Abstract 909: IGF-1 and HGF Promote the Engraftment of Cardiac Stem Cells, which in Turn Regenerate the Entire Coronary Vasculature and the Dead Myocardium after Infarction in Rats
Coronary artery disease is the major cause of cardiac failure in the Western world and accounts for 500,000 cases of bypass surgery per year in the United-States alone. To date, there is no alternative to bypass surgery for severe coronary atherosclerosis, which increases with age and dramatically affects the elderly population. Therefore, we tested whether c-kit-positive cardiac stem cells (c-kit-CSCs), which have the ability to differentiate into smooth muscle and endothelial cells, are capable of creating large, functionally competent coronary vessels, which bypass the region of occlusion and reestablish blood flow to the distal myocardium. For this purpose, c-kit-CSCs, or c-kit-CSCs activated with IGF-1 and HGF prior to their therapeutic use were injected above, laterally and below the site of occlusion of the main left descending coronary artery. Non-activated c-kit-CSCs did not engraft within the myocardium and died by apoptosis, disappearing completely in approximately 2 weeks. Conversely, a relevant fraction of implanted IGF-1-HGF treated c-kit-CSCs home to the myocardium and were present at 12, 24 and 48 hours. Cell engraftment required the expression of the junctional and adhesion proteins connexin 43 and 45, N- and E- cadherin, and L selectin. Engrafted c-kit-CSCs divided and differentiated, and never experienced apoptotic death, which was restricted to non-engrafted cells. CSCs formed rapidly conductive and intermediate-sized coronary arteries, and subsequently small resistance arterioles and capillary profiles. This process took place over a period of one month. The new vessels were connected with the primary coronary circulation so that they increased the vascularization and blood flow to the infarcted heart. Also, from 2 weeks to 1 month, the infarct was replaced by a significant amount of regenerated myocardium, which reduced the original infarct by 35%. Together, these beneficial effects interfered with the development of post-infarction dilated myopathy improving cardiac function. In conclusion, locally delivered activated c-kit-CSCs generate de novo coronary vasculature and myocardium, so that they might be implemented clinically as an option to bypass surgery for restoration of blood supply to the ischemic heart.