Epidermal stem cells control periderm injury repair via matrix-driven specialization of intercellular junctions

Helen Mengze He, Liana C. Boraas, Jon M. Bell, Xiangyu Gong, Sophia L. Iannaccone, Zhang Wen, Michael Mak, Marina Carlson, Kaelyn Sumigray () and Stefania Nicoli ()
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Helen Mengze He: Yale University School of Medicine
Liana C. Boraas: Yale University School of Medicine
Jon M. Bell: Yale University School of Medicine
Xiangyu Gong: Yale University
Sophia L. Iannaccone: Yale University School of Medicine
Zhang Wen: Yale University School of Medicine
Michael Mak: Yale University
Marina Carlson: Yale University School of Medicine
Kaelyn Sumigray: Yale University School of Medicine
Stefania Nicoli: Yale University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Epidermal stem cells interact with the extracellular matrix (ECM) to regulate their differentiation and maintain skin architecture. Here, we demonstrate a role for basal epidermal stem cells (BECs)-ECM interaction in regulating adhesion molecules expressed by the periderm—the superficial epidermal cells (SECs) of the embryonic bilayered skin. Using the developing zebrafish fin fold, we identify BECs form distinct regions of collagen- versus laminin- enriched basement membranes through integrin-mediated adhesions. Mechanistically, collagen-associated BECs form desmosomes and adherens junctions (AJs) with SECs while laminin-associated BECs display reduced desmosomes but sustain AJs and actomyosin expression with SECs. Notably, we show both in vivo and in a bilayered human keratinocyte model, that laminin, compared to collagen, is sufficient to repress desmosome formation while sustaining AJs specifically at the interlayer cell contacts. In vivo, laminin deficiency enhances desmosome expression across layers and impairs the wound-healing capacity of SECs. This defect was partially rescued by genetic reduction of the desmosome protein Desmoplakin-1a, highlighting the role of ECM-dependent junctional specialization in mediating differences in SEC injury response. Overall, our findings identify that stem cells, through their matrix, establish specialized junctions in the overlying stratified epithelium, which contribute to skin healing properties.

Date: 2025
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DOI: 10.1038/s41467-025-64040-7

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