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α-酮戊二酸促进原始人类胚胎干细胞向滋养外胚层的诱导和成熟。

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells.

作者信息

Van Nerum Karlien, Wenzel Anne, Argemi-Muntadas Lidia, Kafkia Eleni, Drews Antar, Brun Ida Sophie, Lavro Viktoria, Roelofsen Annina, Stamidis Nikolaos, Arnal Sandra Bages, Zhao Cheng, di Sanzo Simone, Völker-Albert Moritz, Petropoulos Sophie, Moritz Thomas, Żylicz Jan Jakub

机构信息

Novo Nordisk Foundation Center for Stem Cell Medicine - reNEW, Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

出版信息

Nat Cell Biol. 2025 May;27(5):749-761. doi: 10.1038/s41556-025-01658-1. Epub 2025 Apr 23.

DOI:10.1038/s41556-025-01658-1
PMID:40269259
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12081308/
Abstract

Development and lineage choice are driven by interconnected transcriptional, epigenetic and metabolic changes. Specific metabolites, such as α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin-modifying enzymes. However, how metabolism coordinates cell-state changes, especially in human pre-implantation development, remains unclear. Here we uncover that inducing naive human embryonic stem cells towards the trophectoderm lineage results in considerable metabolic rewiring, characterized by αKG accumulation. Elevated αKG levels potentiate the capacity of naive embryonic stem cells to specify towards the trophectoderm lineage. Moreover, increased αKG levels promote blastoid polarization and trophectoderm maturation. αKG supplementation does not affect global histone methylation levels; rather, it decreases acetyl-CoA availability, reduces histone acetyltransferase activity and weakens the pluripotency network. We propose that metabolism functions as a positive feedback loop aiding in trophectoderm fate induction and maturation, highlighting that global metabolic rewiring can promote specificity in cell fate decisions through intricate regulation of signalling and chromatin.

摘要

发育和谱系选择由相互关联的转录、表观遗传和代谢变化驱动。特定代谢物，如α-酮戊二酸（αKG），作为信号分子影响染色质修饰酶的活性。然而，代谢如何协调细胞状态变化，尤其是在人类植入前发育过程中，仍不清楚。在这里，我们发现诱导人幼稚胚胎干细胞向滋养外胚层谱系分化会导致显著的代谢重编程，其特征是αKG积累。升高的αKG水平增强了幼稚胚胎干细胞向滋养外胚层谱系分化的能力。此外，αKG水平的增加促进囊胚样细胞极化和滋养外胚层成熟。补充αKG不影响整体组蛋白甲基化水平；相反，它会降低乙酰辅酶A的可用性，降低组蛋白乙酰转移酶活性并削弱多能性网络。我们提出，代谢作为一个正反馈回路，有助于滋养外胚层命运的诱导和成熟，突出了整体代谢重编程可以通过对信号传导和染色质的复杂调节来促进细胞命运决定的特异性。

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