CD24+LCN2+ liver progenitor cells in ductular reaction contributed to macrophage inflammatory responses in chronic liver injury

作者：Weijian Huang, Bijun Qiu, Xiao-Shu Qi, Cai–Yang Chen, Wenming Liu, Shen-Ao Zhou, Min Ding, Fengfeng Lu, Jie Zhao, Dan Tang, Xu Zhou, Gongbo Fu, Zhenyu Wang, Hong-Qian Ma, Yu-ling Wu, Hongping Wu, Xiaosong Chen, Weifeng Yu, He‐Xin Yan · 发表于：Cell & Bioscience · 年份：2023 · DOI：10.1186/s13578-023-01123-2 · 被引用次数：11 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment、Organ Transplantation Techniques and Outcomes

Abstract Background CD24 + CK19 + /CD24 + SOX9 + resident liver cells are activated and expanded after chronic liver injury in a ductular reaction. However, the sources and functions of these cells in liver damage remain disputed. Results The current study combined genetic lineage tracing with in vitro small-molecule-based reprogramming to define liver progenitor cells (LPCs) derived from hepatic parenchymal and non-parenchymal tissues. tdTom + hepatocytes were isolated from ROSA26 tdTomato mice following AAV8 -Tbg-Cre -mediated recombination, EpCAM + biliary epithelial cells (BECs) from wild-type intrahepatic bile ducts and ALB/GFP − EpCAM − cells were isolated from Alb CreERT /R26 GFP mice. A cocktail of small molecules was used to convert the isolated cells into LPCs . These in vitro cultured LPCs with CD24 and SOX9 expression regained the ability to proliferate. Transcriptional profiling showed that the in-vitro cultured LPCs derived from the resident LPCs in non-parenchymal tissues expressed Lipocalin-2 ( Lcn2 ) at high levels. Accordingly, endogenous Cd24a + Lcn2 + LPCs were identified by integration of sc-RNA-sequencing and pathological datasets of liver dysfunction which indicates that LPCs produced by ductular reactions might also originate from the resident LPCs. Transplantation of in-vitro cultured Cd24a + Lcn2 + LPCs into CCl 4 -induced fibrotic livers exacerbated liver damage and dysfunction, possibly due to LCN2-dependent macrophage inflammatory response. Conclu...