Maternal Obesity Dysregulates Fetal Hematopoietic Stem and Progenitor Cell Development in Rhesus Macaques

Abstract

ABSTRACTInfants from obese moms have an increased susceptibility to immune dysregulation. However, the mechanisms by which maternal obesity alters fetal hematopoiesis remain largely unknown. Here, we determined the impact of maternal consumption of an obesogenic western-style diet (WSD) on hematopoietic development in fetal rhesus macaques using a combination of phenotypic, functional, and genomic assays. We demonstrate that maternal WSD resulted in accelerated fetal growth and altered fetal hematopoiesis. Specifically, single-cell RNA sequencing analysis of fetal bone marrow HSPCs showed that maternal WSD altered the transcriptional program of the common lymphoid progenitors and decreased the frequencies of bone marrow B-cells and NK-cells. Despite an expansion of monocyte progenitors in FBM, fetal blood monocytes from the WSD group demonstrated a blunted response to bacterial lipopolysaccharide. Furthermore, maternal WSD led to poor engraftment of fetal HSPCs in nonlethally irradiated immunodeficient NOD/SCID/IL2rγ-/-mice. Collectively, this study demonstrates that maternal WSD dysregulates fetal HSPC development.