Cell Research丨鄢和新/王红阳合作团队实现原代肝细胞的逆转和扩增,开创肝病研治新细胞源

2018-10-28 BioArt BioArt

我国是世界肝病大国,有接近4亿的肝病患者,多种致病因素引起的急慢性肝衰竭是死亡率最高的消化系统疾病,严重危害国民健康。目前,原位肝脏移植是唯一有效的治疗手段。然而,由于供体短缺和免疫排斥等问题,绝大多数肝衰竭患者无法得到及时有效的治疗。近年基础与临床研究表明,肝细胞移植是治疗急慢性肝衰竭的有效方法。但是,人类肝细胞无法在体外培养和扩增,如何突破这一难题是实现肝细胞在临床应用的关键。

我国是世界肝病大国,有接近4亿的肝病患者,多种致病因素引起的急慢性肝衰竭是死亡率最高的消化系统疾病,严重危害国民健康。目前,原位肝脏移植是唯一有效的治疗手段。然而,由于供体短缺和免疫排斥等问题,绝大多数肝衰竭患者无法得到及时有效的治疗。近年基础与临床研究表明,肝细胞移植是治疗急慢性肝衰竭的有效方法。但是,人类肝细胞无法在体外培养和扩增,如何突破这一难题是实现肝细胞在临床应用的关键。

Cell Research在线发表了上海交通大学医学院附属仁济医院鄢和新教授、第二军医大学东方肝脏外科医院王红阳院士和同济大学附属东方医院何志颖教授联合研究团队题为Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens的最新研究成果,该工作首次实现体外人类原代肝细胞向肝前体样细胞的可逆转化和扩增,开创了肝病研究与治疗的全新细胞来源。

当肝脏暴露于多种代谢、毒性和炎症损伤刺激下可产生系统性反应,导致肝脏细胞整体损伤和自我更新能力受损。在这种情况下,一群肝前体样细胞会迅速出现并快速扩增,帮助实现肝脏再生。然而,这些肝前体样细胞的来源尚不十分清楚。Tarlow等人报道了人肝细胞和小鼠肝细胞在体内可转化为胆管样前体细胞来逃避损伤,这些细胞在损伤因素减轻后又可重新分化为肝细胞来修复肝脏。另一方面,Lu和Raven等人证明了胆管细胞也可转化为兼性肝前体细胞,。这些结果提示肝细胞和胆管细胞都可能成为肝损伤时修复肝细胞的细胞来源。

因此,在体外从肝细胞或胆管细胞中培养出人类肝脏前体细胞将具有重要意义,这不仅有助于提高对肝前体细胞起源和重编程机制的认识,而且为功能性肝细胞的体外获得提供了新的细胞来源,具有极其重要的临床研究和应用价值。2017年,鄢和新教授/王红阳院士团队和日本科学家团队独立开发出体外小分子重编程培养体系,将鼠类肝细胞转化为肝前体样细胞并实现大量扩增,这一工作首次在体外重现了Tarlow等人的体内实验发现。但是日本科学家团队的培养体系,在当时无法实现人类肝细胞的转化与扩增。

鄢和新教授/王红阳院士团队最新的研究成果报道了在改良的小分子重编程培养体系中可实现人类原代肝细胞向肝前体样细胞的转化和扩增,并且这种无任何外源基因导入的原代肝细胞来源的肝前体样细胞(Hepatocyte-derived liver progenitor-like cells,HepLPCs)能快速分化为功能性肝细胞,实现“Hepatocyte-HepLPCs”之间的可逆转化。研究还发现SIRT1介导的表观调控在肝细胞向肝前体样细胞的可逆转化和扩增中发挥重要作用。

在应用方面,将诱导分化的HepLPCs移植入FAH基因缺陷联合免疫缺陷小鼠后,细胞可定植于肝脏并重建受损肝脏,小鼠血液中可检测到人特异性ALB和AAT(肝实质细胞的marker)分泌,从而首次实现了人肝细胞体外扩增后治疗代谢性肝病,这也使得人们长期向往的肝病自体或异体肝细胞移植治疗或将成为可能。此外,HepLPCs在体外三维培养形成的类器官样组织球还可用于HBV感染与药筛研究,并验证了CRISPR/Cas9技术在HBV感染治疗中的潜在价值。

鄢和新教授早在2010年博后期间开始探索肝细胞体外培养体系,经过近10年努力形成了系列性工作,据了解,该团队更多精彩成果将陆续发表。

原始出处:
Fu GB1, Huang WJ1, Zeng M1,et al.Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens.Cell Res. 2018 Oct 25. doi: 10.1038/s41422-018-0103-x. [Epub ahead of print]

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    2019-05-05 维他命
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    2019-09-03 仁医06
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    2018-10-30 yangshch
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