CARDIAC FIBROBLASTS ARE PREDISPOSED TO CONVERT INTO MYOCYTE PHENOTYPE - SPECIFIC EFFECT OF TRANSFORMING GROWTH-FACTOR-BETA

Cardiac fibroblasts are mainly responsible for the synthesis of major extracellular matrix proteins in the heart, including fibrillar collagen types I and III and fibronectin. In this report we show that these cells, when stimulated by transforming growth factor beta-1 (TGF-beta-1), acquire certain myocyte-specific properties. Cultured cardiac fibroblasts from adult rabbit heart were treated with TGF-beta-1 (10-15 ng/ml) for different periods of time. Northern hybridization analysis of total RNA showed that cells treated with TGF-beta-1 for 24 hr expressed mRNA corresponding to sarcomeric actin mRNA. Immunofluorescence staining and light microscopy showed that cultured cardiac fibroblasts treated with TGF-beta-1 became stained with a monoclonal antibody to muscle-specific actin. After treatment of quiescent cells with TGF-beta-1, cell proliferation (as measured by [H-3]thymidine incorporation) was moderately increased (1.5-fold, P < 0.001). NIH 3T3 cells and human skin fibroblasts, treated with TGF-beta-1, did not express sarcomeric actin mRNA. Treatment of cardiac fibroblasts with the mitogenic agent phorbol 12-myristate 13-acetate or with norepinephrine, angiotensin II, or interleukin 1-beta did not induce myocyte-specific actin mRNA. Cultured cardiac fibroblasts at the subconfluent stage, when exposed to TGF-beta-1 in the presence of 10% fetal bovine serum, gave rise to a second generation of slowly growing cells that expressed muscle-specific actin filaments. Our findings demonstrate that cardiac fibroblasts can be made to differentiate into cells that display many characteristics of cardiac myocytes. TGF-beta-1 seems to be a specific inducer of such conversion.