Integrating mechanical and chemical cues in stem cell migration and differentiation

Adult stem cells are found in most tissues, and the interaction between stem cells and their niche tightly controls their self-renewal and differentiation state. Furthermore, environmental factors can ‘activate’ stem cells leading to acquisition of a migratory phenotype, homing to specific sites and differentiation to mediate tissue maintenance and repair. The stem cell microenvironment consists of a myriad of physical and biochemical cues, and these are decoded by stem cells to produce the appropriate response. How these mechanical and chemical factors that control stem cells are integrated to control stem cell behaviour, however, is not known.

We will use mesenchymal stem cells, which migrate and differentiate in a stereotypical manner in response to specific soluble factors, substrate mechanics and cytoskeletal tension, to understand signal integration. Combining cell biology approaches and state-of-the art microscopy (super resolution, FRET biosensors (Paul et al., 2015)) with mathematical modelling (Hetmanski et al., 2016) will allow us to understand signalling networks that govern differentiation and migratory outcomes. We will further experimentally manipulate substrate rigidity, cell shape (using micropatterning) and the cytoskeleton to reveal their impact on intracellular signalling and inform mathematical models. This interdisciplinary approach will provide insight into stem cell behaviour and how it can be manipulated for application in tissue engineering.

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