Maternal high-fat diet and obesity compromise fetal hematopoiesis

Abstract

ObjectiveRecent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high-fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity.MethodsWe used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high-fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system.ResultsMaternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration.ConclusionsOur data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment.

Maternal high-fat diet is associated with impaired fetal lung development

“…Importantly, there are likely several other aspects of fetal exposure to the maternal HFD that may influence fetal lung maturation such as fetal hyperglycemia and/or fetal hyperinsulinemia (factors not specifically assessed here). Maternal obesity secondary to HFD consumption appears to be deleterious to fetal development in many ways, including by constraint of fetal growth and expansion of fetal liver hematopoietic stem and progenitor cells as discussed in a recent study (19). Collectively, the present study suggests that maternal HFD before and during pregnancy induces elevations in maternal glucose and insulin, placental inflammation resulting in placental insufficiency, FGR, and attenuation of normal fetal lung development and maturation.…”

The initiation of metabolic inflammation in childhood obesity

“…Similar mechanisms may contribute to the impaired fetal hematopoiesis that is observed with maternal obesity (128).…”

Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming

“…Using a combination of colony formation assays, flow cytometry, and gene expression experiments, studies showed that maternal HFD restricts physiologic expansion of fetal HSCs, compromises repopulation of precursor cells in fetal liver, and biases cellular differentiation toward the myeloid branch. 105 This bias toward myeloid lineage and dysregulated hematopoiesis was shown to be dependent on TLR4 signaling. 106 Moreover, metabolic rewiring and increased energy demand of stem cells have been recently reported in mesenchymal stem cells isolated from human cord blood samples obtained from babies born to mothers with obesity.…”

“…Data from several studies indicate that hematopoietic stem cell (HSC) populations are exquisitely sensitive to an obesogenic environment. Using a combination of colony formation assays, flow cytometry, and gene expression experiments, studies showed that maternal HFD restricts physiologic expansion of fetal HSCs, compromises repopulation of precursor cells in fetal liver, and biases cellular differentiation toward the myeloid branch . This bias toward myeloid lineage and dysregulated hematopoiesis was shown to be dependent on TLR4 signaling .…”

“…The precise series of events by which maternal environment/inflammation alter fetal epigenome are still unclear. However, it has been hypothesized that excess lipid exposure in utero or maternal cytokines and hormones exposes the fetus to inflammation, potentially impacting cellular metabolism in immune precursor cells thereby rewiring the epigenomes of mature fetal immune cells. To that extent, efforts to decrease excess maternal lipid availability via dietary interventions has been proposed to be an efficient strategy to limit fetal reprogramming.…”