Mechanical states and plastic fates: Mechano-control of epithelial cell fate decisions during tissue development

Adult stem cells are responsible for generating new, specialised cells on demand, driving tissue growth, or offsetting cellular attrition in response to turnover, injury or ageing. Under certain circumstances, however, lineage- committed epithelial cells can re-acquire stem cell properties to rapidly repair damaged tissues. This cellular 'plasticity' is vital for maintaining the function of diverse organs, including the gut, skin, lung and breast. Yet, we do not know how committed epithelial cells are able to rapidly adapt their fundamental identity on demand. There is increasing evidence that mechanical forces influence cell fate outcomes in several tissues. The underlying dynamic mechanisms, however, remain poorly understood. Using the mammary gland as a model, I will combine real time cell fate-mapping, ex vivo mammary explant cultures and in vivo 4D-intravital imaging with biophysical approaches and mathematical modelling to reveal (a) how mechanical cues influence cell fate identity and plasticity, and (b) the dynamic intra-cellular signalling mechanisms underpinning this process. As mechanisms of epithelial plasticity contribute to tissue repair, regeneration and tumourigenesis, improved knowledge in this area has wide-ranging implications for basic developmental biology, regenerative medicine and cancer research.