10. Stem Cells, Tissue Repair, and Cell Replacement in Aging. Clinical vein grafting is used to revascularize ischemic hearts and lower limbs. Although acute success is achieved in these procedures, an estimated 20-50% undergo stenosis within five years, caused by a hyperproliferation of neointimal cells. Experimental evaluation of new therapeutic directions has been conducted in exclusively young animal models, despite the prevalence of these clinical procedures in older patients and despite findings of age-associated differences in arterial injury-induced models of neointimal formation. The proposed study will evaluate the hypothesis that the extent of vein graft neointimal development varies with age. The experimental design will take advantage of the capacity for transplanting grafts between young and old animals, to discern local tissue effects from systemic (e.g., hormonal) effects. Furthermore, a transgenic mouse line -- Rosa26 mice, which constitutively express the beta-galactosidase reporter gene in all cells -- will be used to discriminate graft versus recipient cell sources of neointimal cells. The extent of neointimal formation will be compared histomorphometrically, with secondary evaluation of cell source through the reporter gene. Future studies based on this work will investigate the genetic basis of age-associated differences in neointimal proliferation through the use of knock-in and knock-out mouse models. Furthermore, the establishment of an age-associated model of vein grafting will permit age-specific evaluation of new therapeutic avenues for inhibiting neointimal formation.
