Bone Marrow Angioblasts for Myocardial Vasculogenesis

骨髓成血管细胞促进心肌血管生成

• 批准号: 7076219
• 负责人: SILVIU ITESCU
• 金额: $ 39.91万
• 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: 2002-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076219
• 关键词: ACE inhibitors; aging; angiogenesis; autologous transplantation; beta antiadrenergic agent; bone marrow; cardiac myocytes; cell biology; cell migration; cell population study; cytokine receptors; flow cytometry; gene expression; heart function; histology; human subject; in situ hybridization; laboratory rat; longitudinal human study; myocardial infarction; myocardial ischemia /hypoxia; myocardium; patient oriented research; stem cell transplantation; stem cells; tissue /cell culture

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 progenitors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to induce vasculogenesis after experimental myocardial infarction. This results in decreased apoptosis of hypertrophied myocytes, long- term salvage and survival of viable myocardium, reduction in collagen deposition, and sustained improvement in cardiac function. Thus, the use of cytokine-mobilized autologous human bone marrow-derived angioblasts offers the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling. However, a number of studies have provided evidence that the ability of bone marrow-derived stem cells to respond to environmental demands such as injury, disease or other physiologic stimuli, may be compromised during aging. In the first part of this proposal we will investigate the relationship between increasing age or progression of ischemic heart disease and changes in the number, phenotypic characteristics, and in vitro and in vivo biologic properties of adult bone marrow-derived endothelial progenitors, or angioblasts. For these studies, 32 patients selected on the basis of incremental increase in age, and with a history of myocardial infarction (within previous 6-12 months with no evidence of heart failure, or greater than 5 years earlier and with heart failure), will be studied cross-sectionally and longitudinally. Phenotypic studies will be performed by flow cytometry of human bone marrow-derived cells obtained by leukapheresis after G-CSF mobilization. In vivo functional studies will involve intravenous injection of human angioblasts into athymic nude rats with experimental myocardial infarction. In the second part of this proposal we will seek to develop complementary strategies to augment the effects of angioblast- dependent vasculogenesis on cardiac function. We will first investigate whether angioblast migration to the infarct bed is regulated by chemokine-dependent interactions. We will then seek to increase angioblast trafficking to the heart and subsequent vasculogenesis by manipulating such interactions through use of monoclonal antibodies against chemokine receptors and induction of chemokine expression in the heart. Additional aims will be to evaluate whether the improvement in myocardial function obtained following angioblast-dependent vasculogenesis involves induction of myocyte proliferation/regeneration, and whether concomitant use of autologous mesenchymal stem cells or pharmacologic agents may provide synergistic, additive benefit. 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 acute and chronic heart disease.

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祖细胞，并且这些特征可用于在实验性心肌梗塞后诱导血管生成。 这导致肥大肌细胞的凋亡减少，可行心肌的长期挽救和存活，胶原蛋白沉积的减少以及心脏功能的持续改善。 因此，使用细胞因子动物自体骨骨髓衍生的血管细胞具有显着降低与左心室重塑相关的发病率和死亡率的潜力。 但是，许多研究提供了证据，表明骨髓来源的干细胞能够应对损伤，疾病或其他生理刺激等环境需求的能力，可能会在衰老期间受到损害。在本提案的第一部分中，我们将研究成年骨髓衍生的内皮祖细胞的年龄增加或缺血性心脏病的增长与体外和体外生物学特性之间的关系，或体外和体内生物学特性。 对于这些研究，将根据年龄增长和心肌梗死史（在过去的6-12个月内没有心力衰竭的证据，或大于5年前，心力衰竭的情况下）选择了32名患者，将在横截面和纵向上进行研究。 表型研究将通过通过G-CSF动员后通过白细胞置换获得的人骨髓来源细胞的流式细胞仪进行。 体内功能研究将涉及通过实验性心肌梗塞静脉注射人类血管细胞进入无胸腺裸鼠。在本提案的第二部分中，我们将寻求制定互补的策略，以增强血管细胞依赖性血管生成对心脏功能的影响。 我们将首先研究血管细胞迁移到梗塞床是否受趋化因子依赖性相互作用的调节。 然后，我们将寻求通过使用针对趋化因子受体的单克隆抗体来操纵这种相互作用，并诱导心脏中趋化因子的表达来通过操纵这种相互作用来增加血管细胞运输和随后的血管生成。 其他目的是评估血管细胞依赖性血管生成后获得的心肌功能的改善是否涉及诱导心肌细胞增殖/再生，以及伴随使用自体间充质干细胞还是药物学的使用可能会提供协同作用，可提供协同作用。 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急性和慢性心脏病的治疗中为人类临床试验制定策略。