Identification of a Csf2rb-dependent yolk sac developmental pathway generating distinct liver-resident Itga4+ macrophages
Description
The functional diversity of tissue-resident macrophages (RTMs) is shaped by both their developmental origins, including the yolk sac, fetal liver, and bone marrow, as well as the local tissue microenvironment. However, the heterogeneity of embryonic-derived RTMs remains poorly characterized. In this study, we integrated single-cell transcriptomic data of human and mouse embryos to establish a cross-species framework for defining human yolk sac-derived RTMs. We identified three evolutionarily conserved erythro-myeloid progenitor (EMP) populations in the yolk sac and uncovered two distinct developmental trajectories defined by lysozyme expression: Lyz2-negative and Lyz2-positive lineages. Lyz2-CD117+CD45-CD93- early-EMPs differentiate into mature macrophages through Lyz2-CD117+CD45+CD93- intermediate-EMPs in a Csf2rb-dependent Lyz2-negative manner. This Csf2rb-dependent Lyz2-negative EMP lineage generates a unique Itga4+ macrophage population in the liver. These Lyz2-negative liver-resident macrophages exhibit distinct transcriptional profiles and promote tumorigenesis during early hepatocellular carcinoma, in contrast to liver-resident macrophages derived from the Lyz2-positive EMP lineage. Moreover, the balance between these functionally divergent macrophage lineages regulates the tumor susceptibility of the tissue microenvironment. Our findings underscores that developmental origin critically contributes to the substantial heterogeneity observed in RTMs.
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Institutions
- Institute of Zoology Chinese Academy of SciencesBeijing, Chaoyang District