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.


中文翻译：

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肝细胞生长因子促进人根尖乳头干细胞的分化潜能和应激反应

恶劣的局部微环境，如缺氧和缺乏移植干细胞的指导线索，严重阻碍了干细胞疗法的疗效。因此，人们不断努力提高干细胞的活力和可塑性。在动物模型研究和一些临床试验中，肝细胞生长因子 (HGF) 先前已被报道可减轻各种人类疾病的并发症。此外，来自根尖乳头（SCAP）的人类干细胞被认为是更好的间充质干细胞资源，因为与其他牙科资源相比，衍生干细胞在体外具有更大的扩增能力。为了向前发展，需要评估 HGF 对 SCAP 牙周再生的影响和了解潜在的分子机制。在这项研究中，HGF 在 SCAP 中转基因表达，在异位矿化模型中，与未处理的对照相比，HGF 增强了 SCAP 的骨/牙本质分化能力。此外，在常氧和缺氧条件下，HGF 减少了 SCAP 的细胞凋亡，而 HGF 和低氧暴露的组合在 8 天的体外培养期间对细胞增殖具有抑制作用。转录组分析进一步显示，在 HGF 过表达时，抑制细胞周期进程并激活 BMP/TGFβ、Hedgehog、WNT、FGF、HOX 和其他形态发生素家族成员，这可能使 SCAP 概括了部分神经嵴干细胞特征。此外，增强的应激反应调节，如未折叠蛋白反应、巨自噬和抗凋亡分子可能解释了 SCAP 活力的增加。在所有，