Stem Cell Induction of Coronary Arteriogenesis

描述(由申请人提供)：本申请涉及广泛的挑战领域，(11)再生医学，和特定的挑战主题，“11-HL-101，开发基于细胞的治疗心血管、肺和血液疾病。”基于细胞的疗法催生了再生医学这一新兴学科，并为推进患者护理提供了新的范式。尽管有这种潜力，迄今为止，基于细胞的治疗心肌梗死的结果仍然存在争议，一些是积极的，一些是负面的，甚至是一些有害的结果。我们认为，干细胞治疗急性心肌梗死可能不是最有效的再生疗法，而刺激冠脉侧支生长是最有可能在治疗缺血性心脏病方面产生立竿见影效果的策略。冠状动脉侧支的生长可以预防猝死和心肌梗死。此外，刺激侧支生长是一个比在梗死区重建心肌更简单的目标，在梗死区，必须重建完整的动脉、毛细血管和静脉血管系统，以及作为功能性和电性联合体的肌细胞和传导系统。尽管存在这一问题，但就某些细节而言，临床研究可能为时过早，例如，最有希望的目标患者群体、使用的最佳细胞类型和数量、最佳分娩方法和时机尚未优化。在这一挑战领域的背景下，在这一应用中，我们建议通过确定哪种类型的干细胞最好地促进心脏中的冠脉侧支生长、心脏中有利于促进侧支生长的条件，以及最后，一种使干细胞抵抗氧化应激以促进其存活并增强其在存在氧化应激的血管疾病模型中的生物学效应的方法，来扩展干细胞治疗的实际方面。具体地说，我们提出了3个目标：1)确定哪种类型的成人干细胞最能刺激冠状动脉侧枝生长。2)确定有利于干细胞刺激侧枝生长的心脏条件。3)确定选择抗氧化应激的干细胞是否会比未选择的干细胞更好地刺激血管疾病中的冠脉侧支生长。这些目标建立在一个跨学科团队的基础上，该团队具有从病毒学、胚胎干细胞研究、分子生物学、生物化学、生理学和血管生物学的经验。 公共卫生相关性：基于细胞的疗法治疗心肌梗死的结果存在争议，有的是积极的，有的是负面的，甚至是有害的。然而，我们认为，干细胞治疗急性心肌梗死可能不是再生疗法的最有效使用，而刺激冠状动脉侧枝生长可能是最有可能在再生疗法治疗缺血性心脏病中产生立竿见影效果的策略。我们的目标是确定哪种成人干细胞，以及在什么特定条件下，最能刺激心脏中的冠脉侧支生长。

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area, (11) Regenerative Medicine, and specific Challenge Topic, "11-HL-101, Develop cell-based therapies for cardiovascular, lung, and blood diseases." Cell-based therapies have spawned the emerging discipline of regenerative medicine and offer new paradigms for advancing patient care. Despite this potential, to date the outcomes of cell- based therapies to treat myocardial infarction are controversial with some positive, some negative, and even some detrimental results. We opine that treatment of acute myocardial infarction with stem cells may not be the most effective regenerative therapy rather stimulation of coronary collateral growth is the most likely strategy to produce an immediate benefit in the treatment of ischemic heart disease. The growth of coronary collaterals could prevent sudden death and myocardial infarction. Moreover, stimulation of collateral growth is a simpler goal than rebuilding myocardium in an infarct zone, where a complete arterial, capillary, and venous vasculature must be rebuilt along with myocytes and a conductible system working as a functional and electrical synctium. Notwithstanding this issue, in some regards the clinical studies may be premature insofar as several details, e.g., the most promising target patient population, the best cell type and number of cells to use, the optimal methods and timing of delivery have not yet been optimized. Within the context of this Challenge Area, in this application we propose to expand on practical aspects of stem cell therapies by determining which type of stem cell best promotes coronary collateral growth in the heart, the conditions in the heart that are conducive to promote collateral growth, and finally, a method to render stem cells resistant to oxidative stress to promote their survival and enhance their biological effect in models of vascular disease with existing oxidative stress. Specifically we propose 3 aims: 1) To determine which type of adult stem cell best stimulates coronary collateral growth. 2) To determine the conditions of the heart that are conducive for stem cell stimulation of collateral growth. 3) To determine if stem cells selected for resistance to oxidative stress will better stimulate coronary collateral growth in vascular disease than non-selected cells. These aims are built upon an interdisciplinary team with experience ranging from virology, study of embryonic stem cells, molecular biology, biochemistry, physiology, and vascular biology. PUBLIC HEALTH RELEVANCE: The outcomes of cell-based therapies to treat myocardial infarction are controversial with some positive, some negative, and even some detrimental results. However, we opine that treatment of acute myocardial infarction with stem cells may not be the most effective use for regenerative therapies, rather stimulation of coronary collateral growth is likely the most likely strategy to produce an immediate benefit in the treatment of ischemic heart disease using regenerative therapies. Our goals are to determine which adult stem cell, and under what specific conditions, best stimulates coronary collateral growth in the heart.