Biophysical determinants of cell fate decisions in skin inflammatory diseases

The skin epidermis provides a protective barrier against external insults. To ensure its maintenance, specialised cells located in its basal layer, known as stem cells, divide and differentiate to replace cells lost through exhaustion and damage. However, the mechanisms that control stem cell renewal and the pathways that lead to their dysregulation in disease remain controversial.

While studies have highlighted the role of stochastic renewal programs where stem cells are constantly lost and replaced by neighbouring cells, the underlying biological and physical mechanisms governing stochastic cell fate decisions remain poorly understood. Recent investigations in skin inflammatory diseases, such as psoriasis or atopic dermatitis, where the balance between proliferation and differentiation is typically disrupted have emphasized the influence of tissue mechanics in priming stem cells for renewal or differentiation and the crucial role niche signals from immune, stromal, and neuro-glial cells in modulating stem cell self-renewal and tissue dynamics.

In this project, you will use the latest spatial transcriptomics methods combined with machine learning to characterise simultaneously the mechanical, biochemical and cellular niches of epidermal stem cells, and how their composition, properties and spatial organisation might be altered in inflammatory skin diseases. You will also have the opportunity to contribute to follow-up experiments and hypothesis testing using mouse models and human epithelial organoids co-cultures, combined with advanced live imaging, AFM, mathematical modelling, genetic lineage tracing and functional genomics approaches such as CRISPR-based gene editing.

Ultimately, the results of this interdisciplinary project will transform our understanding of the mechanisms regulating epithelial tissue dynamics, and lay the foundation for the development of more effective therapeutic interventions targeting the causes, rather than the symptoms, of skin inflammatory diseases.