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

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

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    42 Citations (Scopus)

    Résumé

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

    langue originaleAnglais
    Pages (de - à)283-299.e9
    journalCell Stem Cell
    Volume30
    Numéro de publication3
    Les DOIs
    étatPublié - 2 mars 2023

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