Maternal Western-Style Diet Impairs Bone Marrow Development and Drives a Hyperinflammatory Phenotype in Hematopoietic Stem and Progenitor Cells in Fetal Rhesus Macaques [article]

Suhas Sureshchandra, Chi N. Chan, Jacob J Robino, Lindsay K. Parmelee, Michael J Nash, Stephanie R Wesolowski, Eric M Pietras, Jacob E. Friedman, Diana Takahashi, Weining Shen, Jon D Hennebold, Devorah Goldman (+6 others)
2021 bioRxiv   pre-print
Maternal obesity adversely impacts the in utero metabolic environment and offspring's health, but its effect on fetal hematopoiesis and immune cell development remains incompletely understood, particularly in models that resemble human development. Methods: We studied gestational day 130-135 fetuses derived from rhesus macaque dams chronically exposed to a high-fat Western-style diet (WSD) or a low-fat control diet. Fetal immune cell phenotypes and fetal bone marrow architecture and
more » ... c stem and progenitor cell (FBM HSPC) function were examined using bone computed tomography, histology, flow cytometry, single-cell RNA-sequencing, and HSPC transplantation assays. Findings: Maternal WSD induced premature FBM cavity opening and a codominant increase in the number of FBM adipocytes. Furthermore, a maternal WSD induced a proinflammatory transcriptional response in FBM HSPCs. FBM macrophages from the WSD group exhibited heightened proinflammatory responses to toll-like receptor agonist stimulation. Maternal WSD exposure suppressed the expression of genes required for B-cell development and decreased the frequencies of FBM B-cells. Finally, maternal WSD led to poor engraftment of FBM HSPCs in nonlethally irradiated immunodeficient NOD/SCID/IL2rg-/- mice. Interpretations: Maternal WSD impairs FBM development, drives a hyperinflammatory phenotype, and induces functional and differentiation impairment in FBM HSPCs in a translationally relevant nonhuman primate model.
doi:10.1101/2021.04.26.441556 fatcat:b2g2lkupwfe4hl2pu26ieaccoa