從成纖維細(xì)胞生成具有功能的人肝細(xì)胞的兩步譜系重編程策略

2019年5月，北京大學(xué)生命科學(xué)學(xué)院；北京大學(xué)醫(yī)學(xué)部天然藥物與仿生藥物國家重點(diǎn)實(shí)驗(yàn)室；北京大學(xué)生命科學(xué)中心；細(xì)胞增殖與分化教育部重點(diǎn)實(shí)驗(yàn)室；北京大學(xué)深圳研究生院化學(xué)生物與生物技術(shù)學(xué)院；化學(xué)腫瘤基因組學(xué)國家重點(diǎn)實(shí)驗(yàn)室；廣東深圳518055;北京大學(xué)生物信息學(xué)研究中心；北京大學(xué)生命科學(xué)學(xué)院；北京-清華生命科學(xué)中心；細(xì)胞增殖與分化教育部重點(diǎn)實(shí)驗(yàn)室；上海公共衛(wèi)生臨床中心；北京大學(xué)醫(yī)學(xué)部基礎(chǔ)醫(yī)學(xué)院；復(fù)旦大學(xué)醫(yī)學(xué)分子病毒學(xué)重點(diǎn)實(shí)驗(yàn)室；中國人民解放軍總醫(yī)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(tuán)隊(duì)在《CELL RESEARCH》上發(fā)表論文：

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

“從成纖維細(xì)胞生成具有功能的人肝細(xì)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(xì)胞可以通過譜系重編程產(chǎn)生，然而，譜系重編程受到原始細(xì)胞身份和部分功能殘留的不完全轉(zhuǎn)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(kuò)展的肝祖細(xì)胞和具有功能能力的人肝細(xì)胞。成纖維細(xì)胞**被誘導(dǎo)為人肝祖細(xì)胞樣細(xì)胞(hhplc)，該細(xì)胞能在體外穩(wěn)定擴(kuò)增并在體內(nèi)高效移植。此外，hhplc可以在體外有效地誘導(dǎo)成成熟的人肝細(xì)胞(hiHeps)，其分子特征與原代人肝細(xì)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(jìn)行藥物代謝估計(jì)、毒性預(yù)測和乙型肝炎病毒感染建模。我們的研究結(jié)果強(qiáng)調(diào)了祖細(xì)胞階段對成功的譜系重編程的優(yōu)勢。這一策略有望通過譜系重編程產(chǎn)生其他成熟的人類細(xì)胞類型。

該論文中，原代皮膚的體外培養(yǎng)是使用Ausbian特級胎牛血清完成的。欲了解或購買Ausbian特級胎牛血清可以聯(lián)系北京締一生物400-166-8600.