孕期高脂饮食、肥胖危害胎儿干细胞

　　

生物通报道：高脂饮食可能诱发多种疾病已为人知,Nature：为什么高脂饮食会诱发癌症。但最近也有研究称，高脂饮食可以延缓衰老,Cell子刊亮点文章：高脂饮食可以延缓衰老。有很多研究已经证明，孕期高脂饮食对胎儿不利，可导致孩子长大后肥胖、酗酒等多种问题。最近，美国俄勒冈健康科学大学（OHSU）Doernbecher儿童医院的医学科学家们发现，妊娠期高脂饮食和肥胖，可危害胎肝的血液形成系统或造血干细胞系统，胎肝负责生成和维持终身的血液和免疫系统功能。相关研究结果发表在最近的《Molecular Metabolism》杂志。

西式饮食对心脏和血液循环系统的终身负担，一直以来都备受关注。然而，在这项研究之前，没有人曾经考虑到，发育的造血干细胞是否可能同样易受产前高脂饮食和/或孕妇肥胖的伤害。

本文共同作者、OHSU医学院和OHSU Doernbecher儿童医院Papé家庭儿科研究所儿科内分泌学教授Daniel L. Marks博士指出：“我们的研究结果提供了一种模型，用于检测高脂饮食和肥胖的影响是否可以通过饮食干预得以修复，要将这一数据外推到人群中，这是一个非常关键的问题。”

几年前，Marks及其同事制备了一种小鼠模型，该模型密切模拟当前许多育龄年轻女性所摄食的高脂、高糖饮食。随后的研究表明，在小鼠中，母体营养过剩可显著降低胎肝的大小。

有了这一信息，Marks与另一位干细胞专家、本文共同作者、OHSU医学院和OHSU Doernbecher儿童医院Papé家庭儿科研究所儿科肿瘤学教授Peter Kurre合作。他们共同发现，由于母体高脂饮食和肥胖引起的复杂变化，严重限制了胎肝中造血干细胞的生长和扩张，这最终会危害发育中的免疫系统。

Kurre说：“鉴于西式、高脂饮食的传播和和肥胖的流行，这项研究强调了我们有必要更好地了解以前不为人知的干细胞和祖细胞系统的易感性。这些发现可能为儿童免疫疾病和过敏倾向的增多，提供广阔的背景。

（生物通：王英）

生物通推荐原文摘要：
Maternal high-fat diet and obesity compromise fetal hematopoiesis
Abstract
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.