerative Medicine. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model. United States. doi:10.1016/J.YEXCR.2014.04.017.
Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de, Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de, Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de, Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de, Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de, Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de, Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de, and Translational Centre for Regenerative Medicine. Fri . "Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model". United States. doi:10.1016/J.YEXCR.2014.04.017.
@article{osti_22416918,
title = {Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model},
author = {Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de and Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de and Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de and Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de and Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de and Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de and Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de and Translational Centre for Regenerative Medicine},
abstractNote = {Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.},
doi = {10.1016/J.YEXCR.2014.04.017},
journal = {Experimental Cell Research},
number = 2,
volume = 326,
place = {United States},
year = {Fri Aug 15 00:00:00 EDT 2014},
month = {Fri Aug 15 00:00:00 EDT 2014}
}
  • Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−})more » mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.« less
  • Periodontitis is a chronic inflammatory disease induced by bacterial pathogens, which not only affect connective tissue attachments but also cause alveolar bone loss. In this study, we investigated the anti-inflammatory effects of Human amnion-derived mesenchymal stem cells (HAMSCs) on human bone marrow mesenchymal stem cells (HBMSCs) under lipopolysaccharide (LPS)-induced inflammatory conditions. Proliferation levels were measured by flow cytometry and immunofluorescence staining of 5-ethynyl-2′-deoxyuridine (EdU). Osteoblastic differentiation and mineralization were investigated using chromogenic alkaline phosphatase activity (ALP) activity substrate assays, Alizarin red S staining, and RT-PCR analysis of HBMSCs osteogenic marker expression. Oxidative stress induced by LPS was investigated by assayingmore » reactive oxygen species (ROS) level and superoxide dismutase (SOD) activity. Here, we demonstrated that HAMSCs increased the proliferation, osteoblastic differentiation, and SOD activity of LPS-induced HBMSCs, and down-regulated the ROS level. Moreover, our results suggested that the activation of p38 MAPK signal transduction pathway is essential for reversing the LPS-induced bone-destructive processes. SB203580, a selective inhibitor of p38 MAPK signaling, significantly suppressed the anti-inflammatory effects in HAMSCs. In conclusion, HAMSCs show a strong potential in treating inflammation-induced bone loss by influencing p38 MAPK signaling. - Highlights: • LPS inhibites osteogenic differentiation in HBMSCs via suppression of p38 MAPK signaling pathway. • HAMSCs promote LPS-induced HBMSCs osteogenic differentiation through p38 MAPK signaling pathway. • HAMSCs reverse LPS-induced oxidative stress in LPS-induced HBMSCs through p38 MAPK signaling pathway.« less
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