Induction of coronary ateriogenesis by reprogrammed cells

重编程细胞诱导冠状动脉生成

• 批准号: 8367620
• 负责人: Liya Yin
• 金额: $ 45.48万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8367620
• 关键词: Adipocytes; Adopted; Animal Model; Autologous; Back; Beryllium; Biological; Blood Vessels; Bone Marrow Stem Cell; Cardiac Myocytes; Cell Therapy; Cells; Clinical Trials; Commit; Coronary; Coronary heart disease; Data; Disease; Embryo; Endothelial Cells; Ethics; Fibroblasts; Free Radical Scavenging; Functional disorder; Generations; Goals; Growth; Health; Heart; Heart Diseases; Hepatocyte; Human; Hyperinsulinism; Hypertriglyceridemia; Hypoxia; Impairment; Infarction; Insulin Resistance; Ischemia; Legal; Literature; Mature B-Lymphocyte; Medical; Medicine; Metabolic syndrome; Modeling; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Obesity; Operative Surgical Procedures; Oxidative Stress; Pancreas; Patients; Phenotype; Pre-Clinical Model; Procedures; Process; Rattus; Regenerative Medicine; Reporting; Signal Transduction; Smooth Muscle Myocytes; Somatic Cell; Source; Stem cells; Sudden Death; Testing; Tissues; Transplantation; Umbilical Cord Blood; Vascular Endothelial Growth Factors; Western World; base; cell type; design; high risk; induced pluripotent stem cell; keratinocyte; nerve stem cell; outcome forecast; pluripotency; prevent; progenitor; regenerative therapy; transcription factor; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述(申请人提供)：再生医学在治疗缺血性心脏病方面具有巨大的潜力，但到目前为止，许多临床试验的结果喜忧参半。尽管这些不同发现的原因尚未解决，但这可能与治疗的理想细胞类型(S)尚未使用的想法有关。诱导多能细胞(IPSCs) 显示出希望，因为它们可以是自体的，但它们存在潜在的肿瘤形成问题。为了绕过这个问题，我们推断，将细胞部分重新编程为祖细胞类型的细胞，而不是多能性细胞，将减少肿瘤形成的机会；但仍可使其应用于再生治疗。在我们的模型中，我们选择将内皮细胞部分重新编程为诱导的血管祖型(IVPC)细胞，以刺激冠状动脉侧支生长。我们的目的是创建IVPC，它将继续致力于血管谱系，作为生长血管的关键组件。我们推测，这些细胞比完全重新编程的IPSCs更能刺激冠状动脉侧枝生长，因为后者可以分化为除血管谱系以外的各种细胞类型。我们的目标是在肥胖和胰岛素抵抗的大鼠模型中测试iVPC是否可以刺激冠状动脉侧支生长，这种模型的表型是侧支生长受损。我们之所以选择这一模型，是因为代谢综合征患者发生缺血性心脏病的风险很高，其中近30%~40%的患者冠状动脉侧支生长很少或没有。重要的是，冠状动脉侧支发达的患者比侧支发育不良的患者从心肌梗死中恢复的预后更好。因此，这项提案的首要目标是建立基于细胞的疗法。 在以心脏侧支循环不良为特征的临床前模型中，这会刺激冠脉侧枝生长。在这一背景下，我们有两个目标。在AIM 1中，我们将通过对大鼠内皮细胞的部分重编程来确定导致诱导血管祖细胞(IVPC)产生的条件。我们的方法将侧重于了解部分重新编程的机制，然后利用特定的战略来复制部分重新编程过程。在目标2中，我们将确定在肥胖和胰岛素抵抗的大鼠模型(Zucker肥胖肥胖大鼠[Zof])中，iVPC是否会增加冠状动脉侧枝生长。我们的方法将重点放在优化体外血管内皮细胞刺激ZOF大鼠冠状动脉侧支循环生长的能力的策略上。 公共卫生相关性：患有代谢综合征(以异常肥胖、高甘油三酯血症、胰岛素抵抗和高胰岛素血症为特征的疾病)的患者患缺血性心脏病的风险很高，其中近30%~40%的患者冠状动脉侧支生长很少或没有。重要的是，冠状动脉侧支发达的患者比侧支发育不良的患者从心肌梗死中恢复的预后更好。目前的提案将确定基于细胞的治疗是否可以在以心脏侧支循环较差为特征的临床前模型中刺激冠状动脉侧枝生长。