Uncovering the influence of niche biomechanics on satellite stem cell fate

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A skeletal muscle contains aligned, cylindrical muscle fibres formed by the fusion of cells during development. Adult skeletal muscles possess self-healing properties due to a small number of tiny cells sprinkled within the tissue that sit atop each muscle fibre and are covered by a thin sheet of proteins known as the basement membrane. By virtue of this anatomical positioning, or niche, these satellite' stem cells (SCs) reside in a three-dimensional environment where the protein milieu at their fibre and basement membrane surfaces are distinct. Ongoing studies by others show that the polarized nature of biomolecules in the SC niche is important for regulating their behavior. In parallel, our lab engages multidisciplinary collaborators to define and offer niche biomechanical stress as an additional polarized feature of the niche that, together with biomolecules, regulates SC behavior. ******Skeletal muscles move. We expect that when the muscle fibres contract and relax, that the fibre-associated surface of an SC experiences pushing and pulling forces. By virtue of the closely packed and aligned nature of muscle fibres, the basement membrane-associated surface of an SC is expected to experience squishing forces. We hypothesize that breaking this mechanical homeostasis, as would occur when a muscle is injured, is a direct and localized means to call SCs to reparative action by physically engaging cell surface proteins. ******In local and international collaborations and lab exchanges, our trainees will work closely with experts in biophysics, microscopy, FRET-based tension sensors, and membrane protein biology to test our hypothesis. We will quantify myogenic cell pulling forces in engineered two-dimensional culture microenvironments to define force generation maxima when the cells are unfettered by a third dimension. We will quantify the degree to which SCs are adhered to their niche and identify key membrane proteins contributing to this attachment. Lastly, we will demonstrate that breaking mechanical homeostasis in a living muscle tissue directly engages membrane proteins that push SCs out of slumber to begin repairing tissue damage. ******This research will advance fundamental knowledge about SC biology by gazing at the niche through a new lens. Our trainees will gain skillsets in the physics and mathematics of niche stresses, in hi-resolution microscopy, and in stem cell biology, while building a vast scientific network, and thereby poising them for careers in academia, medicine, or industry. **