An ECM-driven mechanotransductive signaling module promotes NKX6.1-enriched human pancreatic progenitor formation.

Isoxazole-9 (ISX-9) promotes an NKX6.1-enriched human pancreatic progenitor state by engaging a collagen–TRPV–Ca2+/CaMKII mechanotransductive axis.

• Why it matters: Reliable, high-fidelity production of insulin-producing beta cells from human pluripotent stem cells is limited by inefficient PDX1+/NKX6.1+ pancreatic progenitor specification.
• What they did: Transcriptomics plus targeted perturbations showed ISX-9 acts through collagen sensing and TRPV Ca2+ signaling, with collagen I/IV or TRPV agonists phenocopying and integrin α1/α2, TRPV, or CaMKII inhibition blocking effects.
• The result: CaMKII-dependent relief of HDAC4–MEF2 repression and increased cycling of NKX6.1+ cells accompany progenitor expansion, and temporally restricted ISX-9 increases PDX1+/NKX6.1+ progenitors and improves glucose-responsive stem cell-derived islets.

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