Résumé :
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The plasminogen activation (PA) system is a mechanism extensively used by the cell for the generation of proteolytic activity in the extracellular matrix, where it contributes to tissue remodeling in a wide range of physiopathological processes. Increasing evidence is accumulating on the important roles of plasminogen activators, their inhibitors and cognate receptors in the homeostasis of muscle fibers and their surrounding extracellular matrix. The development of mice deficient for the individual components of the PA system has enlightened their proposed muscle functions in vivo. Skeletal muscle regeneration induced by injury has been analyzed in urokinasetype plasminogen activator (uPA)-, tissue-type plasminogen activator (tPA)-, plasminogen (Plg)- and plasminogen activator inhibitor-1 (PAI-1)-deficient mice and has demonstrated profound effects of these molecules on the fibrotic state and the inflammatory response, which contribute to muscle repair. In particular, the opposite roles of uPA and its inhibitor PAI-1 in this process are highlighted. On the other hand, PAI-1 is involved in adhesion and migration of endothelial cells, in the adipocyte differentiation and in response to insulin. In vivo, it facilitates thrombosis, fibrosis and tissue remodeling. Elevated levels of circulating PAI-1 is a biomarker of central obesity and is a prognostic factor for type 2 diabetes. The biological properties of PAI-1 led to the hypothesis that PAI-1 is directly involved in the development of several tissues. Our goal is to assess the specific roles of PAI-1, uPA and tPA in mouse ES cell differentiation towards the adipogenic and myogenic lineages. This experimental model allows investigating potential effects not only on terminal steps of the differentiation process, but, importantly, on the early proliferative events of this process. Gene and protein expression and activities of the various endogenous components of the PA system are analysed during the differentiation protocol from undifferentiated ES cells to the formation of adipocytes and spontaneous contractile myotubes. Striking variations in expression and activities of the various endogenous components of the PA system during ES cell differentiation towards the myogenic, and adipogenic lineages suggested an important biologic role. Furthermore, myogenesis is inhibited in ES cells treated by amiloride, a specific uPA inhibitor. Likewise, ES cell lines expressing stably and ectopically activated form of PAI under the control of an inducible expression system display inhibited myogenic and adipogenic capacities after induction of PAI-1.
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