期刊
MOLECULAR METABOLISM
卷 4, 期 1, 页码 25-38出版社
ELSEVIER
DOI: 10.1016/j.molmet.2014.11.001
关键词
Developmental programming; Hematopoietic stem and progenitor cells; Hematopoiesis; High-fat diet; Obesity; Fetal liver
资金
- NCATS NIH HHS [UL1 TR000128] Funding Source: Medline
- NCRR NIH HHS [UL1 RR024140] Funding Source: Medline
- NHLBI NIH HHS [T32 HL007781] Funding Source: Medline
- NIDDK NIH HHS [R01 DK070333] Funding Source: Medline
- NIGMS NIH HHS [T32 GM071338] Funding Source: Medline
Objective: Recent 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. Methods: We 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. Results: Maternal 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. Conclusions: Our 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. (C) 2014 The Authors. Published by Elsevier GmbH.
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