MOLECULAR and INTEGRATIVE MECHANOBIOLOGY

Présentation

Mechanobiology concerns the role of force in development, physiology, and diseases ^1,2. Our team focuses on the molecular mechanisms by which cells sense and respond to mechanical signals. Some cells in the body are specialized for sensing a specific type of mechanical input: for instance touch sensitive sensory dorsal root ganglion neurons or hair cells in the inner ear. However, all cells of the organism (even non-specialized cells) are mechanosensitive (MS) and can respond to mechanical stress by adaptive responses. A variety of molecular players are involved in cellular mechanotransduction including: the extracellular matrix, adhesion molecules, ion channels,  cytoskeletal elements, nuclear proteins, transcription factors, enzymes, as well as numerous other molecular structures and signaling molecules. It is now well recognized that changes in cellular mechanotransduction significantly contribute to the development of severe pathologies, including atherosclerosis, hypertension, heart failure and cancer. Notably, mechanotherapy is being progressively introduced for clinical use, as for instance in reconstructive medicine.

Collectively cells respond to local mechanical stress by activation of specific molecular pathways resulting in macroscopic changes at the organ level. For instance resistance arteries (small diameter) respond to hypertension by a major structural remodeling caused by the repositioning of arterial smooth muscle cells around a smaller lumen diameter (inward eutrophic remodeling). Hypertensive arterial remodeling allows a normalization of the parietal tension because of an increase in wall thickness (although without hypertrophy) and a reduced arterial diameter. Thus, wall tension is restored to a normal level, despite an increase in luminal pressure [Laplace’s law]. We aim at identifying the sensors and effectors that are involved in these specific adaptive responses to chronic mechanical stress [although these can become maladaptive when hypertension is maintained]^3,4.

Our group has been focusing on the role of ion channels in cellular mechanotransduction for the last 20 years. MS ion channels (i.e. gated by force) are conserved throughout evolution and are already present in microbes, yeast and plants. For instance, osmotic down-shock opens bacterial MS ion channels, such as the large non-selective conductance MscL, allowing osmolyte efflux, relieving pressure and preventing cell lysis ⁵. Additional studies performed on bacterial MS channels have provided strong evidence that its conformation is directly dependent on tension in the lipid bilayer (for review ⁶). Our team members discovered, for the first time, the molecular identity of a mammalian MS ion channel ⁷ (and for review ⁸). We reported that the K_2P channel TREK-1 is a MS K⁺-selective ion channels, directly activated by force generated in the lipid bilayer, as confirmed by more recent structural data and reconstitution experiments ^7-30. Opening of TREK/TRAAK channels in response to mechanical stress (shear stress, membrane stretch or cell swelling) causes cell hyperpolarization leading to a decrease in cell excitability (for review ⁸).

The identity of the non-selective depolarizing MS cationic channels was discovered in 2010 by the Patapoutian group ³¹. Piezo1 is a large trimeric complex, with an N-terminal mechanotransduction module followed by a C-terminal ionic pore ^32,33. Functional reconstitution experiments with purified Piezo1, as well as electrophysiological recordings indicate that membrane tension is the common activating force acting on Piezo1 gating ^34-37. Piezo1 was shown by our group and others to be required for vascular development, flow-mediated dilatation and arterial remodelling ^4,38-40, while Piezo2 plays a key role in mechanosensory transduction, in particular light touch sensitivity and proprioception ^41-45.

Notably, Piezo1/2 are implicated in a variety of rare genetic disorders, including xerocytosis (dominant Piezo1 gain-of-function mutations; GOF), lymphatic dysplasia (recessive Piezo1 loss-of-function mutations; LOF), arthrogryposis (dominant Piezo2 GOF) and muscular atrophy with scoliosis and perinatal respiratory distress (recessive Piezo2 LOF)⁴⁶.

We are currently focusing on four different projects concerning the role of Piezo1 in: 1) obesity; 2) hypertension; 3) atherosclerosis; 4) genetic resistance to malaria.

Expected global outcomes:

Our project is intrinsically pluridisciplinary and aggregates state-of-the-art biophysics, molecular and cellular biology, stem cells research, physiology and bio-engineering. This rationalized and integrated collection of experimental data should allow us to gain important new insights into the basic mechanisms of mechanobiology. We expect that our findings will pave the way for the discovery and development of new strategies, based on the pharmacological and/or mechanical modulation of force-gated ion channels, including Piezo1 (mechanotherapy).

External collaborators:

Serge ADNOT, Institut Mondor de Recherche Biomédicale, Créteil (France)

Ez-Zoubir AMRI, Institut de Biologie Valrose, Unica, Nice (France)

Fenja KNOPP, The University of Giessen (Germany)

Aziz MOQRICH, Institut de Biologie du Développement de Marseille (France)

Stefan OFFERMANNS, Max Planck Institute for Heart and Lung Research, Bad Nauheim (Germany)

Eileen PARKES, Matthew JACKSON and John CHRISTIANSON, University of Oxford (UK)

Ardem PATAPOUTIAN, The Scripps Research Institute, La Jolla, CA (USA)

Mario PENDE, Institut Imagine, Paris (France)

Jean-François TANTI, Laurent YVAN-CHARVET and Patrick AUBERGER, C3M Inserm, Unica, Nice (France)

Kai WENGELNIK, Dynamique des Interactions Membranaires Normales et Pathologiques, Montpellier (France)

Aimin XU, Yu WANG and Leo POON, The University of Hong Kong (China)