Mast Cell Repopulating Ability Is Lost During the Transition From Pre-HSC to FL HSC

Abstract

Recent advances in developmental immunology have revealed a hematopoietic stem cell (HSC)-independent origin for various innate immune lineages, including mast cells (MCs). It is now established that adult bone marrow (BM) long-term HSCs do not regenerate MCs but, instead, the physiological production of MCs starts before the emergence of HSCs in the aorta-gonad-mesonephros (AGM) region and is mostly completed before birth. However, while the AGM region represents a major site of MC generation during ontogeny, whether the first emerging HSCs in the AGM or fetal liver (FL) possess the potential to regenerate MCs is unknown. Here, we combined three fate-mapping mouse models with detailed HSC transplantation assays to determine the potential of AGM and FL HSCs to produce MCs. We show that HSCs from E11.5 AGM and E12.5 FL efficiently repopulated MCs in recipients. In stark contrast, HSCs from ≥E14.5 FL failed to reconstitute MCs. An Endothelial (EC) fate-mapping study confirmed the EC origin of the majority of MCs. Additionally, our HSC-labeling showed that HSCs do not produce MCs in a physiological setting. Hence, although most MCs are generated and maintained via an HSC-independent pathway, the earliest HSCs to emerge in the AGM and seed the early FL can produce MCs, but only during a minimal time window. Our results challenge the stem cell theory in hematology and EC-derived mast cells may contribute to the pathogenesis of postnatal mast cell disorders.

Multiple waves of fetal‐derived immune cells constitute adult immune system

“…Since we have been working to identify the first‐emerging HSCs in the AGM region and FL by utilizing neonatal NSG recipients, we tried to address the question of whether there is MC potential in these first‐emerging HSCs. We tested the MC potential of E11.5 AGM pre‐HSCs (Lin − VECad + kit + EPCR bright ), E12.5 FL HSCs (Lin − CD48 − EPCR + LSK), E14.5–E15.5 FL HSCs, and adult BM HSCs (lin − CD48 − CD150 + LSK) 146 . The results clearly demonstrated that MCs were repopulated in the peritoneal cavity by E11.5 AGM pre‐HSCs and E12.5 FL HSCs but not by E14.5–E15.5 FL HSCs (Figure 4A).…”

“…Because our transplantation assay utilizing NSG neonates (or adults) never eradicates host MCs, host MC depletion (induced by irradiation or use of a Kit W‐sh recipient) is not a required element for the in vivo MC repopulation addressed above. Instead, it is important to precisely identify HSCs with MC potential and MC progenitors in the embryo 144,146 …”

Mast cell ontogeny: From fetal development to life‐long health and disease

“…It thus seems plausible that EMPs will first pass through the fetal liver before committing to the mast cell fate. In support of this notion, progenitors with mast cell potential can be found in the fetal liver from E11.5 onwards, and these progenitors give rise to mast cells when transferred into fetal or newborn recipients 54,69 . Nonetheless, this does not exclude that a direct route from the YS exists as well.…”

“…From a combination of genetic fate mapping, adoptive transfer, and in vitro differentiation assays, Yoshimoto and colleagues conclude that only the earliest HSCs found in the fetal liver give rise to mast cells, but not those present at a time when adult-type HSCs dominate prior to BM colonization. 69 It would follow that mast cells are established from YS EMPs, followed by fetal-restricted HSCs. Adult-type HSCs may contribute in a brief perinatal window without passing through the BM.…”

Hematopoietic Stem Cells and the Immune System in Development and Aging

“…Recent studies have shown that HSCs lose their ability to produce mast cell precursors during development in the fetal liver [ 104 ]. Adult HSC cells are also unable produce mast cells in steady-state haematopoiesis [ 105 ].…”