“凤凰涅槃”小分子诱导肝细胞体外再生助力肝病转化医学
2018/10/26
2017年,鄢和新教授/王红阳院士研究团队通过小分子体外模拟肝再生微环境,借助多种转基因小鼠进行谱系追踪,实现并证明小鼠原代肝细胞向肝前体样细胞的可逆转化,开辟了一条非基因插入的体外肝细胞扩增蹊径。延续性的研究近期在人类原代肝细胞体外培养中取得了突破,相关成果于10月25日发表在Cell Research杂志上。

在此之前,体外功能性肝细胞获取多来自于肝脏肿瘤细胞系或者经过基因改造的正常肝细胞,存在极大的应用风险。上述研究所报道的全新的肝细胞体外再生方式无任何基因导入,小分子培养基就如使凤凰涅槃的火焰,在其作用下原代肝细胞可以高效逆转为可扩增的肝前体样细胞(Hepatocyte-derived liver progenitor-like cells,HepLPCs),而这种原代肝细胞来源的肝前体样细胞在体外极易实现肝向分化,转变回功能性肝细胞。


原代肝细胞在小分子“火焰”下的可逆转化

HepLPCs不仅可用于体外药物筛选和肝脏疾病模拟,而且移植入FAH基因联合免疫缺陷的小鼠体内后能很好的定植于肝脏并重建损伤区域。这些发现为人类肝脏疾病的自体细胞治疗、体外人工肝等提供了一种有安全有效和前景广阔的应用途径。


HepLPCs的应用前景

参考文献:

【1】Wu H, Zhou X, Fu G B, et al. Reversible transition between hepatocytes and liver progenitors for in vitro hepatocyte expansion[J]. Cell Research, 2017, 27(5).

【2】Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens.

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  • Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens

    The study of pathophysiological mechanisms in human liver disease has been constrained by the inability to expand primary hepatocytes in vitro while maintaining proliferative capacity and metabolic function. We and others have previously shown that mouse mature hepatocytes can be converted to liver progenitor-like cells in vitro with defined chemical factors. Here we describe a protocol achieving efficient conversion of human primary hepatocytes into liver progenitor-like cells (HepLPCs) through delivery of developmentally relevant cues, including NAD + -dependent deacetylase SIRT1 signaling. These HepLPCs could be expanded significantly during in vitro passage. The expanded cells can readily be converted back into metabolically functional hepatocytes in vitro and upon transplantation in vivo. Under three-dimensional culture conditions, differentiated cells generated from HepLPCs regained the ability to support infection or reactivation of hepatitis B virus (HBV). Our work demonstrates the utility of the conversion between hepatocyte and liver progenitor-like cells for studying HBV biology and antiviral therapies. These findings will facilitate the study of liver diseases and regenerative medicine.

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