Maternal Western-style diet remodels the transcriptional landscape of fetal hematopoietic stem and progenitor cells in rhesus macaques

• Published in: Stem cell reports 2022-12, Vol.17 (12), p.2595-2609
• Main Authors: Sureshchandra, Suhas, Chan, Chi N., Robino, Jacob J., Parmelee, Lindsay K., Nash, Michael J., Wesolowski, Stephanie R., Pietras, Eric M., Friedman, Jacob E., Takahashi, Diana, Shen, Weining, Jiang, Xiwen, Hennebold, Jon D., Goldman, Devorah, Packwood, William, Lindner, Jonathan R., Roberts, Charles T., Burwitz, Benjamin J., Messaoudi, Ilhem, Varlamov, Oleg
• Format: Article
• Language: English
• Subjects: Animals; B lymphocytes; bone marrow; Diet, Western - adverse effects; Female; fetal development; hematopoietic stem and progenitor cells; high-fat diet; Humans; Macaca mulatta; macrophages; maternal programming; Mice; Mice, Inbred NOD; Mice, SCID; monocytes; nonhuman primates; obesity; Pregnancy; Stem Cells
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2022.10.003

Maternal obesity adversely impacts the in utero metabolic environment, but its effect on fetal hematopoiesis remains incompletely understood. During late development, the fetal bone marrow (FBM) becomes the major site where macrophages and B lymphocytes are produced via differentiation of hematopoietic stem and progenitor cells (HSPCs). Here, we analyzed the transcriptional landscape of FBM HSPCs at single-cell resolution in fetal macaques exposed to a maternal high-fat Western-style diet (WSD) or a low-fat control diet. We demonstrate that maternal WSD induces a proinflammatory response in FBM HSPCs and fetal macrophages. In addition, maternal WSD consumption suppresses the expression of B cell development genes and decreases the frequency of FBM B cells. Finally, maternal WSD leads to poor engraftment of fetal HSPCs in nonlethally irradiated immunodeficient NOD/SCID/IL2rγ−/− mice. Collectively, these data demonstrate for the first time that maternal WSD impairs fetal HSPC differentiation and function in a translationally relevant nonhuman primate model. [Display omitted] •Maternal Western-style diet induces premature adipogenesis in fetal bones•Maternal Western-style diet leads to a proinflammatory phenotype in fetal HSPCs•Maternal Western-style diet enhances proinflammatory responses in fetal macrophages•Maternal Western-style diet impairs lymphoid differentiation of fetal HSPCs In this article, Oleg Varlamov and colleagues show that maternal Western-style diet alters the transcriptional landscape of fetal bone marrow HSPCs at single-cell resolution in rhesus macaques. Authors demonstrate that maternal Western-style diet induces a hyperinflammatory phenotype in fetal HSCs and macrophages, suppresses the B cell development program, and leads to poor engraftment of fetal HSPCs in immunodeficient mice.