A high-fat diet in pregnant monkeys impairs fetal blood stem cells

"This discovery is the first demonstration in primates that maternal unhealthy diet and obesity disrupt the immune system in the developing fetus," says Oleg Varlamov of the Oregon National Primate Research Center. "The main implication of this study is that maternal obesity may influence the development of the fetal bone marrow and fetal immune system."

Pre-pregnancy obesity is associated with an increased risk of infection and aberrant inflammatory responses in the offspring, but the underlying mechanisms remain largely unknown. In particular, very little is known about the effect of a Western-style diet on fetal hematopoiesis -- the formation of blood cellular components -- in animal models that resemble human development.

During late development, the fetal bone marrow becomes the major site where immune cells called macrophages and B-lymphocytes are produced via differentiation of hematopoietic stem and progenitor cells (HSPCs). In the new study, Varlamov and his collaborators analyzed the transcriptional landscape of fetal bone marrow HSPCs at single-cell resolution in fetal macaques exposed to a maternal high-fat, Western-style diet or a low-fat control diet.

"We were motivated to investigate how maternal obesity impacts the fetal immune system during pregnancy in nonhuman primates, representing the most relevant animal model for studying human development," Varlamov says.

The results demonstrated that a Western-style diet induced a hyperinflammatory response in HSPCs and fetal macrophages and suppressed the expression of B-cell development genes. Moreover, the unhealthy diet led to poor engraftment of fetal HSPCs in immunodeficient mice.

"Maternal obesity greatly impacted the ability of fetal blood stem cells to produce B-lymphocytes -- immune cells that make antibodies in response to infection -- and made fetal blood stem cells more inflamed," Varlamov says.

Study limitations included the small sample size, which might limit the ability to detect weaker effects of maternal diet on fetal outcomes. In addition, the researchers didn't explore the effects of maternal obesity on postnatal development and only focused on prenatal development. Further studies are also needed to test whether maternal obesity disrupts offspring responses to infection and inflammation.

"This study sets the stage for understanding the link between maternal obesity, prenatal nutrition, and diseases involving immune progeny of the HSPC compartment in children and highlights the need to better understand the susceptibility of the developing hematopoietic system to metabolic dysregulation over the lifetime," Varlamov says.

This study was supported by the National Institutes of Health.