TY - JOUR
T1 - Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers
AU - Li, Lu
AU - Cui, Lei
AU - Lin, Ping
AU - Liu, Zhaoyuan
AU - Bao, Shujie
AU - Ma, Xiaolong
AU - Nan, Haitao
AU - Zhu, Wencheng
AU - Cen, Jin
AU - Mao, Yunuo
AU - Ma, Xiong
AU - Jiang, Lingyong
AU - Nie, Yu
AU - Ginhoux, Florent
AU - Li, Yixue
AU - Li, Hong
AU - Hui, Lijian
N1 - Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/3/2
Y1 - 2023/3/2
N2 - 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.
AB - 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.
KW - IL-6/STAT3 signaling
KW - Kupffer cells
KW - hepatocyte reprogramming
KW - liver repair
KW - transcriptional regulation of reprogramming/progenitor-related genes
UR - http://www.scopus.com/inward/record.url?scp=85149210867&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2023.01.009
DO - 10.1016/j.stem.2023.01.009
M3 - Article
C2 - 36787740
AN - SCOPUS:85149210867
SN - 1934-5909
VL - 30
SP - 283-299.e9
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 3
ER -