Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
J Cell Biol. 2023 Jul 3;222(7). doi: 10.1083/jcb.202302095. Epub 2023 Apr 27.
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 Ca2+ signaling. We show that basal cells display dynamic intercellular Ca2+ signaling among local neighborhoods. We find that these Ca2+ 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 Ca2+ signaling, while connexin43 connects basal cells to orchestrate tissue-wide coordination of Ca2+ signaling. Lastly, we find that Ca2+ 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.
皮肤稳态由干细胞维持，干细胞必须进行通讯以平衡其再生行为。然而，由于在活体小鼠中研究信号转导动力学的挑战，成年干细胞如何在再生组织中发出信号仍然未知。我们将活体成像与机器学习工具相结合，分析了钙信号转导的模式。我们发现基底细胞在局部邻域之间显示出动态的细胞间钙信号。我们发现这些钙信号在数千个细胞中是协调的，这种协调是干细胞层的一个涌现性质。我们证明 G2 细胞是启动正常钙信号所必需的，而连接蛋白 43 将基底细胞连接起来，以协调钙信号的组织范围协调。最后，我们发现钙信号驱动细胞周期进程，揭示了一种通信反馈回路。这项工作提供了分辨率，说明在表皮再生过程中，不同细胞周期阶段的干细胞如何协调组织范围的信号转导。
