Domíguez-Hüttinger Elisa, Flores-Garza Eliezer, Caldú-Primo José Luis, Day Harley, Roque Ramírez Abihail, Tanaka Reiko J
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, México.
Department of Bioengineering, Imperial College London, South Kensington Campus, London, United Kingdom.
PLoS Comput Biol. 2025 Jun 9;21(6):e1013162. doi: 10.1371/journal.pcbi.1013162. eCollection 2025 Jun.
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.
表皮由角质形成细胞层构成，随着向称为皮肤屏障的外层皮肤方向分化程度的增加，皮肤屏障可保护我们的身体免受环境应激源和脱水的影响。当皮肤屏障受损时，角质形成细胞分化被触发，终末分化的角质形成细胞表达皮肤屏障成分，从而实现皮肤屏障的稳态。然而，对于如何实现皮肤屏障稳态的动态和定量理解仍然未知。为了阐明角质形成细胞分化如何受到皮肤屏障损伤的动态影响，特别是在存在感染的情况下，我们通过整合来自101篇人工整理出版物的实验结果，建立了角质形成细胞分化的机制模型。为了提取模型的关键调控结构，我们应用了模型简化方法，即内核简化方法来获得最小反应网络。关键调控结构的特征是角质形成细胞分化的两个主要调节因子Np63和Stat3之间具有协同作用的正反馈。当皮肤屏障受损且细胞外钙水平发生变化时，这种调控结构会导致角质形成细胞终末分化标志物表达出现双稳态行为。我们通过证实该模型产生了在体外可逆性实验中观察到的依赖历史和类似开关的角质形成细胞分化来验证该模型。对经过验证的模型的分析表明，细菌感染通过降低分化和去分化所需的水平来增强角质形成细胞对皮肤屏障损伤的敏感性。我们的结果表明了即使皮肤暴露于扰乱屏障组成的波动环境中时，皮肤屏障稳态仍得以维持的机制。
