Development of a Cell-Based Therapy to Improve Recovery Following Immobilization

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ABSTRACT Long-term immobilization or extended bed rest following severe injury or disease can initiate rapid and significant loss of skeletal muscle mass and function. Recovery may be slow and long-term disability is a potential outcome, particularly in older adults. Physical rehabilitation is commonly prescribed for individuals subjected to long-term bed rest, yet mobility may be severely compromised in older adults and intensity of movement may not be sufficient to facilitate full recovery. Thus, novel regenerative therapies are necessary to maximize positive outcomes associated with rehabilitation to prevent or treat long-term disability associated with immobilization in older adults. Pericytes are multipotent stem cells that reside around microvessels and capillaries and provide important structural and paracrine support necessary to regulate vessel permeability, vessel diameter and blood flow, endothelial cell proliferation, and stabilization of newly formed capillaries. Data from our laboratory demonstrate that perivascular stem and stromal cells are highly sensitive to biophysical cues in the niche, and that pericyte transplantation in combination with a physiological stimulus (exercise) can promote the release of regenerative growth and neurotrophic factors that positively influence skeletal muscle repair, growth, and strength. Thus, pericytes represent a clinically relevant cell source to expedite recovery of muscle mass and strength following a short or prolonged period of immobilization. The specific objective of this proposal is to exploit the mechanosensing properties of pericytes for the purpose of developing a new and exciting cell-based skeletal muscle rehabilitation strategy. Our central hypothesis is that there are pericyte subpopulations in skeletal muscle that are divergent in their response to a mechanical stimulus and uniquely assist with the recovery of muscle mass and strength following remobilization. Thus, this work seeks to: 1) determine the impact of mechanical strain on pericyte function, 2) determine the contribution of pericytes to skeletal muscle mass recovery following a period of immobilization in mice, and 3) develop a pericyte-derived exosome-based therapy for skeletal muscle recovery following a period of immobilization in mice. The work is highly innovative given the potential to identify a specific perivascular stem/stromal cell source with exceptional potential to recover skeletal muscle mass and function following a period of immobilization. The proposed work is significant because it is expected to create a superior pre-clinical strategy that can prevent and/or treat age-related disabilities, improving the quality of life for our growing aged population and reducing burden on the US healthcare system.