從成纖維細胞生成具有功能的人肝細胞的兩步譜系重編程策略

2019年5月，北京大學生命科學學院；北京大學醫學部天然藥物與仿生藥物國家重點實驗室；北京大學生命科學中心；細胞增殖與分化教育部重點實驗室；北京大學深圳研究生院化學生物與生物技術學院；化學腫瘤基因組學國家重點實驗室；廣東深圳518055;北京大學生物信息學研究中心；北京大學生命科學學院；北京-清華生命科學中心；細胞增殖與分化教育部重點實驗室；上海公共衛生臨床中心；北京大學醫學部基礎醫學院；復旦大學醫學分子病毒學重點實驗室；中國人民解放軍總醫院肝膽外科(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老師研究團隊在《CELL RESEARCH》上發表論文：

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

“從成纖維細胞生成具有功能的人肝細胞的兩步譜系重編程策略”

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：

最終分化的細胞可以通過譜系重編程產生，然而，譜系重編程受到原始細胞身份和部分功能殘留的不完全轉化的阻礙。在這里，我們通過模擬自然再生途徑展示了一種新的重編程策略，該策略允許生成可擴展的肝祖細胞和具有功能能力的人肝細胞。成纖維細胞**被誘導為人肝祖細胞樣細胞(hhplc)，該細胞能在體外穩定擴增并在體內高效移植。此外，hhplc可以在體外有效地誘導成成熟的人肝細胞(hiHeps)，其分子特征與原代人肝細胞(PHHs)高度相似。最重要的是，hiHeps可以大量生成，并且在功能上能夠取代PHHs進行藥物代謝估計、毒性預測和乙型肝炎病毒感染建模。我們的研究結果強調了祖細胞階段對成功的譜系重編程的優勢。這一策略有望通過譜系重編程產生其他成熟的人類細胞類型。

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