Endothelial-to-mesenchymal transition contributes to hypertrophic scarring

Abstract

Hypertrophic scarring, characterized by excessive dermal fibrosis and collagen deposition, is a pathological wound healing response commonly following deep injury of the skin. Fibroblasts as the major effector cell, playing a critical role in production of excessive collagen during scar formation, are central for development of excessive scars and other organ fibrosis [1,2]. However, the origin of these fibroblasts remains unclear and specific anti-fibrotic therapies are not currently available. Recent studies during fibrosis in other epithelial organs, such as the liver, kidney, lung, skin and solid tumors, have demonstrated that fibroblasts are derived from the proliferation of resident fibroblasts, bone marrowederived fibroblasts, recruitmentof circulatingfibrocytesandaccumulation through epithelialemesenchymal transition (EMT) or endothelialmesenchymal transition (EndMT) [2,3]. However, the source of such fibroblasts in hypertrophic scarring is largely unknown. In the recently published reference [4], Song et al. speculate that the inhibition of angiogenesis by RNAi-based anti-VEGF may inhibit the proliferation of fibroblast and collagen production, which demonstrates endothelial cells may contribute to fibroblasts. Based on this literature, the authors here would like to hypothesize that fibroblasts can be increased in number by EndMT in hypertrophic scarring. There are at least three proved points for such a hypothesis [1,2]: (i) excess of endothelial cells and fibroblasts exists simultaneously in hypertrophic scarring; (ii) fibroblasts in hypertrophic scarring produce more TGF-b1 than the counterpart in normal skin tissue; (iii) TGF-b1 solely can induce endothelial cells to undergo EndMT. Hence, once EndMT initiates, promotion of EndMT may further be achieved by paracrine signals of fibroblasts in hypertrophic scarring. Therefore, inhibition of EndMT in vivo by blockage of endothelial cell proliferation through VEGF RNAi may be a promising therapy for hypertrophic scarring.