The fibrogenic differentiation of resident mesenchymal cells is a key parameter in the pathogenesis of radiation fibrosis and is triggered by the profibrotic growth factors TGF-1 and CCN2. TGF-1 is considered the primary inductor of fibrogenic differentiation and is thought to control its long term maintenance, whereas CCN2 is considered TGF-1's secondary effector. Yet, in long-term established fibrosis like that associated with delayed radiation enteropathy, in situ TGF-1 deposition is low, whereas CCN2's is high. To explore this apparent paradox, cell response to increasing dose of TGF-1 was investigated in cells modeling initiation and maintenance of fibrosis i.e. normal and fibrosis-derived smooth muscle cells respectively. Activation of cell specific signaling pathways, by low TGF-1 doses, was demonstrated with a main activation of the Rho/ROCK pathway in fibrosis-derived cells, whereas the Smad pathway was mainly activated in normal cells. This leads to subsequent and cell-specific regulation of the CCN2 gene. These results suggested a specific profibrotic role of CCN2 in fibrosis-initiated cells. Thereby, the modulation of CCN2 expression by itself and the combination of TGF-1 and CCN2 was investigated in fibrosis-derived cells. In fibrosis-initiated cells CCN2 triggered its auto-induction, furthermore low concentration of TGF-1 potentiated CCN2 auto-induction. Our findings showed a differential requirement and action of TGF-1 in the fibrogenic response of normal versus fibrosis-derived cells. This study defines a novel Rho/ROCK, Smad3 independent mode of TGF- signaling that may operate during chronic stages of fibrosis and provides evidence of both specific and combinatorial roles of low TGF-1 dose and CCN2.