Mekaanisten voimien välityksen rooli solu-solu liitoksissa ihon kehityksessä ja ihoesteen muodostuksessa

Le résumé fourni par la source

The formation and homeostatic maintenance of a functional skin epidermal barrier is fundamental for organismal survival, protecting against dehydration and environmental insults while preserving tissue homeostasis. Proper barrier formation and maintenance in a self-renewing tissue such as the epidermis requires the integration of mechanochemical cues that regulate formation and stability of cell adhesions as well as cell dynamics. However, the molecular mechanism by which these processes are coordinated and integrated with the molecular machinery that senses and interprets dynamics changes in cell extrinsic and intrinsic forces remain largely elusive. In addition, the relevance of these processes in intact tissue contexts has not been extensively investigated. In this thesis, I use in vitro and in vivo approaches coupled to high resolution fluorescence microscopy and biophysical measurements to elucidate the function and physiological relevance of two complementary mechanosensory systems that govern skin epidermal morphogenesis and barrier formation through the coordinated regulation of adhesion integrity and proliferation balance. First, I demonstrate that the mechanosensitive ion channel Piezo1 plays a crucial role in the maturation of intercellular adhesions into functional, continuous junctions. Piezo1 deletion impairs the balance of cell surface mechanics, leading to delayed maturation and mechanical stability of intercellular junctions in vitro. Notably, Piezo1 function becomes particularly important in aged skin, where intrinsic changes in tissue mechanics render tight junctions unstable and compromise barrier integrity, highlighting a context-dependent role of Piezo1 in maintaining adhesions under mechanical stress. Second, as part of a collaborative work, I investigate the mechanisms by which a distinct, but interlinked pathway mediated by Plexin-B1/B2 transmembrane receptors, fine tunes proliferation of epidermal stem cells in response to crowding-induced mechanical compression. I observe that loss of B-plexins disrupts the ability of cells to sense and respond to compressive forces, leading to aberrant activation of the mechanotransducer Yes-associated protein (YAP). This leads to enhanced epidermal stem cell proliferation and tissue overgrowth during embryonic skin development. Our data highlights a central role of B-plexins in mechanosensation, coupling cell density to cell division. Together, these studies define a comprehensive framework for how the tension sensing and mechanical feedback coordinate adhesion maturation and proliferative restraint in skin keratinocytes. By identifying Piezo1 and B-plexins as key determinants of mechanoresponsive signaling, this thesis provides a new insight into the molecular understanding that synchronizes mechanical forces with epidermal barrier formation, tissue integrity and homeostasis.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.