Deciphering the output of fetal hematopoietic stem and progenitor cells at homeostasis and in response to inflammation

ABSTRACT Hematopoietic stem and progenitor cells (HSPCs), which include hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), give rise to all blood and immune cells across the lifespan. HSCs first emerge during gestation and ultimately becoming the adult hematopoietic compartment. Human studies have associated events during pregnancy such as maternal infection, diet, or exposure to microbes with increased risk of immune dysfunction in offspring; however, the mechanisms behind this are unknown. Since hematopoietic progenitors arise during gestation and seed the adult hematopoietic compartment, we hypothesize that prenatal inflammation reprograms the cellular output of distinct fetal HSPCs, thus influencing postnatal immune function. Recent data has suggested that fetal HSCs and fetal MPPs emerge independently from the intra-embryonic aorta during development. This suggests that fetal MPPs and fetal HSCs of distinct origin have specific functions and relative contributions to postnatal blood production at homeostasis and during inflammatory insults, but this has not been directly investigated. Our working hypothesis is that fetal MPPs drive the response to prenatal inflammation in order to preserve the HSC pool, shaping the postnatal hematopoietic compartment. We will test our hypothesis by integrating genetic fate mapping experiments, transplantation assays, transcriptomics, and early life infection models. Our preliminary data suggests independent emergence of fetal MPPs and fetal HSCs from the developing aorta and has revealed the first evidence of functional differences between fetal MPPs and HSCs. We have found that fetal MPPs are the first responders to Type II-IFN mediated prenatal inflammation and expand the pool of downstream myeloid cells, which remain expanded in the postnatal period. Our findings also support the idea that timing of emergence influences the functional output of fetal progenitors at steady state and in response to inflammation. The objective of this proposed work is to comprehensively examine the specific effects inflammation has on fetal HSCs and MPPs and will define the mechanisms by which prenatal inflammation shapes the adult hematopoietic system. We will determine how inflammation experienced in utero influences offspring immunity and response to postnatal immune challenges at the level of fetal HSPCs. We anticipate that the insights gained from this proposed work will help inform underlying causes of disease that may start during development.