Hematopoietic Stem Cell Requirement for Macrophage Regeneration Is Tissue Specific

Tissue-resident macrophages (TRMU) are important immune sentinels responsible for maintaining tissue and immune homeostasis within their specific niche. Recently, the origins of TRMU have undergone intense scrutiny, in which now most TRMU are thought to originate early during embryonic development independent of hematopoietic stem cells (HSCs). We previously characterized two distinct subsets of mouse peritoneal cavity macrophages (MU) (large and small peritoneal MU) whose origins and relationship to both fetal and adult long-term (LT) HSCs have not been fully investigated. In this study, we employ highly purified LT-HSC transplantation and in vivo lineage tracing to show a dual ontogeny for large and small peritoneal MU, in which the initial wave of peritoneal MU is seeded from yolk sac-derived precursors, which later require LT-HSCs for regeneration. In contrast, transplanted fetal and adult LT-HSCs are not able to regenerate brain-resident microglia. Thus, we demonstrate that LT-HSCs retain the potential to develop into TRMU, but their requirement is tissue specific in the peritoneum and brain.