Bone Marrow Angioblasts For Cardiac Regeneration

骨髓成血管细胞用于心脏再生

• 批准号: 6570015
• 负责人: SILVIU ITESCU
• 金额: $ 24.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570015
• 关键词: ACE inhibitors; angiogenesis; beta antiadrenergic agent; bone marrow; cardiac myocytes; cell migration; cell proliferation; chemokine; clinical research; cytokine receptors; disease /disorder model; echocardiography; heart failure; heart function; histology; human tissue; intermolecular interaction; laboratory rat; mesenchyme; model design /development; myocardial infarction; myocardial ischemia /hypoxia; regeneration; stem cells

DESCRIPTION (provided by applicant): Congestive heart failure remains a major public health problem, and is frequently the result of left ventricular remodeling after myocardial infarction. We have recently shown that human adult bone marrow contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to induce infarct bed neovascularization after experimental myocardial infarction. The induction of neovascularization in the peri-infarct period results in protection of cardiomyocytes against apoptosis, induction of cardiomyocyte proliferation and regeneration, long-term salvage and survival of viable myocardium, prevention of left ventricular remodeling and sustained improvement in cardiac function. Our striking observation that neovascularization of acutely ischemic myocardium results in regeneration of endogenous cardiomyocytes suggests that a similar process could be induced in myocardium exposed to chronic ischemia, however no information exists to date regarding whether bone marrow-derived angioblasts could reverse established heart failure and myocardial fibrosis. If similar effects could be achieved by angioblast infusion in an animal model of chronic ischemia and established ventricular remodelling and scarring, this would provide a potential new therapeutic modality for the treatment of established heart failure. In the first aim of this proposal we will specifically establish an animal model of chronic heart failure following ischemia and investigate whether angioblast-dependent neovascularization can result in myocardial regeneration and improvement in cardiac function. In the second aim, we will examine the role of specific CXC chemokines in angioblast migration to chronically ischemic myocardium. We will then seek to develop strategies that enable manipulation of interactions between CXC chemokines and their receptors in order to increase selective angioblast trafficking to chronically ischemic myocardium, promote vasculogenesis, and augment myocardial regeneration and functional improvement. In the final aim we will evaluate whether concomitant use of bone marrowderived angioblasts together with autologous mesenchymal stem cells or pharmacologic agents may provide synergistic, additive benefit in terms of cardiomyocyte regeneration and cardiac function. We believe that gaining an understanding of these issues will prove to be of critical importance in order to be able to rationally design and develop strategies for human clinical trials using autologous bone marrow-derived endothelial progenitors in the treatment of chronic heart disease.

描述（由申请人提供）： 充血性心力衰竭仍然是一个主要的公共卫生问题，并且经常是心肌梗塞后左心室重塑的结果。我们最近表明，人类的成年骨髓包含具有胚胎血管细胞表型和功能特征的内皮前体，并且这些特征可用于在实验性心肌梗塞后诱导梗死床新血管形成。侵入周期内新血管形成的诱导导致心肌细胞免受凋亡，心肌细胞增殖和再生的诱导，长期拯救和可行心肌的存活，预防左心室重塑以及心脏功能的持续改善。我们对急性缺血性心肌的新血管形成导致内源性心肌细胞再生的惊人观察表明，在暴露于慢性缺血的心肌中可以诱导类似的过程，但是迄今为止，关于迄今为止，关于骨髓骨髓骨髓骨骼失败的血管损伤是否可以反转心脏失败的心脏失败和肌膜。如果血管细胞输注在慢性缺血动物模型并确定的心室重塑和疤痕中可以实现类似的影响，这将为既定心力衰竭的治疗提供一种潜在的新治疗方式。在本提案的第一个目的中，我们将专门建立一个慢性心力衰竭的动物模型，并研究血管细胞依赖性的新生血管形成是否会导致心肌再生和心脏功能的改善。在第二个目标中，我们将研究特定的CXC趋化因子在血管细胞迁移到慢性缺血性心肌中的作用。然后，我们将寻求制定能够操纵CXC趋化因子及其受体之间相互作用的策略，以增加选择性的血管细胞运输到慢性缺血性心肌，促进血管生成和增强心肌再生和功能改善。在最终目的中，我们将评估同时使用骨髓衍生的血管细胞以及自体间质干细胞或药理学剂是否可以在心肌细胞再生和心脏功能方面提供协同的，添加剂的好处。我们认为，了解这些问题将被证明至关重要，以便能够使用自体骨髓衍生的内皮祖细胞在治疗慢性心脏病的治疗中为人类临床试验制定策略。