Hepatic stellate cells stimulate hepatocyte differentiation of rats bone marrow derived mesenchymalstem cells in vitro

Abstract

Wide dissemination of chronic hepatitis and lowefficiency of their medication require development of newapproaches for treatment of this pathology. One of the mostperspective search directions is connected with stimulationof mesenchymal stem cells differentiation into hepatocytesby applying fibroblast growth factor 4 (FGF-4) and hepatocytegrowth factor (HGF), which determine primary differentiationof anterior gut epithelial cells into hepatocytes during prenatalontogenesis in mammals. It is known that hepatic stellate cells(HSC) are the natural source of these growth factors in theliver and they are essential component of microenvironmentfor differentiating epithelial cells during liver ontogenesis andregeneration. The aim of this survey was to study the ability ofstimulation of bone marrow derived multipotent mesenchymalcells (MMSC) hepatic differentiation by cultivation in thehepatic stellate cells conditioned media. MMSC were cultivatedin various models: 1) in the media free of growth factors;2) in the media by sequential exposure of growth factors;3) in HSC conditioned media; 4) co-cultivation together withHSC separated by semipermeable membrane on the boydenchambers; 5) in the mixed co-culture. Results of the surveyshowed that factors and cytokines, produced by HSC in themedia render significant effect on MMSC and lead to theirdifferentiation into hepatoblasts and hepatocytes with stableexpression (unlike expression of MMSC cultivated with growthfactors) of epithelial markers and ƒ-fetoprotein. Directintercellular contacts between MMSC and HSC in the mixedco-culture stimulate bulk and apparent expression of hepaticmarkers unlike in monoculter, but the phenomenon of cellfusion was not detected. Thus, results of this study confirmthe hypothesis of the HSC role as an important element ofmicroenvironment for MMSC hepatic differentiation in vitro.

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