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Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver.

Baertschiger RM, Serre-Beinier V, Morel P, Bosco D, Peyrou M, Clément S, Sgroi A, Kaelin A, Buhler LH, Gonelle-Gispert C - PLoS ONE (2009)

Bottom Line: Expansion capacity of pediatric MSC was significantly higher when compared to adult 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.

View Article: PubMed Central - PubMed

Affiliation: Surgical Research Unit, Department of Surgery, University Hospital Geneva, Geneva, Switzerland.

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.

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Related in: MedlinePlus

Telomerase activity in adult and pediatric MSC.Telomerase activity of adult and pediatric MSC from 4 different donors and at different passages (1 to 4) was measured and normalized to a provided positive control set as 100 percent. Immortalized human hepatocytes (IHH) were used as quality controls of cell extracts containing telomerase; IHH are immortalized cells transduced with lentivectors coding for telomerase [44]. As compared to control, telomerase activity was low and not significantly different between aMSC and pMSC (p>0.4).
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pone-0006657-g002: Telomerase activity in adult and pediatric MSC.Telomerase activity of adult and pediatric MSC from 4 different donors and at different passages (1 to 4) was measured and normalized to a provided positive control set as 100 percent. Immortalized human hepatocytes (IHH) were used as quality controls of cell extracts containing telomerase; IHH are immortalized cells transduced with lentivectors coding for telomerase [44]. As compared to control, telomerase activity was low and not significantly different between aMSC and pMSC (p>0.4).

Mentions: Telomerase activity of MSC in culture remains controversial [16], [17], [21]. We analyzed telomerase activity of aMSC and pMSC in order to determine whether differences in expansion capacities could be related to different activity of telomerase (Fig. 2). Telomerase activity of MSC was measured and normalized to a positive control provided by the assay. IHH, cells transduced with lentivectors coding for telomerase, were used as a positive control for quality of cell extracts. These cells displayed almost fourteen times more telomerase activity than the provided positive control. As shown in figure 2, telomerase activity in MSC extracts was low compared to positive control and not significantly different between aMSC and pMSC (p>0.4).


Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver.

Baertschiger RM, Serre-Beinier V, Morel P, Bosco D, Peyrou M, Clément S, Sgroi A, Kaelin A, Buhler LH, Gonelle-Gispert C - PLoS ONE (2009)

Telomerase activity in adult and pediatric MSC.Telomerase activity of adult and pediatric MSC from 4 different donors and at different passages (1 to 4) was measured and normalized to a provided positive control set as 100 percent. Immortalized human hepatocytes (IHH) were used as quality controls of cell extracts containing telomerase; IHH are immortalized cells transduced with lentivectors coding for telomerase [44]. As compared to control, telomerase activity was low and not significantly different between aMSC and pMSC (p>0.4).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2722022&req=5

pone-0006657-g002: Telomerase activity in adult and pediatric MSC.Telomerase activity of adult and pediatric MSC from 4 different donors and at different passages (1 to 4) was measured and normalized to a provided positive control set as 100 percent. Immortalized human hepatocytes (IHH) were used as quality controls of cell extracts containing telomerase; IHH are immortalized cells transduced with lentivectors coding for telomerase [44]. As compared to control, telomerase activity was low and not significantly different between aMSC and pMSC (p>0.4).
Mentions: Telomerase activity of MSC in culture remains controversial [16], [17], [21]. We analyzed telomerase activity of aMSC and pMSC in order to determine whether differences in expansion capacities could be related to different activity of telomerase (Fig. 2). Telomerase activity of MSC was measured and normalized to a positive control provided by the assay. IHH, cells transduced with lentivectors coding for telomerase, were used as a positive control for quality of cell extracts. These cells displayed almost fourteen times more telomerase activity than the provided positive control. As shown in figure 2, telomerase activity in MSC extracts was low compared to positive control and not significantly different between aMSC and pMSC (p>0.4).

Bottom Line: Expansion capacity of pediatric MSC was significantly higher when compared to adult 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.

View Article: PubMed Central - PubMed

Affiliation: Surgical Research Unit, Department of Surgery, University Hospital Geneva, Geneva, Switzerland.

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.

Show MeSH
Related in: MedlinePlus