小柯机器人

美国麻省理工学院Rudolf Jaenisch课题组发现，核受体THRB促进人类PSC分化为更成熟的肝细胞。相关论文于2022年4月21日在线发表于国际学术期刊《细胞—干细胞》。

为了了解hPSC来源肝细胞体外成熟的调节机制，研究人员开发了一个3D分化系统，并通过RNA-seq、ATAC-seq和H3K27Ac ChIP-seq比较了人类原代肝细胞与在2D或3D条件下分化的hPSC-肝细胞中的基因调控元件。调控组比较显示，甲状腺受体THRB模体在可及性的染色质和活跃的增强子中的富集程度降低，而THRB的转录却没有减少。加入甲状腺激素T3增加了THRB与CYP3A4近端增强子的结合，恢复了NFIC的超级增强子状态和基因表达，并减少了AFP的表达。

由此产生的hPSC-肝细胞在基因表达、表观遗传学状态和超级增强子景观方面更接近原生肝细胞，并激活了包括与肝脏相关疾病有关的非编码SNP在内的调控区域。移植hPSC-肝细胞后，人类肝细胞被整合到小鼠肝脏，而不破坏正常的肝脏组织学。这项工作揭示了环境因素-核受体轴如何调节hPSC-肝细胞的成熟。

附：英文原文

Title: The nuclear receptor THRB facilitates differentiation of human PSCs into more mature hepatocytes

Author: Haiting Ma, Esmée de Zwaan, Yang Eric Guo, Paloma Cejas, Prathapan Thiru, Martijn van de Bunt, Jacob F. Jeppesen, Sudeepa Syamala, Alessandra Dall’Agnese, Brian J. Abraham, Dongdong Fu, Carrie Garrett-Engele, Tong Ihn Lee, Henry W. Long, Linda G. Griffith, Richard A. Young, Rudolf Jaenisch

Issue&Volume: 2022-04-21

Abstract: To understand the mechanisms regulating the in vitro maturation of hPSC-derived hepatocytes, we developed a 3D differentiation systemand compared gene regulatory elements in human primary hepatocytes with those in hPSC-hepatocytesthat were differentiated in 2D or 3D conditions by RNA-seq, ATAC-seq, and H3K27AcChIP-seq. Regulome comparisons showed a reduced enrichment of thyroid receptor THRBmotifs in accessible chromatin and active enhancers without a reduced transcriptionof THRB. The addition of thyroid hormone T3 increased the binding of THRB to the CYP3A4 proximal enhancer, restored the super-enhancer status and gene expression of NFIC, and reduced the expression of AFP. The resultant hPSC-hepatocytes showed gene expression, epigenetic status, and super-enhancerlandscape closer to primary hepatocytes and activated regulatory regions includingnon-coding SNPs associated with liver-related diseases. Transplanting the hPSC-hepatocytesresulted in the engraftment of human hepatocytes into the mouse liver without disruptingnormal liver histology. This work implicates the environmental factor-nuclear receptoraxis in regulating the maturation of hPSC-hepatocytes.

DOI: 10.1016/j.stem.2022.03.015

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00150-3

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