HSC-requirement for macrophage regeneration is tissue-specific

Abstract

Abstract The current paradigm posits that a single long-term hematopoietic stem cell (LT-HSC) is capable of regenerating all components of the immune system. However, recent studies have overturned this paradigm by showing that tissue-resident macrophages (in brain, skin, and liver) develop from fetal progenitors in the yolk sac that emerge separate from, and prior to, the LT-HSC. Recently, we have identified novel subsets of tissue-resident macrophages in the mouse peritoneum, namely Small and Large Peritoneal Macrophages (SPM and LPM). Here, using Runx1 lineage-tracing assays, we show that, similar to brain microglia, both SPM and LPM emerge at around embryonic day 8 (E8), prior to, and independent of, the conventional LT-HSC. However, after E11, the fetal liver LT-HSC can be called upon to regenerate both SPM and LPM, but not microglia. Single-cell high-dimensional phenotypic and gene expression assays reveal that LT-HSC-derived SPM and LPM are phenotypically and functionally comparable to their E8-derived yolk sac counterpart. After birth, and throughout adulthood, both peritoneum and liver, but not the brain, call upon LT-HSCs in the bone marrow to continuously regenerate their fetal-derived tissue-resident macrophages. These results suggest that the requirement for LT-HSCs to regenerate macrophages is tissue-specific. In rodents, both peritoneum and liver, but not the brain, might be exposed to injuries and other exogenous insults that could require constant regeneration of their tissue-resident macrophages. Collectively, these findings add a new layer to the complex developmental landscape of the myeloid lineage and challenge the current notion that tissue-resident macrophages develop independently of the LT-HSCs.