中国科学院分子细胞科学卓越创新中心惠利健等研究发现，Kupffer细胞来源的IL-6通过激活损伤特异性增强子的祖基因而被重新用于肝细胞去分化。相关研究成果2023年2月13日在线发表于《细胞—干细胞》杂志上。

据介绍，分化细胞的干细胞非依赖性重编程最近被确定为修复受损组织的重要范式。门静脉周围损伤后，成熟肝细胞重新激活重编程/祖细胞相关基因（RRG），并在小鼠和人类中去分化为肝祖细胞样细胞（LPLC），这对再生有显著贡献。然而，尚不清楚哪些外部因素以及如何触发肝细胞重编程。

通过使用单细胞转录谱和谱系特异性缺失工具，研究人员发现门静脉周围特异性LPLC的形成是由区域激活的Kupffer细胞而非外周单核细胞来源的巨噬细胞启动的。使用体内筛选，促炎因子IL-6被鉴定为通过STAT3激活重新用于RRG诱导的小生境信号，STAT3激活通过与预先可获得的增强子结合来驱动RRG表达。值得注意的是，RRG是通过损伤特异性而非肝脏胚胎发生相关的增强子激活的。

总之，这些发现描述了损伤特异性小生境信号和炎症介导的转录在驱动肝细胞转化为祖细胞表型中的作用。

附：英文原文

Title: Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers

Author: Lu Li, Lei Cui, Ping Lin, Zhaoyuan Liu, Shujie Bao, Xiaolong Ma, Haitao Nan, Wencheng Zhu, Jin Cen, Yunuo Mao, Xiong Ma, Lingyong Jiang, Yu Nie, Florent Ginhoux, Yixue Li, Hong Li, Lijian Hui

Issue&Volume: 2023-02-13

Abstract: Stem cell-independent reprogramming of differentiated cells has recently been identifiedas an important paradigm for repairing injured tissues. Following periportal injury,mature hepatocytes re-activate reprogramming/progenitor-related genes (RRGs) and dedifferentiateinto liver progenitor-like cells (LPLCs) in both mice and humans, which contributeremarkably to regeneration. However, it remains unknown which and how external factorstrigger hepatocyte reprogramming. Here, by employing single-cell transcriptional profilingand lineage-specific deletion tools, we uncovered that periportal-specific LPLC formationwas initiated by regionally activated Kupffer cells but not peripheral monocyte-derivedmacrophages. Unexpectedly, using in vivo screening, the proinflammatory factor IL-6 was identified as the niche signal repurposedfor RRG induction via STAT3 activation, which drove RRG expression through bindingto their pre-accessible enhancers. Notably, RRGs were activated through injury-specificrather than liver embryogenesis-related enhancers. Collectively, these findings depictan injury-specific niche signal and the inflammation-mediated transcription in drivingthe conversion of hepatocytes into a progenitor phenotype.

DOI: 10.1016/j.stem.2023.01.009

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00009-7