Project description:Human naïve 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 2 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.

			Action	DRS
		Other
	GSE237669_PALLY_DM_SI_barcodes.tsv.gz	Tabular
	GSE237669_PALLY_DM_SI_features.tsv.gz	Tabular
	GSE237669_PALLY_DM_SI_matrix.mtx.gz	Other
	GSE237669_PALLY_SI_barcodes.tsv.gz	Tabular

Dataset Information

DMSO Drives Trophectoderm and Blastoid Formation from Human Naïve Pluripotent Stem Cells without Lineage-Specifying Signals

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