Harnessing endothelial cell transdifferentiation for cardiovascular therapy

Cardiovascular disease is the leading cause of death, so recent efforts have focused on using emerging genetic technologies to remediate cardiac and vascular pathologies. These efforts are largely based on a growing number of studies, including our preliminary data, that have observed transgene delivery to cardiac myocytes via intravenous injection of a viral vector. However, to date, there is no empirically backed rationale for any mechanism underlying this important finding. My lab has focused on the prospect of endothelial cell transdifferentiation for many years and accrued evidence that this process exists in adult mice and may be responsible for the homeostasis of diverse cell types. Our preliminary data coupled with our proposed approach will determine whether cardiac myocyte labeling is the result of a transdifferentiation event (endothelial cell or otherwise) or the product of extracellular vesicle transfer. This work will also confirm whether the source of this labeling is endothelial cells. We are also interested in determining the nature of intravenous transgene delivery to other cell types, which could yield information about the localization of endothelial cell transdifferentiation to discrete niches. The existence of such niches could have important implications for enhancing the vascular pathology of those regions. This work will be undertaken using separate state-of-the-art cell lineage tracing strategies that encompass virus, protein, and cell-based methods. The answers provided by this study will help guide efforts for cardiac genetic therapy, advance our understanding of endothelial cell biology, and provide potentially new insights into cardiovascular disease.