A Single Small-Molecule-Based Human Embryo Model Reveals V-ATPase Requirement in Mammalian Blastocyst Cavitation

ABSTRACT: Human naïve pluripotent stem cells (nPSCs) can be indued by various combinations of signaling factors to genearte blastocyst-like structures known as blastoids. Despite the rapid advances in human blastoid models, their potential to uncover fundamental mechanisms of early development remains limited, leaving key morphogenetic processes poorly understood. Here, we present a simple and robust system in which dimethyl sulfoxide (DMSO) alone induces blastoid formation from human nPSCs. This model faithfully recapitulates pre- and post-implantation features, including amniotic cavity formation, and reveals a previously unrecognized mechanism of trophectoderm (TE) cavitation. Using this system, we identified lysosome-related genes—particularly those encoding subunits of the proton pump V-ATPase—are essential for blastoid cavitation. DMSO treatment upregulates key V-ATPase subunits (ATP6V0A4 and ATP6V1B1), which are also enriched in the TE of human embryos. Inhibition of V-ATPase disrupted lysosomal acidification, blocked intracellular vacuole formation, and impaired blastoid cavitation. Furthermore, both genetic and pharmacological disruption of V-ATPase function significantly impaired cavitation in mouse and human blastocysts. Thus, our simple DMSO model recapitulates key aspects of human blastocyst development and reveals a conserved mechanism involving V-ATPase–mediated lysosomal acidification during early mammalian embryogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316552 | GEO | 2026/03/11

REPOSITORIES: GEO