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WDR36通过糖酵解代谢调节人类植入前胚胎发育过程中的滋养外胚层分化。

WDR36 Regulates Trophectoderm Differentiation During Human Preimplantation Embryonic Development Through Glycolytic Metabolism.

作者信息

An Shiyu, Hou Shuyue, Xu Feifei, Yan Huanyu, Zhang Wenyi, Xiang Jinfeng, Chen Haoran, Zhang Hanwen, Dong Lingling, Sun Xiaobin, Huo Ran, Chen Yun, Wang Xi, Yang Yang

机构信息

State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.

School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.

出版信息

Adv Sci (Weinh). 2025 Feb;12(5):e2412222. doi: 10.1002/advs.202412222. Epub 2024 Dec 10.

DOI:10.1002/advs.202412222
PMID:39656902
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11791977/
Abstract

Mammalian pre-implantation development is a complex process involving sophisticated regulatory dynamics. WD repeat domain 36 (WDR36) is known to play a critical role in mouse early embryonic development, but its regulatory function in human embryogenesis is still elusive due to limited access to human embryos. The human pluripotent stem cell-derived blastocyst-like structure, termed a blastoid, offers an alternative means to study human development in a dish. In this study, after verifying that WDR36 inhibition disrupted polarization in mouse early embryos, it is further demonstrated that WDR36 interference can block human blastoid formation, dominantly hindering the trophectoderm lineage commitment. Both transcriptomics and targeted metabolomics analyses revealed that WDR36 interference downregulated glucose metabolism. WDR36 can interact with glycolytic metabolic protein lactate dehydrogenase A (LDHA), thereby positively regulating glycolysis during the late stage of human blastoid formation. Taken together, the study has established a mechanistic connection between WDR36, glucose metabolism, and cell fate determination during early embryonic lineage commitment, which may provide potential insights into novel therapeutic targets for early adverse pregnancy interventions.

摘要

哺乳动物植入前发育是一个涉及复杂调控动态的过程。已知WD重复结构域36（WDR36）在小鼠早期胚胎发育中起关键作用，但由于获取人类胚胎的机会有限，其在人类胚胎发生中的调控功能仍不清楚。人类多能干细胞衍生的囊胚样结构，即类囊胚，为在培养皿中研究人类发育提供了一种替代方法。在本研究中，在验证WDR36抑制会破坏小鼠早期胚胎的极化后，进一步证明WDR36干扰会阻碍人类类囊胚的形成，主要阻碍滋养外胚层谱系的定向分化。转录组学和靶向代谢组学分析均显示，WDR36干扰会下调葡萄糖代谢。WDR36可与糖酵解代谢蛋白乳酸脱氢酶A（LDHA）相互作用，从而在人类类囊胚形成后期正向调节糖酵解。综上所述，该研究在早期胚胎谱系定向分化过程中建立了WDR36、葡萄糖代谢和细胞命运决定之间的机制联系，这可能为早期不良妊娠干预的新治疗靶点提供潜在见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/2511383d666b/ADVS-12-2412222-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/c683c9e73c64/ADVS-12-2412222-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/4959f8dbb7b8/ADVS-12-2412222-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/c79994800bc4/ADVS-12-2412222-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/6711b8b69fe4/ADVS-12-2412222-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/3e06fa75a3cb/ADVS-12-2412222-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/2511383d666b/ADVS-12-2412222-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/c683c9e73c64/ADVS-12-2412222-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/4959f8dbb7b8/ADVS-12-2412222-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/c79994800bc4/ADVS-12-2412222-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/6711b8b69fe4/ADVS-12-2412222-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/3e06fa75a3cb/ADVS-12-2412222-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a27a/11791977/2511383d666b/ADVS-12-2412222-g003.jpg

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本文引用的文献

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WD repeat domain 82 (Wdr82) facilitates mouse iPSCs generation by interfering mitochondrial oxidative phosphorylation and glycolysis.WD 重复结构域 82（Wdr82）通过干扰线粒体氧化磷酸化和糖酵解来促进小鼠 iPSCs 的生成。
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Single-cell quantification of ribosome occupancy in early mouse development.
单细胞定量分析早期小鼠发育过程中的核糖体占据情况。
Nature. 2023 Jun;618(7967):1057-1064. doi: 10.1038/s41586-023-06228-9. Epub 2023 Jun 21.
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Lineage segregation in human pre-implantation embryos is specified by YAP1 and TEAD1.人类着床前胚胎中的谱系分离由 YAP1 和 TEAD1 决定。
Hum Reprod. 2023 Aug 1;38(8):1484-1498. doi: 10.1093/humrep/dead107.
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Modeling human pregastrulation development by 3D culture of blastoids generated from primed-to-naïve transitioning intermediates.通过对处于原始态向幼稚态转变中间态的胚状体进行 3D 培养，来模拟人类胚前期发育。
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Single-cell metabolic fingerprints discover a cluster of circulating tumor cells with distinct metastatic potential.单细胞代谢指纹图谱发现具有不同转移潜能的循环肿瘤细胞簇。
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