Fetal liver hematopoietic stem cells possess the mast cell repopulation ability within a limited time window

Abstract

Recent progress in developmental immunology has revealed the hematopoietic stem cell (HSC)-independent ontogeny for the various hematopoietic lineages, including mast cells (MC). Adult bone marrow (BM) HSCs fail to generate MC in both lineage tracing and transplantation assays. However, it is unclear whether fetal liver (FL) HSCs can generate MC in vivo. We investigated the MC potential of HSCs from FL and the aorta-gonad-mesonephros (AGM) in lineage tracing and transplantation assays. We employed different genetic mouse models that allowed us to identify the Tomato+ progeny of hematopoietic precursors (Runx1mer-cre-mer), endothelial cells (EC, Cdh5ERT2Cre) and HSCs (Fgd5ERT2Cre) by injecting tamoxifen (TAM) at different embryonic days starting at E7.5. TdTomato (Tom)+ HSCs and MCs were quantified after birth. In addition, we transplanted HSCs from AGM (11.5), FL (E12.5 and E15.5), and adult BM (>6 wks) into irradiated mice. Results: The EC-labeling at E7.5 efficiently generated Tomato+ MC, but not HSCs (similar results were obtained for the Runx1mer-cre-mer model). EC-labeling at E9.5 made equivalent Tom+ labeling efficiency in MC and HSCs (~85%). However, E11.5 EC mostly failed to mark MC, but still generated Tom+ HSCs (~25%). HSC-labeling at E14 or postnatal day 2 efficiently marked HSCs, but not MC. Collectively, our results indicate that active MC production terminates before E12 and that HSCs after E14 lack MC potential. Our transplantation study also shows lack of MC repopulation by HSCs after E15. However, E11.5 AGM and E12.5 FL HSCs repopulated MC, revealing a transient MC production potential of HSCs. Conclusion: MC production by hemogenic ECs terminates before E12 and early HSCs produce MC within a limited time window.