Oral mucosal wounds are characterized by rapid healing with minimal scarring, partly attributable to the “enhanced” wound healing properties of oral mucosal ﬁbroblasts (OMFs). Hepatocyte growth factor (HGF) is a pleiotropic growth factor, with potential key roles in accelerating healing and preventing ﬁbrosis. HGF can exist as full-length or truncated (HGF-NK), NK1 and NK2 isoforms. As OMFs display elevated HGF expression compared to dermal ﬁbroblasts (DFs), this study investigated the extent to which HGF mediates the preferential cellular functions of OMFs, and the inﬂuence of pro-ﬁbrotic, transforming growth factor-β1 (TGF-β1) on these responses. Knockdown of HGF expression in OMFs by short-interfering RNA (siHGF) signiﬁcantly inhibited OMF proliferative and migratory responses. Supplementation with exogenous TGF-β1 also signiﬁcantly inhibited proliferation and migration, concomitant with signiﬁcantly down-regulated HGF expression. In addition, knockdown abrogated OMF resistance to TGF-β1-driven myoﬁbroblast differentiation, as evidenced by increased α-smooth muscle actin (α-SMA) expression, F-actin reorganisation, and stress ﬁbre formation. Responses were unaffected in siHGF-transfected DFs. OMFs expressed signiﬁcantly higher full-length HGF and NK1 levels compared to patient-matched DFs, whilst NK2 expression was similar in both OMFs and DFs. Furthermore, NK2 was preferentially expressed over NK1 in DFs. TGF-β1 supplementation signiﬁcantly down-regulated full-length HGF and NK1 expression by OMFs, while NK2 was less affected. This study demonstrates the importance of HGF in mediating “enhanced” OMF cellular function. We also propose that full-length HGF and HGF-NK1 convey desirable wound healing properties, whilst ﬁbroblasts preferentially expressing more HGF-NK2 readily undergo TGF-β1-driven differentiation into myoﬁbroblasts.
Dally, J., Khan, J. S., Voisey, A., Charalambous, C., John, H. L., Woods, E. L., … Midgley, A. C. (2017). Hepatocyte growth factor mediates enhanced wound healing responses and resistance to transforming growth factor-β1-driven myoﬁbroblast differentiation in oral mucosal fibroblasts. International Journal of Molecular Sciences, 18(9). https://doi.org/10.3390/ijms18091843