Collagen binding α2β1 and α1β1 integrins play contrasting roles in regulation of Ets-1 expression in human liver myofibroblasts
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Activation of hepatic stellate cells from quiescence to myofibroblast-like cells (MFBs) is a pivotal event in hepatic fibrogenesis. Plastic-cultured stellate cells (an established in vitro model of the activated phenotype) recultured on Matrigel™ revert to quiescence. In the present study we analyzed the molecular mechanism underlying this process, focusing on the effect of collagen receptors α2β1 and α1β1 integrin signaling on the expression of Ets-1 transcription factor and its target gene MMP1 in cultured human MFBs. Cells grown in 3-dimensional (3D) substrates (Matrigel™ or collagen type I gel) markedly upregulated Ets-1 and MMP1 messages, in comparison to cells cultured on plastic. A similar effect but less intense was mimicked by stimulation of α2β1 or blocking of α1β1 integrin in cells grown on plastic. We observed increased expression of MMP1 transcripts with parallel changes in MMP1 promoter activity, and in mRNA and protein levels of upstream transcription factors Ets-1 and c-Jun. Interference with α2β1 and α1β1 integrin function in cells cultured in a 3D collagen substrate resulted in an even greater effect. Morphologically, stimulation of α2β1 integrin resulted in formation of multicellular networks, probably by facilitation of cell migration. Thus, we report the novel observation that in cultured human MFBs reverting to quiescence, the expression of transcription factor Ets-1 and its downstream target MMP1 can be modulated by changes in the microenvironment, which are mediated, at least in part, by the balance between collagen receptor integrin α2β1 and α1β1 activities
Key wordsEts-1 transcription factor extracellular matrix hepatic fibrogenesis integrin signaling microenvironment
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