Ablation of FAP+ stromal cells impairs endogenous revascularization during hind limb ischemia
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Stromal cells have long been studied for their putative role in maintaining tissue homeostasis, driving tissue remodeling processes during injury, and modulating inflammation by synergizing with immune cells. Studying the pathophysiological role of these stromal cells and their function within an animal has been less developed. Cell ablation animal models have recently emerged as a unique tool for analyzing the in vivo function of cells and have been utilized by researchers to perform “loss-of-function” studies. In this thesis, we used the FAPDM2 diphtheria toxin receptor-mediated conditional cell knockout (TRECK) model to study the role of stromal cells in their vascular function during limb ischemia. This transgenic model identified FAP+ tissue-resident stromal cells and by injecting diphtheria toxin, we observed a significant depletion of FAP+ stromal cells in both the bone marrow and skeletal muscle of ablated mice, as well as a phenotype of weight loss and increased expression of atrophy-related genes. Furthermore, during a hind limb ischemia (HLI) injury model, we found that FAPablated mice exhibited a phenotype of attenuated and impaired revascularization of blood flow to the paw, indicating that this stromal cell subtype plays a key role in the endogenous revascularization ability of the animal. Attempts at rescuing were performed by exogenously delivering murine bone marrow-derived stromal cells into the skeletal muscle following ischemia; however, we found that this was not sufficient in repairing the observed vascular phenotype, indicating that while FAP+ stromal cells play a role in the animal’s endogenous ability to revascularize ischemic tissues, the exogenous administration of stromal cells to counteract and ameliorate this phenotype was not sufficient.
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