Maternal Obesity Compromises Offspring Immunity by Altering the Differentiation of Lymphocytes and Myeloid Cells in Fetal bone marrow

Obesity in pregnant women is associated with increased susceptibility to neonatal infections. However, the mechanisms by which maternal obesity alters the development of the offspring's immune system are still largely unknown. Here, we determined the impact of maternal obesogenic western-style diet (WSD) on fetal development and hematopoiesis in rhesus macaques using a combination of phenotypic, functional, and genomic assays. We demonstrate that maternal WSD resulted in accelerated fetal development and significantly altered the immunological landscape of the fetal bone marrow. Specifically, the single-cell RNA-seq analysis of fetal bone marrow HSPCs shows that maternal WSD induced an expansion of the common lymphoid as well as monocyte/granulocyte progenitors. Although the relative abundance of B cell progenitors was increased within CD34+ HSCs, the frequencies of B lymphocytes in FBM were reduced with maternal WSD. Finally, maternal WSD led to a bias towards myelopoiesis following the engraftment of fetal HSPCs in nonlethally irradiated immunodeficient NOD/SCID/IL2rg-/- mice. Despite the accelerated monocyte progenitor differentiation within CD34+ cells and increased frequencies of monocytes in the spleen of NSG mice, fetal blood monocytes from the maternal WSD group generated blunted response following LPS stimulation. Collectively, this study demonstrates that maternal WSD remodels the fetal immune landscape.