An innovative in vitro system unveils IGF1R signaling regulating Merkel cell generation

Merkel cells (MCs) are specialized mechanoreceptors crucial for tactile sensation, yet their developmental investigation remains challenging, particularly in humans, due to the lack of validated in vitro culture system. Here, we establish novel approaches, including short-term ex vivo vibrissae explants, innovative mouse skin organoids (mSKOs), and human pluripotent stem cell-derived skin organoids (hSKOs), to monitor MC development. We demonstrate that Polycomb repressive complex inhibitors (PRCis) efficiently promote MC generation in these culture systems. Through single-cell and spatial transcriptomics analysis, together with pharmacological screening, we identify IGF1R as a potential regulator of MC formation, which likely exerts its effects through the AKT pathway. Furthermore, we validate the role of FGFR2 signaling in MC generation. These systems constitute a versatile platform that harnesses complementary strengths to not only advance MC biology and skin development but also enable stem cell research, supporting organoid-based disease modeling, therapeutic compound screening, and regenerative medicine.