Accueil du site > Equipes > Fonctionnalité et dynamique du tissu cutané (D. Sigaudo-Roussel) > Thématiques > Mécano-biologie du tissu élastique > Mechanobiology of elastic tissues
Project leader : R. Debret
Persons involved in the project : J. Sohier, J. Decorps, P. Sommer, C. Mainzer, C. Lorion, J. Vial, A. Josset-Lamaugarny, G. Aimond, D. Benzoni, D. Sigaudo-Roussel, J.L. Saumet
It is now established that the cells are sensitive to surrounding forces and are able to convert mechanical signals into a biochemical response : mechanotransduction. However, cells use various mechanisms to respond to mechanical forces, according to their type, environment, ageing, and these mechanisms are far from being fully understood.
Among the components of the extracellular matrix (ECM), the elastic fibres provide elastic rheological properties of tissues in all vertebrates, but also modulate cell proliferation and differentiation within those tissues. After growth (20 years), the progressive degradation of elastic fibres is not offset by a neosynthesis of functional fibres. Visually, the most striking feature of this degradation is probably the appearance of wrinkles on the skin, while the most harmful consequence is the alteration of cardiovascular and pulmonary functions.
Neosynthesis and assembly of elastic fibres
In a previous study regarding the cutis laxa syndrome (progeroïd genetic disease) we demonstrated that downregulation of LOXL1 gene was due to promoter hypermethylation preventing the binding of the transcription factor Sp- 1 in the -494/-323 region. This hypermethylation could be linked to an abnormal DNA-methyltransferase activity (DNMT) since the use of an inhibitor of DNMTs (5- aza -2’-deoxycytidine) rescues LOXL1 gene expression. More recently, we observed that a similar mechanism occurs in normal skin ageing.
So the research will focus on the regulatory mechanisms of DNMT activity targeting elastic fibres-related genes during skin ageing. This implicates basic research on the regulation of DNMT partners in skin cells, and the selection of active compounds able to modulate those mechanisms. Such pharmacological compounds will be tested in pathological cells (cutis laxa, Williams- Beuren) to provide a therapeutic solution for the symptomatic treatment of elastic deficit in genetic diseases
Development of synthetic matrices adapted to the biomechanical and elastic tissue engineering
Dozens of skin substitutes are available, mainly collagen-based matrices, with the same major drawback : they do not reproduce elastic properties of the native tissue. This absence of elasticity is driven by : (i) the ignorance of biological parameters leading to a functional elastogenesis in adult tissues ; and (ii) the absence of an adapted supportive matrix to bring a correct cell microenvironment in terms of elasticity and visco-elasticity. The DHERMIC project proposes a very important breakthrough to unlock some of these technological bolts and will provide a new generation of skin bio-substitutes integrating :
• An elastic behavior inspired from the human tropoelastin ;
• A “green”, simple and cheap synthesis process ;
• Easily adjustable mechanical parameters to mimic different kind of tissues.
If successful, the hybrid elastic biomaterial delivered by the consortium will provide dramatic advances in terms of public health by improving severe burns care and age-related chronic wounds healing. Thanks to the in vitro modelling, this new skin substitute will initiate a dynamic research on rare diseases related to connective tissues defects and for which no treatment exists at the present time.
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