Varlamov, O. | bioRxiv Science

bioRxiv2021

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

BackgroundMaternal obesity adversely impacts the in utero metabolic environment and offsprings health, but its effect on fetal hematopoiesis and immune cell development remains incompletely understood, particularly in models that resemble human development. MethodsWe 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 hematopoietic stem and progenitor cell (FBM HSPC) function were examined using bone computed tomography, histology, flow cytometry, single-cell RNA-sequencing, and HSPC transplantation assays. FindingsMaternal 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/IL2r{gamma}-/- mice. InterpretationsMaternal WSD impairs FBM development, drives a hyperinflammatory phenotype, and induces functional and differentiation impairment in FBM HSPCs in a translationally relevant nonhuman primate model. FundingNational Institute of Health RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSMaternal obesity is associated with increased risk of infections and proinflammatory disease in offspring. The translationally-relevant rhesus macaque model was utilized to address the effects of maternal obesogenic diet on fetal hematopoietic and immune cell development. Added value of this studyWe assessed changes in fetal immune cell phenotypes and fetal hematopoietic stem and progenitor cell function using immunohistochemistry, flow cytometry, single-cell RNA sequencing, and transplantation assays. We determined that chronic consumption of a maternal obesogenic diet induced the development of adipogenic and proinflammatory environments in the fetal bone marrow. Additionally, we detected the impairment in B-cell differentiation program in fetal hematopoietic stem and progenitor cells. Implications of all the available evidenceThese data demonstrate that maternal obesogenic diet modulates fetal hematopoietic development and could impact the offsprings immune system, including proinflammatory phenotype and a decline in B-cell function.

immunology↗

bioRxiv2020

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

BACKGROUNDRegulatory innovation is central to the evolution of species. Different nutritional sources are one environmental pressure that can lead to selection for novel regulatory elements. Dietary composition changes, including exposure to "western" diets with excess fat and sugar content, can lead to transcriptional regulatory changes in the liver. In order to investigate how transcriptional regulatory changes in response to a high fat diet diverge across species, we profiled chromatin accessibility, histone modifications and the transcriptome in livers of rhesus macaques and mice fed high fat and normal diets. RESULTSWhile the majority of elements exhibiting changes in chromatin accessibility in response to a high fat diet are enriched for similar transcription factors across species, the loci that change are mostly species specific. These unique responsive regulatory elements are largely derived from transposable elements and are enriched for liver-specific transcription factors, such as HNF4. Furthermore, the majority of genes that respond to a high fat diet in rhesus macaques do not have a shared response in mice and are proximal to regulatory elements that display changes in chromatin accessibility only in rhesus macaques. CONCLUSIONSOur study demonstrates that most of the liver regulatory elements that exhibit changes in chromatin accessibility in response to a high fat diet do so in a species-specific manner. These findings illustrate how a similar environmental stimulus can drive a divergent chromatin and transcriptional responses in evolutionary distinct mammalian species.

genomics↗