It appears that limited transmigration through the endothelial ba

It appears that limited transmigration through the endothelial barrier hampers MSC to enter liver parenchyma. In order to expose MSC directly to liver tissue, we injected cells into the remaining 30% of liver and observed long-term survival. However, selleckchem Nutlin-3a differentiation of MSC into hepatocytes did not occur as well. Differentiation of human MSC into hepatocyte-like cells after direct injection into liver parenchyma has been described in a rat model of chronic liver injury [37]. Sato and colleagues identified human albumin and ��FP-positive clusters in CCl4-treated and immunosuppressed rats. Using an allogeneic rat model, Popp and colleagues reported that MSC do not stably engraft into retrorsine-treated and partially hepatectomized mice [34].

The discrepancy of survival and engraftment of MSC in liver might be related to the immunocompetent model used [34] as clearing of MSC might be under the control of the immune-system [38]. In our study using immunodeficient recipients, we observed long-term engraftment of MSC in liver parenchyma. Histology showed that cells integrated randomly into the tissue without specific distribution. MSC expressed ��SMA, a marker for myofibroblasts [39] and vascular smooth muscle cells [40]. In transplanted liver, MSC localization merged with collagen deposition. Injured liver secretes large amount of growth factors and cytokines, i.e. tumor necrosis factor alpha (TNF��), interleukin 6 (IL6) and later transforming growth factor beta 1 (TGF��1) [41]. Therefore, increased levels of TGF�� may induce migration of MSC through up regulation of molecules such as CD44 [42] and differentiation of MSC into myofibroblast [43].

Fibrogenic potential of adult bone marrow-derived MSC was described in a mouse model of chronic liver injury [36]. Expression of ��SMA has also been observed in umbilical cord-derived MSC in vitro but their fibrogenic effect had not been confirmed in vivo [14]. Despite beneficial effects of MSC on liver fibrosis [13], [12], [11], our data showed that bone-marrow-derived MSC from adult and pediatric donors, transplanted into regenerating liver, displayed fibrogenic activity, indicating a potential harmful effect on liver parenchyma. In conclusion, in vitro albumin expression was induced frequently in MSC derived from pediatric donors but could not be detected at protein level.

Further, under such conditions MSC showed increased fibrogenic potential. In vivo, both aMSC and pMSC Anacetrapib implanted in injured and regenerating liver parenchyma were not able to differentiate into hepatocytes. In the liver parenchyma, MSC remained mesenchymal, expressed ��SMA and their localization merged with collagen deposition. These results indicate that adult as well as pediatric MSC were able to develop into fibrogenic tissue in our mice model.

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