Work

History-dependent switch-like differentiation of keratinocytes in response to skin barrier damage

Year: 2025

Type: 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.

Source: PLoS Computational Biology

DOI: 10.1371/journal.pcbi.1013162

Authors: Elisa Domíguez-Hüttinger, Eliezer Flores-Garza, José Luis Caldú-Primo, Harley Day, Abihail Roque Ramírez, Reiko J. Tanaka

Institutions: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Universidad Nacional Autónoma de México, Imperial College London

Language: English

Topic: Gene Regulatory Network Analysis

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,043