Cell cycle controls long-range calcium signaling in the regenerating epidermis

Skin homeostasis is maintained by stem cells, which must communicate to balance their regenerative behaviors. Yet, how adult stem cells signal across regenerative tissue remains unknown due to challenges in studying signaling dynamics in live mice. We combined live imaging in the mouse basal stem cell layer with machine learning tools to analyze patterns of Ca(2+) signaling. We show that basal cells display dynamic intercellular Ca(2+) signaling among local neighborhoods. We find that these Ca(2+) signals are coordinated across thousands of cells and that this coordination is an emergent property of the stem cell layer. We demonstrate that G2 cells are required to initiate normal levels of Ca(2+) signaling, while connexin43 connects basal cells to orchestrate tissue-wide coordination of Ca(2+) signaling. Lastly, we find that Ca(2+) signaling drives cell cycle progression, revealing a communication feedback loop. This work provides resolution into how stem cells at different cell cycle stages coordinate tissue-wide signaling during epidermal regeneration.