Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors
Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors
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通过确定的因素从小鼠成纤维细胞诱导功能性肝细胞样细胞
DOI：
10.1038/nature10116
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发表时间：
2011-07-21
期刊：
影响因子：
64.8
通讯作者：
Hui, Lijian
中科院分区：
文献类型：
--
作者：
Huang, Pengyu;He, Zhiying;Hui, Lijian
独立于供体肝脏器官的功能性肝细胞的产生在再生医学和肝脏疾病的可能治疗方面具有很大的治疗兴趣。诱导肝分化已经实现以前使用胚胎干细胞或诱导多能干细胞，，，，，，。特别是，从理论上讲，由患者自身诱导的多能干细胞产生的肝细胞可以避免免疫排斥。然而，诱导多能干细胞诱导肝细胞是一个复杂的过程，可能会随着技术的改进而被取代。谱系特异性转录因子的过度表达直接将终末分化的细胞转化为其他谱系，，，，，包括神经元、心肌细胞和血液祖细胞；然而，目前尚不清楚这些谱系转化细胞是否能在体内修复受损组织。在这里，我们证明了通过转导Gata4、Hnf1α和Foxa3，以及p19Arf的失活，直接诱导小鼠尾尖成纤维细胞产生功能性肝细胞样细胞（iHep）。iHep细胞具有典型的上皮形态，表达肝脏基因并获得肝细胞功能。值得注意的是，移植的iHep细胞可以重新填充富马酰乙酸-水解酶缺陷（Fah−/−）小鼠的肝脏，并通过恢复肝功能拯救近一半的受体免于死亡。我们的研究为肝工程和再生医学提供了一种产生功能性肝细胞样细胞的新策略。
The generation of functional hepatocytes independent of donor liver organs is of great therapeutic interest with regard to regenerative medicine and possible cures for liver disease. Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells,,,,,,. Particularly, hepatocytes generated from a patient’s own induced pluripotent stem cells could theoretically avoid immunological rejection. However, the induction of hepatocytes from induced pluripotent stem cells is a complicated process that would probably be replaced with the arrival of improved technology. Overexpression of lineage-specific transcription factors directly converts terminally differentiated cells into some other lineages,,,, including neurons, cardiomyocytes and blood progenitors; however, it remains unclear whether these lineage-converted cells could repair damaged tissuesin vivo. Here we demonstrate the direct induction of functional hepatocyte-like (iHep) cells from mouse tail-tip fibroblasts by transduction of Gata4, Hnf1α and Foxa3, and inactivation of p19Arf. iHep cells show typical epithelial morphology, express hepatic genes and acquire hepatocyte functions. Notably, transplanted iHep cells repopulate the livers of fumarylacetoacetate-hydrolase-deficient (Fah−/−) mice and rescue almost half of recipients from death by restoring liver functions. Our study provides a novel strategy to generate functional hepatocyte-like cells for the purpose of liver engineering and regenerative medicine.