Wang, Y.; He, Q.; Has, O.; Forouzesh, K.; Eom, D. S.

The skin, the largest organ in our body, serves as our primary defense mechanism. Epidermal stem cells supply undifferentiated keratinocytes, which undergo differentiation as they migrate towards the outermost skin layer. This replenishment mechanism is conserved in vertebrates and various human skin diseases exhibit disruption of this process. However, its underlying cellular and molecular mechanisms remain elusive. Through high-resolution live imaging and in vivo manipulations, we unveil that cytoneme-mediated Notch signaling between keratinocytes is essential for their differentiation and proliferation. We show that IL-17, associated with human skin diseases like psoriasis, cell autonomously regulate keratinocyte cytonemes. Our findings highlight the significance of keratinocyte communication via cytonemes in epidermal remodeling and maintenance. Moreover, this could shed light on potential therapeutic targets for treating human skin diseases.