Differentiation of Cardiac Fibroblasts to Myofibroblasts During 1 β Stimulation of Collagen Production by Transforming Growth Factor-Print

The aim of the present study was to elucidate how transforming growth factor1 (TGF1) can stimulate collagen deposition in cardiac tissue by interstitial cells via stimulation of fibroblasts, via myofibroblasts, or via differentiation of fibroblasts to myofibroblasts. The doseand time-dependent stimulation of collagen production and of expression of -smooth muscle actin ( -SMA), a marker of myofibroblasts, was studied in cultures of second-passage adult rat cardiac fibroblasts. The TGF1–stimulated collagen production is positively correlated (r 0.68, P 0.001) with the appearance of -SMA. Only at high concentrations (40 to 600 pmol/L) and after a long time (24 to 48 hours) of incubation, TGF1 increases the collagen production and stimulates the differentiation of fibroblasts to myofibroblasts. The maximal stimulation of the collagen production (2-fold, P 0.001) observed after incubation of cultures of fibroblasts with 600 pmol/L TGF1 for 48 hours is accompanied by a maximal stimulation of -SMA expression (3.5-fold, P 0.001), when cultures consist mainly of myofibroblasts. The stimulation of collagen production cannot be reversed either after additional incubation of TGF1–stimulated second-passage cultures for 2 days or in their offspring in the next third passage after incubation for 7 days without TGF1. The increased collagen production in these third-passage cultures cannot be further stimulated by TGF1. Our data suggest that TGF1-stimulated collagen production in cultures of adult rat cardiac ventricular fibroblasts cannot be explained by a direct stimulation of the collagen production either in fibroblasts or in myofibroblasts. Instead, TGF1 induces the differentiation of fibroblasts to myofibroblasts, which have a higher activity for collagen production than fibroblasts. (Hypertension. 2002;39:258263.)