Molecular mechanisms of cell responses to mechanical stress through modulation of actin dynamics

Cells in the body are under constant tension within the various tissues to maintain organ integrity and function. Modification of the local force equilibrium through direct stretch or pressure regulates cell differentiation and behaviour. However, uncontrolled mechanical stress is also linked to a large number of ailments ranging from abnormal wound healing, scarring and fibrosis, to pathologies associated with stress-prone organs such as the cardiovascular system, cartilage or the eye. In the eye only, scarring accounts for the pathogenesis or failure of treatment of virtually all blinding diseases, and differential response to mechanical stress may underpin susceptibility to blindness in glaucoma patients. As these complex interactions are being unravelled, the basic mechanisms that govern the response to mechanical stress remain largely unknown. Some of our earlier work suggested that the cells’ response to the stress is linked to the state of their actin cytoskeleton, a dynamic network of cables that constitutes the internal cell scaffolding. This project aims at characterizing the mechanisms involved in the cell’s sensing and response to mechanical stress, and identify novel targets to control and modulate wound healing and tissue contraction, ultimately providing the basis for the development of improved regeneration-based therapies in ocular scarring.

Mechanical stress is believed to be an essential component of wound healing and its associated pathologies such as scarring processes and fibrosis, as well as in pathologies associated with stress-prone organs such as the cardiovascular system, cartilage or the eye. With the recent advances in stem cell research, tissue engineering and regenerative medicine, there is also a growing body of evidence suggesting that mechanical stimulation of cells and/or re-creation of the 3D-mechanical constraints are essential for proper cell differentiation and behaviour. As these complex interactions are being unravelled, the basic mechanisms that govern response to mechanical stress in 3 dimensions remain largely unknown. Using a unique device that allows us to study mechanical stress in cells within a 3D environment, this project propose to investigate the hypothesis that mechanical stress sensing and celullar responses to mechanical stress, especially in terms of acquisition of a contractile behaviour, are linked to the modulation of actin dynamics and specific activation of the transcription factor SRF through its co-activator MAL. Testing the links between mechanical stress and cell behaviour in the context of tissue contraction, this project will use a combination of qualitative and quantitative 3D and 4D image analysis to determine the nature if the relationship between the dynamics of the actin cytoskeleton and the response to mechanical stress, especially in terms of SRF activation. These studies should prove not only essential to the fundamental understanding of the molecular basis of cellular responses to mechanical stress, but will also identify novel targets to control and modulate wound healing and tissue contraction, and ultimately lead to novel therapies for tissue repair and regeneration.