Abstract
Harsh local microenvironment, such as hypoxia and lack of instructive clues for transplanted stem cells, presents the serious obstacle for stem cell therapies’ efficacy. Therefore, continued efforts have been taken to improve stem cells’ viability and plasticity. Hepatocyte growth factor (HGF) have previously been reported to mitigate complications of various human diseases in animal model studies and in some clinical trials. Besides, human stem cells from root apical papilla (SCAP) are deemed a better resource of mesenchymal stem cells due to derived stem cells holding greater amplification ability in vitro compared with those from other dental resources. To move forward, evaluating effects and understanding underlying molecular mechanisms of HGF on SCAP for periodontal regeneration are needed. In this study, HGF was transgenic expressed in SCAP, and it was found that HGF enhanced osteo/dentinogenic differentiation capacity of SCAP compared with those non-treated control in an ectopic mineralization model. Moreover, HGF reduced apoptosis of SCAP under both normoxia and hypoxia condition, whereas combination of HGF and hypoxia exposure had inhibitory effects on cell proliferation during an eight-day in vitro culture period. Transcriptome analysis further revealed that suppressed cell cycle progression and activated BMP/ TGFβ, Hedgehog, WNT, FGF, HOX and other morphogen family members upon HGF overexpression, which may render SCAP recapitulate part of neural crest stem cells characteristics. Moreover, strengthened stress-response modulation such as unfolded protein response, macroautophagy and anti-apoptotic molecules might explain increased viability of SCAP. In all, our results imply that these potential mechanisms underlying HGF promoting SCAP differentiation could be further elucidated and harnessed to improve dental tissue regeneration.