Regenerative medicine has great potential in treating ischemic heart disease, but to date, there have been mixed results in many clinical trials. Although the reasons for these disparate findings are not resolved, it could be related to the idea that the ideal cell type(s) for therapy has (have) not used. Induced pluripotent cells (iPSCs) show promise, because they can be autologous, but they suffer from the problem of potential tumor formation. To circumvent this problem, we reasoned that partially reprogramming cells to a progenitor-type cell, rather than to pluripotency, would reduce the chance for tumor formation;but still enable their application in regenerative therapies. In our model, we chose to partially reprogram endothelial cells to an induced vascular progenitor type (IVPC) cells to stimulate coronary collateral growth. Our purpose was to create the IVPC that would remain committed to a vascular lineage, which would serve as key components for growing blood vessels. We hypothesized that these cells would better stimulate coronary collateral growth than fully reprogrammed iPSCs because the latter can differentiate into various cell types other than vascular lineage. Our goal is to test if iVPCs can stimulate coronary collateral growth in a rat model of obesity and insulin resistance, which has a phenotype of impaired collateral growth. The reason we choose this model is that patients with metabolic syndrome have high risk of ischemic heart diseases and nearly 30~40% of these patients show little or no coronary collateral growth. Importantly, patients with well-developed coronary collaterals have a better prognosis in recovering from a myocardial infarction than those with poorly developed collaterals. Accordingly the overarching goal of this proposal is to establish cell-based therapies that stimulate coronary collateral growth in a pre-clinical model characterized by poor collateralization in the heart. Within this context, we have two aims.
In aim1 we will determine conditions leading to generation of induced vascular progenitor cells (iVPCs) by partial reprogramming of rat endothelial cells. Our approach will focus on understanding the mechanisms of partial reprogramming and then utilizing specific strategies to replicate the partial reprogramming process.
In aim 2, we will determine if iVPCs will augment coronary collateral growth in a rat model of obesity and insulin resistance (Zucker Obese Fatty rat [ZOF]). Our approach will focus on strategies to optimize the capability to iVPCs to stimulate the coronary collateral growth in ZOF rat.
Patients with metabolic syndrome (a condition characterized by abnormal obesity, hypertriglyceridemia, insulin resistance and hyperinsulinemia) have a high risk of ischemic heart disease and nearly 30~40% of these patients show little or no coronary collateral growth. Importantly, patients with well- developed coronary collaterals have a better prognosis in recovering from a myocardial infarction than those with poorly developed collaterals. The current proposal will establish if cell based therapies can stimulate coronary collateral growth in a pre-clinical model characterized by poor collateralization in the heart.
|Pung, Yuh Fen; Sam, Wai Johnn; Stevanov, Kelly et al. (2013) Mitochondrial oxidative stress corrupts coronary collateral growth by activating adenosine monophosphate activated kinase-* signaling. Arterioscler Thromb Vasc Biol 33:1911-9|