Liu Chuanjun, Wang Kai, Mei Junpu, Zhao Ruizhen, Shen Juan, Zhang Wei, Li Liangyu, Roy Bhaskar, Fang Xiaodong
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
BGI Research, Shenzhen, China.
Hepatol Commun. 2025 Feb 26;9(3). doi: 10.1097/HC9.0000000000000662. eCollection 2025 Mar 1.
Liver progenitor cells (LPCs) with bipotential differentiation capacities are essential for restoring liver homeostasis and hepatocyte population after damage. However, the low proportion and shared markers with epithelial cells make studying LPC heterogeneity difficult, especially in humans. To address this gap, we explored over 259,400 human liver single cells across 4 conditions (fetal, healthy, cirrhotic, and HCC-affected livers).
Human liver tissue samples were analyzed using spatial transcriptomics sequencing technologies to describe the heterogeneity of LPCs. Liver tissue was characterized by LPC heterogeneity at single-cell resolution by employing cellular modules, differentiation trajectories, and gene co-expression patterns.
We annotated and identified 1 LPC cluster, 3 LPC subpopulations, and 4 distinct cellular modules, indicating the heterogeneity within LPC and the diversity between LPCs and epithelial cells. LPCs showed spatial colocalization with cholangiocytes and comprised a small proportion (2.95±1.91%) within the merged epithelial cells and LPC populations, exhibiting marked differences in marker expression patterns compared to those in mice. LPCs exhibited distinct cellular states in functional restoration, activation, proliferation, and cell transition. Additionally, the gene co-expression network of LPCs exhibited 3 unique modules, reflecting the distinct connectivity of genes encoding apolipoproteins and heat shock proteins in the gene co-expression network modules.
Our study provides valuable insights into the multifaceted heterogeneity of human LPCs. Future studies focusing on spatial gene expression dynamics will contribute to our understanding of the spatial arrangement of liver regeneration.
具有双潜能分化能力的肝祖细胞（LPCs）对于损伤后恢复肝脏内环境稳定和肝细胞数量至关重要。然而，LPCs比例低且与上皮细胞存在共同标志物，这使得研究LPCs的异质性变得困难，尤其是在人类中。为了填补这一空白，我们在4种条件（胎儿肝脏、健康肝脏、肝硬化肝脏和肝癌受累肝脏）下对超过259,400个人类肝脏单细胞进行了探索。
使用空间转录组测序技术分析人类肝脏组织样本，以描述LPCs的异质性。通过采用细胞模块、分化轨迹和基因共表达模式，在单细胞分辨率下对肝脏组织进行LPCs异质性特征分析。
我们注释并鉴定出1个LPC簇、3个LPC亚群和4个不同的细胞模块，表明LPCs内部的异质性以及LPCs与上皮细胞之间的多样性。LPCs与胆管细胞呈现空间共定位，在合并的上皮细胞和LPCs群体中占比小（2.95±1.91%），与小鼠相比，其标志物表达模式存在显著差异。LPCs在功能恢复、激活、增殖和细胞转变中表现出不同的细胞状态。此外，LPCs的基因共表达网络呈现出3个独特的模块，反映了基因共表达网络模块中编码载脂蛋白和热休克蛋白基因的不同连接性。
我们的研究为人类LPCs多方面的异质性提供了有价值的见解。未来聚焦于空间基因表达动态变化的研究将有助于我们理解肝脏再生中的空间排列情况。
