Uncovering the regulation and role of tissue-wide calcium signaling in the regenerating epidermis
Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics
First Advisor
Greco, Valentina
Abstract
Skin epidermal homeostasis is maintained via constant regeneration by stem cells, which must communicate to coordinate their behaviors. Calcium signaling has been implicated as a signal integrator in developing and wounded epithelial tissues. Yet how adult stem cells signal across regenerative tissue remains unknown due to significant challenges in studying signaling dynamics in live mice. In this thesis, I combined live imaging of calcium signaling in the mouse basal stem cell layer with new machine learning tools to analyze patterns of signaling either between direct or distant stem cell neighbors. I show that epidermal basal cells display dynamic intercellular calcium signaling among neighborhoods of up to 10 cells and that this calcium signaling is coordinated across the basal layer. I find that this coordinated calcium signaling is an emergent property of the skin stem cell compartment. I demonstrate that basal cells display different calcium dynamics throughout the cell cycle and that G2 cells are required for proper levels of calcium signaling via an unknown molecular mechanism. I found that Cx43 is highly localized around G1 cells and connects local signaling neighborhoods to facilitate long-range coordination of calcium signaling. This reveals that G2 cells are essential for initiation of homeostatic calcium signaling, while Cx43, enriched in G1 cells coordinate signaling across the tissue. Lastly, I find that calcium signaling influences cell cycle progression, revealing a feedback loop of communication. This work provides resolution into how stem cells at different stages of the cell cycle communicate and how that diversity of phases is essential for tissue wide communication and signaling flow during epidermal regeneration. This approach provides a framework to investigate stem cell populations and their signaling dynamics, previously not possible.
Recommended Citation
Moore, Jessica L., "Uncovering the regulation and role of tissue-wide calcium signaling in the regenerating epidermis" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1016.
https://elischolar.library.yale.edu/gsas_dissertations/1016
