Direct reprogramming to endothelial cells for the treatment of ischemic diseases
Over 8 million people in the US suffer from peripheral arterial disease (PAD). PAD causes leg pain, ulcers, and gangrene formation due to narrowing of the vessels in the arms and legs. PAD is associated with diseased endothelial cells that occupy the inner lining of blood vessels. Cell therapy approaches to restore blood flow to the leg by generating new vessels is promising. We propose to improve the generation of functional endothelial cells by direct reprogramming using chemical compounds in a safe and efficacious manner. These “induced endothelial cells” (iECs) will be evaluated for their ability to function like native endothelial cells. After optimization of iEC generation, we will develop reproducible scale-up method of the cells using standards that meet the requirements of clinical trials. We anticipate our proposed studies will have tremendous impact on cardiovascular health and regenerative medicine.
Over 8 million people in the US suffer from peripheral arterial disease (PAD). PAD causes leg ischemia due to atherosclerotic occlusive disease, and may cause intermittent claudication, ulceration and gangrene. A feature of PAD is dysfunction or damage to the vascular endothelium, a layer of endothelial cells (ECs) that exerts control over vascular reactivity, remodeling and angiogenesis. Cell-based approaches to restore or regenerate the endothelium so as to enhance the formation of neovessels hold promise for the treatment of PAD. In order to obviate the possibility of teratoma formation associated with pluripotent stem cells, an emerging paradigm is direct reprogramming of somatic cells into induced ECs (iECs) without genetic modification. Therefore, the broad objective of this work is to utilize small molecule-based approaches to develop a highly efficient and reproducible approach to generate iECs with high fidelity to endothelial phenotype and genotype. A high yield, high speed direct reprogramming protocol will enhance the clinical feasibility of an autologous iEC therapy. Accordingly, California will be the main beneficiaries in the treatment of PAD using safe and autologous iECs. Furthermore, this research will stimulate the development of businesses interested in developing iEC therapy for other ischemic diseases, thus providing important economic revenue and resources to California.