小鼠单细胞 RNA 转录组学揭示了母体肥胖导致纤维化的胚胎起源。

IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-11-01 Epub Date: 2024-10-30 DOI:10.1016/j.ebiom.2024.105421
Md Nazmul Hossain, Yao Gao, Xinrui Li, Liang Zhao, Xiangdong Liu, Jeanene Marie de Avila, Mei-Jun Zhu, Min Du
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引用次数: 0

摘要

背景美国超过 40% 的孕妇肥胖,这对胎儿发育和后代健康产生了负面影响。母体肥胖(MO)会导致后代成年后多个组织和器官发生纤维化浸润,但其起源和机制尚不清楚:方法:用对照组和高脂饮食喂养 C57BL/6J 雌性小鼠,以模拟 MO 状态。从对照组(CON)和MO组小鼠的E9.5、E11.5和E13.5(相当于人类怀孕6周)获得胚胎体细胞组织,进行单细胞RNA测序(scRNA-seq)。为了探索AMP激活蛋白激酶(AMPK)的作用,AMPK被二甲双胍和A769662激活,并在胚胎间充质细胞(EMC)中被AMPKα1基因缺失小鼠敲除:通过无监督聚类,我们发现了三种具有纤维化能力的主要细胞群。与CON相比,MO导致的纤维化细胞数量急剧增加(增加了125%),支持了后代纤维化的胚胎起源。MO诱导了胚胎的炎症反应和转化生长因子β(TGFβ)信号及纤维化基因的表达。MO 可抑制 AMPK,二甲双胍和 A769662 可抑制 TGFβ 信号传导和纤维形成:MO能显著增强胚胎纤维化,解释了肥胖母亲后代纤维化的起源。我们的数据强调了在怀孕5-6周前进行早期干预对改善胚胎发育的重要性,AMPK是抑制MO胚胎过度纤维化的一个有利靶点,可帮助越来越多的肥胖母亲生育健康子女:本研究由美国国立卫生研究院 R01HD067449 号基金资助。
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Single-cell RNA transcriptomics in mice reveals embryonic origin of fibrosis due to maternal obesity.

Background: Over 40% of pregnant women in the USA are obese which negatively affects fetal development and offspring health. Maternal obesity (MO) leads to fibrotic infiltration in multiple tissues and organs of offspring during their adulthood although the origin and mechanisms are unclear.

Methods: C57BL/6J female mice were fed a control and high-fat diet to mimic MO condition. Embryonic somatic tissues were obtained at E9.5, E11.5, and E13.5 (equivalent to 6 weeks of human pregnancy) from control (CON) and MO mice for single-cell RNA-sequencing (scRNA-seq). To explore the role of AMP-activated protein kinase (AMPK), AMPK was activated by metformin and A769662, and knocked out in embryonic mesenchymal cells (EMC) using AMPKα1 floxed mice.

Findings: Using unsupervised clustering, we identified three major cell populations with fibrogenic capacity. Compared to CON, the population of fibrogenic cells increased dramatically (by ∼125%) due to MO, supporting an embryonic origin of fibrosis in the offspring. MO induced inflammatory response and elevated expression of transforming growth factor β (TGFβ) signalling and fibrogenic genes in embryos. MO inhibited AMPK and its activation by metformin and A769662 inhibited TGFβ signalling and fibrogenesis.

Interpretation: MO profoundly enhances embryonic fibrogenesis, explaining the origin of fibrosis in the offspring of mothers living with obesity. Our data underscore the importance of early intervention, before 5-6 weeks of pregnancy, in improving embryonic development, and AMPK is an amiable target for suppressing excessive fibrogenesis in MO embryos to assist increasing populations of obese mothers having healthy children.

Funding: This work was funded by National Institutes of Health Grant R01HD067449.

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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