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.
Highlights
The rise in obesity rates over the past several decades coincides with an increased disease burden in obese individuals and their children
Weight gain in high-fat diet-fed and obese pregnant mice To test the effects of a lipid-rich diet and/or obesity on fetal hematopoiesis, we used three different dietary strategies: a HFD alone, a HFD with maternal obesity, and obesity without HFD (Figure A.1A)
Diet reversal during pregnancy ameliorates liver cellularity but not hematopoietic stem and progenitor cell (HSPC) content Our results offer a model in which to test whether the effects of HFD and obesity could be mitigated by a dietary intervention, a key question when extrapolating to human populations
Summary
The rise in obesity rates over the past several decades coincides with an increased disease burden in obese individuals and their children. Several studies point to developmental origins of postnatal neurological, cardiovascular and endocrine complications via maternal high-fat diet (HFD), a simplified model of the western-style diet, in the absence of gross organ compromise during infancy [3e7]. These multiple lines of evidence present prenatal development as a period of global susceptibility for diet-induced metabolic injury, fetal programming and postnatal organ dysfunction [8], but it remains unclear as to what extent the developing hematopoietic system is vulnerable. HSCs first emerge in the early embryo and go on to rapidly expand in the fetal liver before
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