History-dependent switch-like differentiation of keratinocytes in response to skin barrier damage
File(s)
Published version
Author(s)
Domíguez-Hüttinger, Elisa
Flores-Garza, Eliezer
Caldú-Primo, José Luis
Day, Harley
Roque Ramírez, Abihail
Type
Journal Article
Abstract
The epidermis is formed by layers of keratinocytes with increasing levels of differentiation towards the outer skin called skin barrier, which protects our body from environmental stressors and dehydration. When skin barrier is damaged, keratinocyte differentiation is triggered, and terminally differentiated keratinocytes express skin barrier components, achieving skin barrier homeostasis. However, the dynamic and quantitative understanding of how skin barrier homeostasis is achieved remains unknown. To elucidate how keratinocyte differentiation is dynamically affected by skin barrier damage, especially in the presence of infection, we developed a mechanistic model of keratinocyte differentiation by integrating experimental results from 101 manually curated publications. To extract the key regulatory structure of the model, we applied model reduction, called the kernel reduction methodology to obtain the minimal reaction network. The key regulatory structure is characterised by positive feedback with cooperativity between Np63 and Stat3, two master regulators of keratinocyte differentiation. This regulatory structure gives rise to bistable behaviour for the expression of terminal differentiation markers of keratinocytes when the skin barrier is damaged and the extracellular calcium level is varied. We validated the model by confirming it produces the history-dependent and switch-like keratinocyte differentiation observed in in vitro reversibility assays. Analysis of the validated model shows that bacterial infection augments keratinocytes’ sensitivity to skin barrier damage by decreasing the level required for differentiation and de-differentiation. Our results suggest the mechanisms by which skin barrier homeostasis is maintained even when the skin is exposed to fluctuating environments that perturb the barrier composition.
Date Issued
2025-06-09
Date Acceptance
2025-05-24
Citation
PLoS Computational Biology, 2025, 21 (6)
ISSN
1553-734X
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS Computational Biology
Volume
21
Issue
6
Copyright Statement
© 2025 Domíguez-Hüttinger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Identifier
10.1371/journal.pcbi.1013162
Publication Status
Published
Article Number
e1013162