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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| Veröffentlicht in: | PloS one 2009-08, Vol.4 (8), p.e6657-e6657 |
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| creator | Baertschiger, Reto M Serre-Beinier, Véronique Morel, Philippe Bosco, Domenico Peyrou, Marion Clément, Sophie Sgroi, Antonino Kaelin, André Buhler, Leo H Gonelle-Gispert, Carmen |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0006657 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0006657</identifier><identifier>PMID: 19684854</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Actin ; Actins - metabolism ; Age ; Analgesics ; Animals ; Antigens ; Blotting, Western ; Bone marrow ; Bone marrow transplantation ; Carbon ; Cell culture ; Cell Differentiation ; Collagen ; Collagen - metabolism ; Developmental Biology/Stem Cells ; Differentiation ; Engraftment ; Extracellular matrix ; Fibroblast growth factor 4 ; Fibroblast growth factors ; Fibroblasts ; Fibrosis ; Gastroenterology and Hepatology/Hepatology ; Gene expression ; Growth factors ; Hepatectomy ; Hepatocyte growth factor ; Hepatocytes ; Hepatoma ; Hospitals ; Humans ; Immunohistochemistry ; Injection ; Intermediate filament proteins ; Liver ; Liver - metabolism ; Liver - pathology ; Liver Cirrhosis - pathology ; Liver diseases ; Liver transplantation ; Liver transplants ; Localization ; Markers ; Mesenchymal stem cells ; Mesenchyme ; Mesoderm - cytology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Morphology ; Oncostatin M ; Pediatrics ; Polymerase chain reaction ; Proteins ; Retrorsine ; Reverse Transcriptase Polymerase Chain Reaction ; Rodents ; Smooth muscle ; Spleen ; Stem cells ; Stromal cells ; Stromal Cells - cytology ; Surgery ; Surgery/Transplantation ; Therapy ; Transplants & implants ; Tumor necrosis factor-TNF</subject><ispartof>PloS one, 2009-08, Vol.4 (8), p.e6657-e6657</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Baertschiger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Baertschiger et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c729t-6d41bb0b732d2c87bc9eb833a3777ee4f4d56c666411c3d9f75a97c935c2b7693</citedby><cites>FETCH-LOGICAL-c729t-6d41bb0b732d2c87bc9eb833a3777ee4f4d56c666411c3d9f75a97c935c2b7693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722022/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722022/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19684854$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Egles, Christophe</contributor><creatorcontrib>Baertschiger, Reto M</creatorcontrib><creatorcontrib>Serre-Beinier, Véronique</creatorcontrib><creatorcontrib>Morel, Philippe</creatorcontrib><creatorcontrib>Bosco, Domenico</creatorcontrib><creatorcontrib>Peyrou, Marion</creatorcontrib><creatorcontrib>Clément, Sophie</creatorcontrib><creatorcontrib>Sgroi, Antonino</creatorcontrib><creatorcontrib>Kaelin, André</creatorcontrib><creatorcontrib>Buhler, Leo H</creatorcontrib><creatorcontrib>Gonelle-Gispert, Carmen</creatorcontrib><title>Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver</title><title>PloS one</title><addtitle>PLoS One</addtitle><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. 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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.</description><subject>Actin</subject><subject>Actins - metabolism</subject><subject>Age</subject><subject>Analgesics</subject><subject>Animals</subject><subject>Antigens</subject><subject>Blotting, Western</subject><subject>Bone marrow</subject><subject>Bone marrow transplantation</subject><subject>Carbon</subject><subject>Cell culture</subject><subject>Cell Differentiation</subject><subject>Collagen</subject><subject>Collagen - metabolism</subject><subject>Developmental Biology/Stem Cells</subject><subject>Differentiation</subject><subject>Engraftment</subject><subject>Extracellular matrix</subject><subject>Fibroblast growth factor 4</subject><subject>Fibroblast growth factors</subject><subject>Fibroblasts</subject><subject>Fibrosis</subject><subject>Gastroenterology and Hepatology/Hepatology</subject><subject>Gene expression</subject><subject>Growth factors</subject><subject>Hepatectomy</subject><subject>Hepatocyte growth factor</subject><subject>Hepatocytes</subject><subject>Hepatoma</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Injection</subject><subject>Intermediate filament proteins</subject><subject>Liver</subject><subject>Liver - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Baertschiger, Reto M</au><au>Serre-Beinier, Véronique</au><au>Morel, Philippe</au><au>Bosco, Domenico</au><au>Peyrou, Marion</au><au>Clément, Sophie</au><au>Sgroi, Antonino</au><au>Kaelin, André</au><au>Buhler, Leo H</au><au>Gonelle-Gispert, Carmen</au><au>Egles, Christophe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2009-08-17</date><risdate>2009</risdate><volume>4</volume><issue>8</issue><spage>e6657</spage><epage>e6657</epage><pages>e6657-e6657</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19684854</pmid><doi>10.1371/journal.pone.0006657</doi><tpages>e6657</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2009-08, Vol.4 (8), p.e6657-e6657 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1291064555 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Actin Actins - metabolism Age Analgesics Animals Antigens Blotting, Western Bone marrow Bone marrow transplantation Carbon Cell culture Cell Differentiation Collagen Collagen - metabolism Developmental Biology/Stem Cells Differentiation Engraftment Extracellular matrix Fibroblast growth factor 4 Fibroblast growth factors Fibroblasts Fibrosis Gastroenterology and Hepatology/Hepatology Gene expression Growth factors Hepatectomy Hepatocyte growth factor Hepatocytes Hepatoma Hospitals Humans Immunohistochemistry Injection Intermediate filament proteins Liver Liver - metabolism Liver - pathology Liver Cirrhosis - pathology Liver diseases Liver transplantation Liver transplants Localization Markers Mesenchymal stem cells Mesenchyme Mesoderm - cytology Mice Mice, Inbred NOD Mice, SCID Morphology Oncostatin M Pediatrics Polymerase chain reaction Proteins Retrorsine Reverse Transcriptase Polymerase Chain Reaction Rodents Smooth muscle Spleen Stem cells Stromal cells Stromal Cells - cytology Surgery Surgery/Transplantation Therapy Transplants & implants Tumor necrosis factor-TNF |
| title | Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver |
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