Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF betais abrogated by pre-treatment with the heritable differentiation effector FGF1

MMH (Met murine hepatocyte) liver cells derived from transgenic mice expres sing a truncated constitutively active form of human c-Met are non-transfor med immortalized cell lines. We have previously shown that they harbor: (1) epithelial cells that express the liver-enriched transcription factors HNF 4 and HNF1 alpha, and that can be stably induced by FGF1 to express liver f unctions, and (2) fibroblast-like bi-potential palmate cells that can diffe rentiate into bile duct-like structures in Matrigel cultures, or into epith elial cells competent to express hepatic functions. Low concentrations of T GF beta have been found to inhibit growth and differentiation of MMH cells. The factor stabilized the palmate cell phenotype, and it provoked epitheli al cells to acquire palmate-like morphological characteristics, in parallel with down-regulation of expression of HNF4 and HNF1 alpha and activation o f Snail transcripts. The effects of TGF beta were dominant if it was added with FGF1, but the effects on differentiation were abrogated if cells had b een pre-treated with FGF1, This work identifies TGF beta as a factor that c ould be implicated in maintaining bi-potential precursor cells in the liver , FGF1 as one that could override the TGF beta effects and Snail as a candi date for mediation of the signal.