Community Research and Development Information Service - CORDIS


DURACELL Report Summary

Project ID: 617233
Funded under: FP7-IDEAS-ERC
Country: France

Periodic Report Summary 2 - DURACELL (Cell Migration under Mechanical Constraints)

Cellular mechanical sensing and transduction are essential processes that control form and function of the organism and go awry in diseases such as cancer and cardiovascular problems. Cell adhesion and migration are not only affected by extracellular cues such as biochemical gradients but also by physical cues such as the environmental stiffness. Our project aims at understanding, at multiple temporal and spatial scales, the influence of mechanical constraints on single and collective cell migration. To do so, we first analysed single cell responses to substrate rigidity and found that cells can respond to the rigidity of their surrounding environment by adapting their internal mechanical properties. In other words, cells behave as a fluid on soft substrates and as an elastic solid on stiff ones through a large scale remodeling of the cytoskeleton. This global sensing mechanism may be the basic mechanism that explains various responses to rigidity such the preferential migration of tissue cells towards stiffer regions or even the increase of the apoptotic rate on softer substrates. Consequently, our findings could have important implications in pathological situations such as tumor formation where tumors appear as more rigid tissues than healthy tissues but also physiological ones such cell differentiation processes where cytoskeleton organization and forces may favor different routes.
In addition, we also studied collective cell migration in response to geometrical constraints and in particular, during epithelial gap closure. Epithelial gap closure is particularly relevant for wound healing mechanisms in skin tissues but wounds may also occur deep inside the body in any tissue or organ, and these can lead to the development of chronic diseases such as diabetes and asthma. We revealed key mechanistic features of epithelial wound healing. Our findings clarify the roles of two gap-closing mechanisms—cell crawling and purse-string contractile dynamics—and describes how the relative contributions of the two mechanisms are affected by gap geometry. In tissue regions of positive curvature, cells predominantly crawl. In areas of negative curvature, purse-string closure and crawling operate additively to fill the gap, leading to faster tissue velocity in such regions. Along this line, we showed that efficient gap closure mechanism required the maintenance of proper cell-cell junctions.
Finally, we started to develop new substrates that could better describe cell migration within 3-dimensional environments. We thus studied single cell migration along suspended nanofibers and described new modes of migration that rely on a balance between cell contractility and cell body extension through cytoskeleton polymerisation.

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