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Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver

Multipotent mesenchymal stromal cells (MSC) are currently investigated clinically as cellular therapy for a variety of diseases. Differentiation of MSC toward endodermal lineages, including hepatocytes and their therapeutic effect on fibrosis has been described but remains controversial. Recent evid...

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Autores principales: Baertschiger, Reto M., Serre-Beinier, Véronique, Morel, Philippe, Bosco, Domenico, Peyrou, Marion, Clément, Sophie, Sgroi, Antonino, Kaelin, André, Buhler, Leo H., Gonelle-Gispert, Carmen
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722022/
https://www.ncbi.nlm.nih.gov/pubmed/19684854
http://dx.doi.org/10.1371/journal.pone.0006657
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author Baertschiger, Reto M.
Serre-Beinier, Véronique
Morel, Philippe
Bosco, Domenico
Peyrou, Marion
Clément, Sophie
Sgroi, Antonino
Kaelin, André
Buhler, Leo H.
Gonelle-Gispert, Carmen
author_facet Baertschiger, Reto M.
Serre-Beinier, Véronique
Morel, Philippe
Bosco, Domenico
Peyrou, Marion
Clément, Sophie
Sgroi, Antonino
Kaelin, André
Buhler, Leo H.
Gonelle-Gispert, Carmen
author_sort Baertschiger, Reto M.
collection PubMed
description Multipotent mesenchymal stromal cells (MSC) are currently investigated clinically as cellular therapy for a variety of diseases. Differentiation of MSC toward endodermal lineages, including hepatocytes and their therapeutic effect on fibrosis has been described but remains controversial. Recent evidence attributed a fibrotic potential to MSC. As differentiation potential might be dependent of donor age, we studied MSC derived from adult and pediatric human bone marrow and their potential to differentiate into hepatocytes or myofibroblasts in vitro and in vivo. Following characterization, expanded adult and pediatric MSC were co-cultured with a human hepatoma cell line, Huh-7, in a hepatogenic differentiation medium containing Hepatocyte growth factor, Fibroblast growth factor 4 and oncostatin M. In vivo, MSC were transplanted into spleen or liver of NOD/SCID mice undergoing partial hepatectomy and retrorsine treatment. Expression of mesenchymal and hepatic markers was analyzed by RT-PCR, Western blot and immunohistochemistry. In vitro, adult and pediatric MSC expressed characteristic surface antigens of MSC. Expansion capacity of pediatric MSC was significantly higher when compared to adult MSC. In co-culture with Huh-7 cells in hepatogenic differentiation medium, albumin expression was more frequently detected in pediatric MSC (5/8 experiments) when compared to adult MSC (2/10 experiments). However, in such condition pediatric MSC expressed alpha smooth muscle more strongly than adult MSC. Stable engraftment in the liver was not achieved after intrasplenic injection of pediatric or adult MSC. After intrahepatic injection, MSC permanently remained in liver tissue, kept a mesenchymal morphology and expressed vimentin and alpha smooth muscle actin, but no hepatic markers. Further, MSC localization merges with collagen deposition in transplanted liver and no difference was observed using adult or pediatric MSC. In conclusion, when transplanted into an injured or regenerating liver, MSC differentiated into myofibroblasts with development of fibrous tissue, regardless of donor age. These results indicate that MSC in certain circumstances might be harmful due to their fibrogenic potential and this should be considered before potential use of MSC for cell therapy.
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spelling pubmed-27220222009-08-17 Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver Baertschiger, Reto M. Serre-Beinier, Véronique Morel, Philippe Bosco, Domenico Peyrou, Marion Clément, Sophie Sgroi, Antonino Kaelin, André Buhler, Leo H. Gonelle-Gispert, Carmen PLoS One Research Article Multipotent mesenchymal stromal cells (MSC) are currently investigated clinically as cellular therapy for a variety of diseases. Differentiation of MSC toward endodermal lineages, including hepatocytes and their therapeutic effect on fibrosis has been described but remains controversial. Recent evidence attributed a fibrotic potential to MSC. As differentiation potential might be dependent of donor age, we studied MSC derived from adult and pediatric human bone marrow and their potential to differentiate into hepatocytes or myofibroblasts in vitro and in vivo. Following characterization, expanded adult and pediatric MSC were co-cultured with a human hepatoma cell line, Huh-7, in a hepatogenic differentiation medium containing Hepatocyte growth factor, Fibroblast growth factor 4 and oncostatin M. In vivo, MSC were transplanted into spleen or liver of NOD/SCID mice undergoing partial hepatectomy and retrorsine treatment. Expression of mesenchymal and hepatic markers was analyzed by RT-PCR, Western blot and immunohistochemistry. In vitro, adult and pediatric MSC expressed characteristic surface antigens of MSC. Expansion capacity of pediatric MSC was significantly higher when compared to adult MSC. In co-culture with Huh-7 cells in hepatogenic differentiation medium, albumin expression was more frequently detected in pediatric MSC (5/8 experiments) when compared to adult MSC (2/10 experiments). However, in such condition pediatric MSC expressed alpha smooth muscle more strongly than adult MSC. Stable engraftment in the liver was not achieved after intrasplenic injection of pediatric or adult MSC. After intrahepatic injection, MSC permanently remained in liver tissue, kept a mesenchymal morphology and expressed vimentin and alpha smooth muscle actin, but no hepatic markers. Further, MSC localization merges with collagen deposition in transplanted liver and no difference was observed using adult or pediatric MSC. In conclusion, when transplanted into an injured or regenerating liver, MSC differentiated into myofibroblasts with development of fibrous tissue, regardless of donor age. These results indicate that MSC in certain circumstances might be harmful due to their fibrogenic potential and this should be considered before potential use of MSC for cell therapy. Public Library of Science 2009-08-17 /pmc/articles/PMC2722022/ /pubmed/19684854 http://dx.doi.org/10.1371/journal.pone.0006657 Text en Baertschiger et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Baertschiger, Reto M.
Serre-Beinier, Véronique
Morel, Philippe
Bosco, Domenico
Peyrou, Marion
Clément, Sophie
Sgroi, Antonino
Kaelin, André
Buhler, Leo H.
Gonelle-Gispert, Carmen
Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver
title Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver
title_full Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver
title_fullStr Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver
title_full_unstemmed Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver
title_short Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver
title_sort fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722022/
https://www.ncbi.nlm.nih.gov/pubmed/19684854
http://dx.doi.org/10.1371/journal.pone.0006657
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