ETVs dictate hPSC differentiation by tuning biophysical properties

Natalia M. Ziojła, Magdalena Socha, M. Cecilia Guerra, Dorota Kizewska, Katarzyna Blaszczyk, Edyta Urbaniak, Sara Henry, Malgorzata Grabowska, Kathy K. Niakan, Aryeh Warmflash and Malgorzata Borowiak ()
Additional contact information
Natalia M. Ziojła: Adam Mickiewicz University
Magdalena Socha: Adam Mickiewicz University
M. Cecilia Guerra: Rice University
Dorota Kizewska: Adam Mickiewicz University
Katarzyna Blaszczyk: Adam Mickiewicz University
Edyta Urbaniak: Adam Mickiewicz University
Sara Henry: Adam Mickiewicz University
Malgorzata Grabowska: Adam Mickiewicz University
Kathy K. Niakan: University of Cambridge
Aryeh Warmflash: Rice University
Malgorzata Borowiak: Adam Mickiewicz University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Stem cells maintain a dynamic dialog with their niche, integrating biochemical and biophysical cues to modulate cellular behavior. Yet, the transcriptional networks that regulate cellular biophysical properties remain poorly defined. Here, we leverage human pluripotent stem cells (hPSCs) and two morphogenesis models – gastruloids and pancreatic differentiation – to establish ETV transcription factors as critical regulators of biophysical parameters and lineage commitment. Genetic ablation of ETV1 or ETV1/ETV4/ETV5 in hPSCs enhances cell-cell and cell-ECM adhesion, leading to aberrant multilineage differentiation including disrupted germ-layer organization, ectoderm loss, and extraembryonic cell overgrowth in gastruloids. Furthermore, ETV1 loss abolishes pancreatic progenitor formation. Single-cell RNA sequencing and follow-up assays reveal dysregulated mechanotransduction via the PI3K/AKT signaling. Our findings highlight the importance of transcriptional control over cell biophysical properties and suggest that manipulating these properties may improve in vitro cell and tissue engineering strategies.

Date: 2025
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DOI: 10.1038/s41467-025-56591-6

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