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G2 stem cells orchestrate time-directed, long-range coordination of calcium signaling during skin epidermal regeneration

View ORCID ProfileJessica L Moore, Feng Gao, View ORCID ProfileCatherine Matte-Martone, View ORCID ProfileShuangshuang Du, View ORCID ProfileElizabeth Lathrop, View ORCID ProfileSmirthy Ganesan, View ORCID ProfileLin Shao, View ORCID ProfileDhananjay Bhaskar, View ORCID ProfileAndy Cox, Caroline Hendry, View ORCID ProfileBastian Rieck, View ORCID ProfileSmita Krishnaswamy, View ORCID ProfileValentina Greco
doi: https://doi.org/10.1101/2021.10.12.464066
Jessica L Moore
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Feng Gao
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Catherine Matte-Martone
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Shuangshuang Du
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Elizabeth Lathrop
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Smirthy Ganesan
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Lin Shao
2Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA
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Dhananjay Bhaskar
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Andy Cox
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Caroline Hendry
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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Bastian Rieck
3Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland
4SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
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Smita Krishnaswamy
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
5Department of Computer Science, Yale University, New Haven, CT 06510, USA
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  • For correspondence: smita.krishnaswamy@yale.edu valentina.greco@yale.edu
Valentina Greco
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
6Departments of Cell Biology and Dermatology, Yale Stem Cell Center, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA
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  • For correspondence: smita.krishnaswamy@yale.edu valentina.greco@yale.edu
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Abstract

Skin epidermal homeostasis is maintained via constant regeneration by stem cells, which must communicate to balance their self-renewal and differentiation. A key molecular pathway, Ca2+ signaling has been implicated as a signal integrator in developing and wounded epithelial tissues[1, 2, 3, 4]. Yet how stem cells carry out this signaling across a regenerative tissue remains unknown due to significant challenges in studying signaling dynamics in live mice, limiting our understanding of the mechanisms of stem cell communication during homeostasis. To interpret high dimensional signals that have complex spatial and temporal patterns, we combined optimized imaging of Ca2+ signaling in thousands of epidermal stem cells in living mice with a new machine learning tool, Geometric Scattering Trajectory Homology (GSTH). Using a combination of signal processing, data geometry, and topology, GSTH captures patterns of signaling at multiple scales, either between direct or distant stem cell neighbors. Here we show that epidermal stem cells display dynamic intercellular Ca2+ signaling among neighborhoods of up to 10 cells that is surprisingly coordinated and directed through time across a pool of thousands of stem cells. We find that this collective coordination is an emergent property of the stem cell compartment, distinct from excitatory quiescent neuronal tissues. We demonstrate that cycling stem cells, specifically G2 cells, govern homeostatic patterns of Ca2+ signaling. Stem cells in different cell cycle stages dynamically regulate localization of the gap junction component Connexin43 (Cx43). Lastly, we uncouple global from local communication and identify Cx43 as the molecular mediator necessary for connectivity between local signaling neighborhoods. This work provides resolution in 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. Our approach provides a framework to investigate stem cell populations and their signaling dynamics, previously not possible.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 08, 2022.
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G2 stem cells orchestrate time-directed, long-range coordination of calcium signaling during skin epidermal regeneration
Jessica L Moore, Feng Gao, Catherine Matte-Martone, Shuangshuang Du, Elizabeth Lathrop, Smirthy Ganesan, Lin Shao, Dhananjay Bhaskar, Andy Cox, Caroline Hendry, Bastian Rieck, Smita Krishnaswamy, Valentina Greco
bioRxiv 2021.10.12.464066; doi: https://doi.org/10.1101/2021.10.12.464066
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G2 stem cells orchestrate time-directed, long-range coordination of calcium signaling during skin epidermal regeneration
Jessica L Moore, Feng Gao, Catherine Matte-Martone, Shuangshuang Du, Elizabeth Lathrop, Smirthy Ganesan, Lin Shao, Dhananjay Bhaskar, Andy Cox, Caroline Hendry, Bastian Rieck, Smita Krishnaswamy, Valentina Greco
bioRxiv 2021.10.12.464066; doi: https://doi.org/10.1101/2021.10.12.464066

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