A role of hepatocyte growth factor in regulation of hepatic development and differentiation

诱导iPS细胞向肝脏分化需要多个步骤，包括内胚层细胞、肝内胚层细胞和肝祖细胞的诱导以及肝细胞的成熟。在本研究中，我们发现，HGF增加了肝脏内皮细胞白蛋白和甲胎蛋白的表达，这是由激活素A、碱性成纤维细胞生长因子、骨形态发生蛋白-2和成纤维细胞生长因子-4诱导的iPS细胞的类胚体诱导的。这些结果表明，HGF在肝内皮细胞向肝脏分化过程中起重要作用。相反，肝内皮细胞表达Dlk1，而不表达EpCAM，这意味着肝内皮细胞中可能存在肝母细胞样细胞。这项研究的发现有助于建立利用HGF诱导的高效肝分化来治疗难治性肝病的新的细胞移植疗法。相反，HGF对各种受损组织的修复和再生也是必不可少的。事实上，HGF通过修饰紧密连接蛋白来刺激胃上皮细胞的迁移，导致在体外溃疡模型中增加上皮修复。此外，在肺动脉高压的大鼠模型中，给予HGF可降低肺动脉压，从而延长动物的存活时间。这些结果还表明，HGF本身是一种有效的治疗各种顽固性疾病的药物。

Induction of hepatic differentiation of iPS cells requires multiple steps including induction of endodermal, hepatic endodermal, and hepatic progenitor cells, and maturation of hepatocytes. In this study, we found that, HGF increased albumin and alpha-fetoprotein expression in hepatic endodermal cells, which were induced in embryoid bodies of iPS cells treated with Activin A, bFGF, followed by BMP-2 and FGF-4 exposure. These results indicate that HGF plays an essential role in hepatic differentiation of hepatic endodermal cells. Conversely, hepatic endodermal cells expressed Dlk1, but not EpCAM, meaning the possibility that hepatoblast-like cells exist in the hepatic endodermal cells. The findings in this study contribute to establishment of novel cell transplantation therapies for intractable liver diseases using HGF-induced high efficient hepatic differentiation. Conversely, HGF is also essential for repair and regeneration of various injured tissues. Actually, HGF stimulated migration of gastric epithelial cells through modification of tight junction proteins, resulting in increased epithelial restitution in an in vitro ulcer model. Additionally, administration of HGF decreased pulmonary arterial pressure in a rat model of pulmonary arterial hypertension, resulting in prolonged animal survival. These results also indicate that HGF itself is a potent therapeutic agent for various intractable diseases.