Mapping the regulatory wiring of endothelial cell differentiation reveals a critical role for Hippo mechanosignaling

Hippo mechanosignaling is unexpectedly required for arterial endothelial cell specification, activating ETV2 during lateral mesoderm differentiation and shaping fate outcomes in vitro and in zebrafish embryos.

• Why it matters: A comprehensive, step-by-step map of gene programs and regulators that govern human cell differentiation remains incomplete, limiting mechanistic control over endothelial lineage decisions.
• What they did: The study used circular capture Perturb-seq (CC-Perturb-seq) with genome-wide CRISPR screens, single-cell RNA-seq, and gene program inference to perturb regulators during human pluripotent stem cell differentiation, identifying 174 regulators that promote or inhibit EC differentiation.
• The result: Hippo inhibition blocked ETV2 even with VEGF and diverted progenitors to a mesenchymal fate in vitro, while Hippo was also needed for maximal etv2 expression in developing zebrafish embryos; Hippo activation increased arterial and venous EC purity in vitro.

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