Hypoxia and cardiac stem cell homing

缺氧与心脏干细胞归巢

• 批准号: 7789484
• 负责人: YAO LIANG TANG
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789484
• 关键词: Acute; Adult; Back; Binding; Bone Marrow; CXC Chemokines; Cardiac; Cell Death; Cell Survival; Cell fusion; Cells; Chemicals; Chronic; Colony-Forming Units Assay; Congestive Heart Failure; Cytoprotection; Deferoxamine Methanesulfonate; Failure; Gene Transfer; Graft Survival; Healed; Heart; Home environment; Homing; Hypoxia; In Vitro; Infarction; Infusion procedures; Interleukin 8A Receptor; Ischemia; Kinetics; Knockout Mice; Mediating; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Oxidative Stress; Patients; Play; Recombinant adeno-associated virus (rAAV); Recruitment Activity; Regulation; Role; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Stem cell transplant; Stem cells; Stromal Cell-Derived Factor 1; Technology; Testing; Tissues; Up-Regulation; Virus; base; chemokine receptor; gene therapy; healing; in vivo; injured; overexpression; paracrine; preconditioning; reconstitution; regenerative; repaired; research study; response; self-renewal; spatial relationship; stem cell population

DESCRIPTION (provided by applicant): Ischemic heart disease is the leading cause of congestive heart failure. The ultimate therapy would pursue stem cell-based regeneration. Bone marrow (BM) can be regarded as the major reservoir of stem cells. Stromal-derived factor-11 (SDF-11) induced by myocardial ischemia plays a critical role for recruiting circulating BM-derived stem cells (BMSC) to ischemia myocardium for heart repair via binding of SDF-1 to CXC chemokine receptor 4 (CXCR4). Besides exogenous stem cells, compelling evidence has accumulated suggesting that the heart has endogenous regenerative potential. Resident cardiac stem cells (CSCs) are potentially available for self-renewing of adult heart. However, myocardial damage from ischemia is usually irreversible. Proposed mechanisms for the failure of endogenous heart repair include: acute depletion of resident CSCs after myocardial infarction (MI), inadequate proliferation and self-renewal of CSCs to rapidly reconstitute CSC population in heart, and limited and transient endogenous homing signals (e.g. SDF-11) induced by myocardial ischemia. We propose to replenish the stem cell pool for heart repair, by isolating and expanding CSCs from heart in vitro, infusing them systemically back in vivo post MI, and recruiting them to the ischemic myocardium using SDF-11/CXCR4 signal pathway. However, major challenges remain, including low level of CXCR4 expression of CSCs under normal conditions, the poor survival of grafted cells, which has limited the reparative capacity of stem cells in vivo. We propose a series of in vitro experiments and in vivo experiments to verify that hypoxia preconditioning can be utilized to increase CSC homing via regulation of CXCR4 expression and enhance survival of homed cells via cytoprotection in acute ischemic myocardium. In addition, recombinant adeno-associated virus (rAAV) mediated SDF-1 gene therapy may permit us to conduct CSC transplantation for patients with chronic myocardial ischemia. To test these hypotheses, we propose the following Specific Aims: (1) To evaluate hypoxia induced cardiac stem cell homing: role of CXCR4 and HIF-11 in cell recruitment and retention. (2) To determine whether hypoxia-preconditioning can enhance homed CSC survival and characterize the mechanism. (3) To investigate the possibility of homing CSC to chronic ischemia myocardium via rAAV virus mediated SDF-11 gene therapy.

描述（由申请人提供）：缺血性心脏病是充血性心力衰竭的主要原因。最终的治疗方法将是基于干细胞的再生。骨髓（BM）可以被认为是干细胞的主要储存库。心肌缺血诱导的基质衍生因子-11（SDF-11）通过与CXC趋化因子受体4（CXCR 4）结合，在募集循环中的骨髓源性干细胞（BMSC）到缺血心肌中进行心脏修复中起关键作用。除了外源性干细胞，令人信服的证据已经积累表明，心脏具有内源性再生潜力。驻留心脏干细胞（CSCs）是一种潜在的可用于成人心脏自我更新的细胞。然而，缺血引起的心肌损伤通常是不可逆的。内源性心脏修复失败的机制包括：心肌梗死（MI）后驻留CSC的急性耗竭，CSC的增殖和自我更新不足，无法快速重建心脏中的CSC群体，以及心肌缺血诱导的有限和短暂的内源性归巢信号（如SDF-11）。我们建议通过体外分离和扩增心脏中的CSC，在MI后将其全身输注回体内，并使用SDF-11/CXCR 4信号通路将其招募到缺血心肌中，以补充用于心脏修复的干细胞库。然而，主要的挑战仍然存在，包括正常条件下CXCR 4表达水平低，移植细胞存活率低，这限制了干细胞体内修复能力。我们提出了一系列体外和体内实验来验证低氧预处理可以通过调节CXCR 4表达来增加CSC归巢，并通过细胞保护来增强归巢细胞在急性缺血心肌中的存活。此外，重组腺相关病毒（rAAV）介导的SDF-1基因治疗可能使我们能够对慢性心肌缺血患者进行CSC移植。为了验证这些假设，我们提出了以下具体目的：（1）评估缺氧诱导的心脏干细胞归巢：CXCR 4和HIF-11在细胞募集和保留中的作用。(2)探讨缺氧预处理是否能提高归巢CSC的存活率及其机制。(3)目的：探讨rAAV病毒介导SDF-11基因治疗慢性缺血心肌的可行性。