Mechanotransduction of adipose stem cells implemented to soft tissue engineering – MecanoAdipo

Obesity affects about 10% of the world population and is the most prevalent cause of metabolic syndrome. Adipose growth in response to a high fat diet is mediated by two separate mechanisms: hypertrophy (increase in cell size) and hyperplasia (increase in cell number). Adipocytes are characterized by a unique ability for volume expansion upon triglyceride accumulation, increasing their size by more than 30-fold. Consequently, within fat pads, hypertrophic adipocytes generate a mechanical stress transmitted to resident cells including adipose stem cells. Moreover, it is recognized that a sedentary lifestyle potentiates the differentiation of adipocytes, whereas exercise (associated with dynamic loading modes of tissues) has the opposite effect. These two observations prompt us to revisit the influence of internally generated or externally applied mechanical stress on adipose growth. Is adipose hyperplasia driven by the mechanotransduction mechanisms of adipose stem cells?
Specifically, the MecanoAdipo project aims at: 1) elucidating the role of mechanical cues in adipose hyperplasia associated with obesity; 2) deciphering the molecular basis of adipose precursor cells mechanotransduction; 3) designing an optimal tissue engineering strategy for soft tissue grafting. Our approach synergistically combines in vitro and in vivo experimental strategies to explore the physiological relevance of Piezo1 in adipose stem cells. Aim 1 will be achieved by combining genetic manipulations in adipose precursor cells with micromechanical assays coupled to high resolution live optical microscopy on multicellular 2D and 3D culture systems. Aim 2 consists in dissecting the determinant mechanisms of adipose hyperplasia in an integrated multiscale manner from the molecular to the tissue scale. Guided by unambiguous preliminary findings, our working hypothesis postulates that the mechanosensitive ion channel Piezo1 might play a central regulatory role in the proliferation and/or differentiation of adipose precursor cells, impacting adipogenesis. Piezo 1 has been shown to be implicated in mechanosensory transduction and is associated with a variety of clinical disorders. However, its possible role in body weight control remains to be investigated. Aim 3 relies on the development of 3D organoids of adipose precursor cells for implantation in mice, as a proof of concept for soft tissue engineering and regenerative medicine applications.
Our transdisciplinary consortium assembles the staff, knowledge, tools, facilities and collaborations required for a sustained, effective research program into the functional inference of Piezo1 in the mechanotransduction-mediated adipose hyperplasia. The MecanoAdipo program has the necessary technical ingredients for success plus the vision, the teamwork and laboratory commitment to sustain its progress with: i) biophysicists interested in bio-microfluidics and biophotonics for tissue engineering (P. Nassoy), ii) physiologists with recognized expertise in mechanosensitive ion channels and physiopathology (E. Honoré), and ii) mechano-biologists who pioneered the use of micropatterned model 2D tissues (B. Ladoux).
In brief, this rationalized and integrated collection of experimental data within the reach of our combined expertise, should allow us to gain important new insights into the mechanotransduction of adipose stem cells. We expect that our findings will pave the way for the discovery and development of new strategies, based on the pharmacological modulation of Piezo1, to impact obesity and to improve soft tissue engineering procedures.