从成纤维细胞生成具有功能的人肝细胞的两步谱系重编程策略

2019年5月，北京大学生命科学学院；北京大学医学部天然药物与仿生药物国家重点实验室；北京大学生命科学中心；细胞增殖与分化教育部重点实验室；北京大学深圳研究生院化学生物与生物技术学院；化学肿瘤基因组学国家重点实验室；广东深圳518055;北京大学生物信息学研究中心；北京大学生命科学学院；北京-清华生命科学中心；细胞增殖与分化教育部重点实验室；上海公共卫生临床中心；北京大学医学部基础医学院；复旦大学医学分子病毒学重点实验室；中国人民解放军总医院肝胆外科(School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China；State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology & Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055,   China；Center for Bioinformatics,Peking University, Beijing 100871, China；MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China；Shanghai Public Health Clinical Center, Shanghai 201508, China；Hangzhou Repugene Technology Co,.   Ltd, Hangzhou, China；School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China；Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai 200032, China and；Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China) Shicheng Sun老师研究团队在《CELL RESEARCH》上发表论文：

“A two-step lineage reprogramming strategy to generate functionally competent human hepatocytes from fibroblasts”

“从成纤维细胞生成具有功能的人肝细胞的两步谱系重编程策略”

Abstract：

Terminally differentiated cells can be generated by lineage reprogramming, which is, however, hindered by incomplete conversion with residual initial cell identity and partial functionality. Here, we demonstrate a new reprogramming strategy by mimicking the natural regeneration route, which permits generating expandable hepatic progenitor cells and functionally competent human hepatocytes. Fibroblasts were first induced into human hepatic progenitor-like cells (hHPLCs), which could robustly expand in vitro and efficiently engraft in vivo. Moreover, hHPLCs could be efficiently induced into mature human hepatocytes (hiHeps) in vitro, whose molecular identity highly resembles primary human hepatocytes (PHHs). Most importantly, hiHeps could be generated in large quantity and were functionally competent to replace PHHs for drug-metabolism estimation, toxicity prediction and hepatitis B virus infection modeling. Our results highlight the advantages of the progenitor stage for successful lineage reprogramming. This strategy is promising for generating other mature human cell types by lineage reprogramming.

Conclusions: Our findings demonstrate that stable iPS cells could be generated in LCDM medium, which could give rise to both embryonic and extraembryonic cells in vivo. However, the efficiency and level of chimeric contribution of pig LCDM-iPS cells were found low.

摘要：

最终分化的细胞可以通过谱系重编程产生，然而，谱系重编程受到原始细胞身份和部分功能残留的不完全转化的阻碍。在这里，我们通过模拟自然再生途径展示了一种新的重编程策略，该策略允许生成可扩展的肝祖细胞和具有功能能力的人肝细胞。成纤维细胞**被诱导为人肝祖细胞样细胞(hhplc)，该细胞能在体外稳定扩增并在体内高效移植。此外，hhplc可以在体外有效地诱导成成熟的人肝细胞(hiHeps)，其分子特征与原代人肝细胞(PHHs)高度相似。最重要的是，hiHeps可以大量生成，并且在功能上能够取代PHHs进行药物代谢估计、毒性预测和乙型肝炎病毒感染建模。我们的研究结果强调了祖细胞阶段对成功的谱系重编程的优势。这一策略有望通过谱系重编程产生其他成熟的人类细胞类型。

该论文中，原代皮肤的体外培养是使用Ausbian特级胎牛血清完成的。欲了解或购买Ausbian特级胎牛血清可以联系北京缔一生物400-166-8600.