Muscle homeostasis: role of the microvascular niche

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Background/rationale: During normal muscle homeostasis and repair, an inflammatory response is initiated to remove damaged myofibers. This is accompanied by robust angiogenesis to restore blood flow to the damaged muscle as well as activation of normally quiescent muscle-resident satellite cells (SCs) or other muscle progenitor cell populations (MPCs) that migrate to the site of injury to form new myofibers. However, a fundamental and unanswered question is how activated SCs/MPCs and endothelial cells (ECs) and pericyte/mural cells of the microvasculature interact following induction of an inflammatory response to facilitate efficient tissue repair. While a growing body of evidence implicates the Angiopoietin/Tie2 signaling pathway in this process, heterogeneity in microvascular cell populations and their relationships to hemodynamics and muscle repair is still poorly understood due to the limited ability of traditional immunhistological methods to examine these parameters at high resolution. Overarching goal: To implement and test a novel musclespecific stem/progenitor cell tracking system, developed by my group with past NSERC DG funding, in conjunction with advanced epifluorecence confocal/intravital microscopy (IVM) technologies to assess complex intercellular relationships during muscle repair. Short-term Aims: 1) To utilize our novel cell tracking system and advanced epifluorecence confocal microscopy/ IVM technologies to assess intercellular interactions between SCs/MPCs, ECs and pericyte/mural cells of the microvasculature, and inflammatory cells in organoid cultures established from our reporter gene transgenic (Tg) mouse model. 2) To assess modulation of: (a) SC/MPC activation; (b) microvasculature in organoid cultures established from Tg mice following induction or blocking of an inflammatory response. 3) To assess, as above for organoids, intercellular interactions between SCs/MPCs, microvasculature, and inflammatory cells at a site of injury in the intact hind limb muscle of Tg mice in vivo. Routine biomechanical tests will be conducted. 4) To assess modulation of stem/progenitor cells, microvasculature and inflammatory cells at a site of injury in the intact hind limb muscle of Tg mice in vivo. Biomechanical tests again to be conducted. Longterm Objective(s): to build on tool/animal model development by incorporating PET imaging to allow us to noninvasively assess homing/migration of these cell populations in living animals. Impact: Studies aimed at closing the clear gap in our current understanding of the relationship between muscle stem/progenitor cell homing, the vascular niche and inflammatory cells during normal muscle homeostasis and repair are essential to restore muscle mass and function when the natural ability of muscle for homeostasis and repair is exhausted or impaired. This requires development of leading edge, novel tools/animal models.