阿卜杜拉国王科技大学李默团队的一项最新研究发现了基于单个小分子的人类胚胎模型揭示了哺乳动物囊胚空化对V-ATP酶的需求。2026年4月6日，国际知名学术期刊《细胞研究》发表了这一成果。

课题组研究人员描述了一个简单和自动化的系统，其中二甲亚砜（DMSO）单独诱导人类nPSCs形成囊胚。该模型概括了胚胎着床前和着床后的关键特征，并表现出极性滋养外胚层（TE）组织的增强，在着床相关窗口内更有效的附着，与羊膜腔形成相关的外胚层管腔形成的改善，以及着床后胚胎谱系更自然、更稳定的扩展。利用这个系统，课题组揭示了一个以前未被认识的TE空化机制，并确定溶酶体相关基因-特别是质子泵V-ATP酶的亚基-是囊胚空化的重要调节因子。DMSO处理上调关键的V-ATP酶亚基（ATP6V0A4和ATP6V1B1），它们也在人类胚胎的TE中富集。遗传或药理学抑制V-ATP酶活性会破坏溶酶体酸化，阻断细胞内液泡形成，并损害囊胚空化，而V-ATP酶亚基的过度表达则会挽救这种表型。

此外，基因和药理学上对V-ATP酶功能的干扰会显著损害母鼠和人囊胚的空化。最后，DMSO处理诱导早期胚胎发育特征的膜生物力学变化，表明不同于传统的基于信号通路的小分子诱导策略的作用模式。这个简单的基于DMSO的囊胚模型概括了人类囊胚发育的关键方面，并揭示了早期哺乳动物胚胎发生过程中V-ATP酶介导的溶酶体酸化的保守需求。

研究人员表示，人类幼稚多能干细胞（nPSCs）可以通过多种信号因子的组合诱导产生囊胚样结构，称为囊胚。尽管人类囊胚模型进展迅速，但它们揭示早期人类发育基本机制的潜力仍然有限，对关键的形态发生过程知之甚少。

附：英文原文

Title: A single small molecule-based human embryo model reveals V-ATPase requirement in mammalian blastocyst cavitation

Author: Alsolami, Samhan, Chandrasekaran, Arun Pandian, Jin, Yiqing, Wang, Yibo, Zhang, Ling, Shakir, Ismail M., Zhang, Yingzi, Siddique, Aisha, Ramos-Mandujano, Gerardo, Yuan, Baolei, Ayach, Maya, Saera-Vila, Alfonso, Fan, Zejun, Fu, Siyi, Zhang, Huoming, Xin, Saige, AlDakhil, Kholoud Khalid, Izpisua Belmonte, Juan Carlos, Zhang, Jin, Yu, Yang, Li, Mo

Issue&Volume: 2026-04-06

Abstract: Human nave pluripotent stem cells (nPSCs) can be induced by various combinations of signaling factors to generate blastocyst-like structures, termed blastoids. Despite rapid progress in human blastoid models, their potential to uncover fundamental mechanisms of early human development remains limited, leaving key morphogenetic processes poorly understood. Here, we describe a simple and robust system in which dimethyl sulfoxide (DMSO) alone induces blastoid formation from human nPSCs. This model recapitulates key pre- and post-implantation features and exhibits enhanced polar trophectoderm (TE) organization, more efficient attachment within an implantation-relevant window, improved epiblast lumenogenesis associated with amniotic cavity formation, and more robust, sustained expansion of embryonic lineages following attachment. Using this system, we reveal a previously unrecognized mechanism underlying TE cavitation and identify lysosome-associated genes — particularly subunits of the proton pump V-ATPase — as essential regulators of blastoid cavitation. DMSO treatment upregulates key V-ATPase subunits (ATP6V0A4 and ATP6V1B1), which are also enriched in the TE of human embryos. Genetic or pharmacological inhibition of V-ATPase activity disrupts lysosomal acidification, blocks intracellular vacuole formation, and impairs blastoid cavitation, whereas overexpression of V-ATPase subunits rescues this phenotype. Furthermore, genetic and pharmacological perturbations of V-ATPase function significantly compromise cavitation in both mouse and human blastocysts. Finally, DMSO treatment induces membrane biomechanical changes characteristic of early embryonic development, suggesting a mode of action distinct from conventional small-molecule, signaling pathway-based induction strategies. This simple DMSO-based blastoid model recapitulates key aspects of human blastocyst development and reveals a conserved requirement for V-ATPase-mediated lysosomal acidification during early mammalian embryogenesis.

DOI: 10.1038/s41422-026-01239-3

Source: https://www.nature.com/articles/s41422-026-01239-3