MR imaging of stem cell-gene therapy of atheroscleroses

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DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease is a unique illness with multiply-located and diffusely-fashioned, as well as differently-staged plaques, that can involve the entire body. To date, there are no established methods available for either early diagnosis or efficient treatment of multiple/diffuse atheroscleroses. Recent studies have confirmed that the migration of bone marrow cells can give rise to vascular progenitor cells that home in the damaged vessels and differentiate into either endothelial cells or smooth muscle cells in various models of atherosclerotic lesions. The transfused hematopoietic stem-progenitor cells (SC) are strictly restricted to atherosclerotic plaques, which accelerates re-endothelialization and thereby reduces neointima formation. This concept, "plaque-specific trafficking of hematopoietic SCs," motivated us to develop a new technology using MR imaging to monitor and guide plaque-specific, stem cell-mediated early diagnosis and therapy of multiple/diffuse atheroscleroses. In the current proposal, we will develop two novel techniques: (a) plaque-specific, SC-mediated MR imaging of early multiple/diffuse atheroscleroses by creating magnetically-labeled stem cells that traffic/target specifically the multiple/diffuse plaques; and (b) MR imaging-guided, plaque-specific, SC-mediated gene therapy of multiple/diffuse atheroscleroses by transducing a therapeutic gene to the magnetically-labeled stem cells that traffic/target specifically the multiple/diffuse plaques. The principles of these two novel technical developments will be first tested and proved in a series of in vitro and in vivo experiments with hematopoietic bone marrow stem cells of donor mice and atherosclerotic models of recipient mice using molecular MR imaging. Subsequently, the two novel techniques will be validated in a preclinical setting using near human-sized Yucatan pig models with multiple/diffuse atheroscleroses under clinical MR imaging. We firmly believe that the success of this project will open up new avenues for the future efficient management of cardiovascular ischemic disorders in humans using MR imaging-based, stem cell-mediated vascular gene/drug therapy. (End of Abstract)