中国科学院分子细胞科学卓越创新中心惠利健等研究人员，合作绘制出小鼠胆汁淤积性损伤和修复的时空图谱。2024年4月16日，《自然—遗传学》杂志在线发表了这一最新研究成果。

研究人员通过整合空间增强分辨的组学测序和单细胞转录组学，生成了小鼠胆汁淤积性损伤和修复过程中基因表达的高清时空图谱。时空分析揭示了胆管细胞驱动的信号传导与门静脉周围损伤-修复反应相关的关键作用。胆管细胞表达与脂质相关巨噬细胞的招募和分化有关的基因，这些基因产生的反馈信号增强了导管反应。此外，胆管细胞表达高浓度的TGFβ，这与损伤期间肝祖细胞转化为胆管细胞以及恢复期间肝门周围细胞增殖受抑制有关。

值得注意的是，Atoh8在3,5-diethoxycarbonyl-1,4-dihydro-collidin损伤期间限制肝细胞增殖，并在损伤退出后迅速下调，使肝细胞能够对生长信号做出反应。这些发现为深入研究胆汁淤积性损伤的细胞动力学和分子机制奠定了基石，这可能会进一步发展成为胆管疾病的疗法。

据介绍，胆汁淤积性肝脏损伤以胆管周围区域性损伤为特征，缺乏治疗方法并导致大量死亡。

附：英文原文

Title: A spatiotemporal atlas of cholestatic injury and repair in mice

Author: Wu, Baihua, Shentu, Xinyi, Nan, Haitao, Guo, Pengcheng, Hao, Shijie, Xu, Jiangshan, Shangguan, Shuncheng, Cui, Lei, Cen, Jin, Deng, Qiuting, Wu, Yan, Liu, Chang, Song, Yumo, Lin, Xiumei, Wang, Zhifeng, Yuan, Yue, Ma, Wen, Li, Ronghai, Li, Yikang, Qian, Qiwei, Du, Wensi, Lai, Tingting, Yang, Tao, Liu, Chuanyu, Ma, Xiong, Chen, Ao, Xu, Xun, Lai, Yiwei, Liu, Longqi, Esteban, Miguel A., Hui, Lijian

Issue&Volume: 2024-04-16

Abstract: Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFβ in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

DOI: 10.1038/s41588-024-01687-w

Source: https://www.nature.com/articles/s41588-024-01687-w