Metabolic regulation of cardiac stem cells

 描述(由申请人提供)：在美国，缺血性心脏病是导致死亡的主要原因，占死亡人数的八分之一。虽然一些实验和临床研究表明，CSC移植后心脏功能有所改善，但这些细胞的治疗效果可能会受到肥胖和糖尿病等共病条件的限制。在美国，很大比例的心力衰竭患者患有2型糖尿病(T2D)；然而，我们不了解与肥胖和糖尿病相关的代谢失调如何影响CSC治疗。我们的初步数据显示，CSCs保持着相对较高的糖酵解率，尽管它们表达功能性的胰岛素受体，但它们的葡萄糖运输不受胰岛素的调节。结果，在高血糖期间，它们的糖酵解活性增加，CSC治疗肥胖-高血糖小鼠的疗效减弱。我们还发现，糖尿病小鼠长期暴露在高血糖下会上调CSC的糖酵解，并阻止CSC的增殖和分化。此外，将糖尿病CSCs移植到非糖尿病小鼠体内似乎会加重梗塞引起的心力衰竭。基于这些观察，我们认为过度的糖酵解促进干细胞休眠，阻止分化，并降低CSCs的修复能力。为了验证这一假设，我们将：(1)确定糖酵解活性的实验调节如何影响CSC功能；(2)阐明糖尿病影响CSC的机制；以及(3)描绘糖酵解对糖尿病小鼠CSC治疗的贡献。该项目的结果将确定调节CSC功能和能力的关键代谢途径，并阐明它们如何受到糖尿病和胰岛素抵抗等疾病的影响。我们期望找出调节CSC治疗效果的特定代谢因素，并勾勒出加强CSC介导的心肌修复的代谢策略。这一认识将有助于促进糖尿病和非糖尿病患者细胞治疗方案的优化，并为正在进行的和未来的临床试验提供新的方向。

 DESCRIPTION (provided by applicant): Ischemic heart disease is a leading cause of mortality in the United States and accounts for 1 in 8 deaths. While several experimental and clinical studies have shown improvements in heart function after CSC transplantation, the therapeutic efficacy of these cells may be limited by co-morbid conditions, such as obesity and diabetes. In the US, a large percentage of patients with heart failure have Type 2 diabetes (T2D); however, we do not understand how metabolic dysregulation associated with the conditions of obesity and diabetes affect CSC therapy. Our preliminary data show that CSCs maintain relatively high rates of glycolysis, and although they express functional insulin receptors, their glucose transport is not regulated by insulin. As a result, their glycolytic activity increases during hyperglycemia, and the efficacy of CSC therapy is attenuated in obese-hyperglycemic mice. We have also found that prolonged exposure to hyperglycemia in diabetic mice upregulates CSC glycolysis and prevents CSC proliferation and differentiation. Moreover, diabetic CSCs transplanted into non-diabetic mice appear to worsen infarct-induced heart failure. Based on these observations, we propose that excessive glycolysis promotes stem cell dormancy, prevents differentiation, and diminishes the reparative capacity of CSCs. To test this hypothesis, we will: (1) determine how experimental modulation of glycolytic activity affects CSC function; (2) elucidate the mechanism by which diabetes affects CSCs; and (3) delineate the contribution of glycolysis to CSC therapy in diabetic mice. Results of this project will identify key metabolic pathways that regulate CSC function and competence and elucidate how they are affected by disease conditions such as diabetes and insulin resistance. We expect to identify specific metabolic factors that regulate the efficacy of CSC therapy and to delineate metabolic strategies to enhance CSC-mediated myocardial repair. This understanding will help facilitate the optimization of cell therapy protocols for both diabetic and non-diabetic patients and provide new direction to ongoing and future clinical trials.