Acetyl-CoA metabolism maintains histone acetylation for syncytialization of human placental trophoblast stem cells

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-07-30 DOI:10.1016/j.stem.2024.07.003
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Abstract

During pregnancy, placental-fetal nutrient allocation is crucial for fetal and maternal health. However, the regulatory mechanisms for nutrient metabolism and allocation in placental trophoblasts have remained unclear. Here, we used human first-trimester placenta samples and human trophoblast stem cells (hTSCs) to discover that glucose metabolism is highly active in hTSCs and cytotrophoblasts, but during syncytialization, it decreases to basal levels, remaining necessary for fueling acetyl-CoA and differentiation potential. Acetate supplementation could rescue syncytiotrophoblast fusion from glycolysis deficiency by replenishing acetyl-CoA and maintaining histone acetylation, thus rescuing the activation of syncytialization genes. Even brief glycolysis deficiency could permanently inhibit differentiation potential and promote inflammation, which could also be permanently rescued by brief acetate supplementation in vivo. These results suggest that hTSCs retain only basal glycolytic acetyl-CoA metabolism during syncytialization to regulate cell fates via nutrient-responsive histone acetylation, with implications for our understanding of the balance between placental and fetal nutrition.

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乙酰-CoA 代谢维持组蛋白乙酰化,促进人胎盘滋养层干细胞的合胞化
妊娠期间,胎盘-胎儿的营养分配对胎儿和母体的健康至关重要。然而,胎盘滋养层细胞营养代谢和分配的调控机制仍不清楚。在这里,我们利用人类一胎胎盘样本和人类滋养层干细胞(hTSCs)发现,葡萄糖代谢在hTSCs和细胞滋养层中高度活跃,但在合胞化过程中,葡萄糖代谢降至基础水平,但仍是乙酰-CoA和分化潜能所必需的燃料。补充乙酸盐可补充乙酰-CoA并维持组蛋白乙酰化,从而挽救合胞化基因的活化,从而拯救因糖酵解缺乏而发生的合胞滋养细胞融合。即使是短暂的糖酵解缺乏也会永久性地抑制分化潜能并促进炎症,而体内短暂的乙酸补充也能永久性地挽救这种情况。这些结果表明,hTSCs在合胞化过程中只保留了乙酰-CoA的基础糖酵解代谢,通过营养响应组蛋白乙酰化来调节细胞命运,这对我们理解胎盘和胎儿营养之间的平衡具有重要意义。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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