科学家首次获得转化型肝脏细胞

2011/05/13 19:51:08

转化型肝脏细胞移植肝衰竭小鼠一半存活

5月12日，国际学术期刊《自然》在线发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所惠利健研究小组关于转化型肝脏细胞的研究成果，证明肝脏以外的体细胞可以被诱导直接转化为肝脏细胞，为将来从病人自身体细胞诱导获得肝脏细胞进行移植的应用奠定了基础。

人体的皮肤、血液、神经、肝脏等终末分化的功能细胞是由多能干细胞分化而来，在自然界，这个过程是不可逆的，但从理论来看，通过生物工程它是可逆的。科学家已通过实验方法将皮肤细胞转化为多能干细胞，然后又把多能干细胞分化为肝脏细胞。而该研究则简化了这一过程，将小鼠尾巴上的皮肤成纤维细胞直接诱导为肝脏细胞，这种细胞具有和体内肝脏细胞类似的上皮细胞形态、基因表达谱、且获得了肝脏细胞的功能。

研究所通过实验发现，将转化型肝脏细胞移植于肝衰竭的小鼠，有近一半仍然存活，证明了转化型肝脏细胞具有体内功能。据悉，该项研究尚处于动物实验阶段，应用于临床，还需要相当长时间优化。

《自然》杂志的编委和评审专家高度评价此项工作的开创性意义，他们认为研究中所建立的技术体系，作为一项重大突破，对同领域的研究工作具有指导意义。

除了在细胞移植的临床应用前景外，转化型肝脏细胞在制药工业有关的药物代谢和药物毒理研究中，在基础医学和临床医学中对肝脏疾病机理研究也具有广泛的应用前景。目前已申请了相关专利，并有意投入开发利用，争取将实验室的基础研究成果转化为真正的科研生产力，回报社会，造福人类。这一工作得到了科技部、国家自然科学基金委、中国科学院的经费支持。

Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors

Pengyu Huang; Zhiying He; Shuyi Ji; Huawang Sun; Dao Xiang; Changcheng Liu; Yiping Hu; Xin Wang; Lijian Hui

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 disease1. Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells2, 3, 4, 5, 6, 7, 8. 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 lineages9, 10, 11, 12, including neurons13, cardiomyocytes14 and blood progenitors15; however, it remains unclear whether these lineage-converted cells could repair damaged tissues in 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.