It is well established that during lung development the fate and specification of epithelial cells is mediated by paracrine signals derived from lung stromal cells in the distal tip mesenchyme. It is now proposed that this epithelial-mesenchymal interaction is also critical for tissue regeneration in the adult lung. Evidence suggests that the recruitment of resident lung stromal cell progenitors to the subepithelial space of injured airways is part of a primary wound healing response. Mesenchymal stromal cells are thought to contribute to tissue regeneration through various mechanisms, including the secretion of trophic factors that may act directly on epithelial stem cells to promote epithelialization. We have previously shown that the in vitro colony-forming potential of lung epithelial stem/progenitor cells (EpiSPC) requires coculture with resident Sca-1pos lung stromal cells. In this study we show that the epithelial-supportive capacity of resident lung stromal cells is regulated by TGF-β1. We show that the differentiation of stromal cells in the presence of TGF-β1 results in the loss of their ability to support EpiSPC colony-formation. However, the epithelial-supportive capacity of lung stromal cells could be restored by treatment with the TGF-β1 inhibitor SB431542. Comparative analysis of gene expression in supportive and non-supportive stromal cells showed that their epithelial-supportive capacity correlated with the level of FGF-10 expression and the reactivation of several lung development-associated genes. In summary, these studies suggest that TGF-β signaling in stromal cells acts upstream of FGF-10 to regulate epithelial stem cell growth in the adult lung. This supports the concept that the regenerative potential of lung EpiSPC is regulated by their interaction with the stromal microenvironment and suggests that its inhibitory or permissive nature is regulated by TGF-β1.
Supported by: NHMRC Australia Project Grant – 1009374
Conflict of interest: None