Hypoxia and cardiac stem cell homing

缺氧与心脏干细胞归巢

基本信息

批准号：
7372776
负责人：
YAO LIANG TANG
金额：
$ 37.88万
依托单位：
KECK GRADUATE INST OF APPLIED LIFE SCIS
依托单位国家：
美国
项目类别：
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/7372776
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 Condition 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 Localized Mediating Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Oxidative Stress Patients Play Population Protein Overexpression Purpose 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 paracrine preconditioning reconstitution repaired research study response self-renewal spatial relationship

项目摘要

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。最终的疗法将追求基于干细胞的再生。骨髓（BM）可以视为干细胞的主要储层。心肌缺血诱导的基质衍生因子-11（SDF-11）在招募循环BM衍生的干细胞（BMSC）到缺血性心肌症中起着至关重要的作用，可通过SDF-1与CXC趋化因子受体4（CXCR4）结合而进行心脏修复。除了外源干细胞外，令人信服的证据表明心脏具有内源性再生潜力。常驻心脏干细胞（CSC）可能可用于自我更新成人心脏。但是，缺血的心肌损害通常是不可逆的。内源性心脏修复失败的提议机制包括：心肌梗死后常驻CSC的急性耗竭（MI），CSC的增殖不足和心脏快速重新构成CSC的CSC人群，并且有限且短暂的内生内源性归巢信号（例如SDF-111 sdf-111）诱导的byocchem（例如SDF-111）。我们建议通过在体外从心脏中隔离和扩展CSC来补充干细胞池以进行心脏修复，从而在MI后全身地将其融入体内，并使用SDF-11/CXCR4信号途径将其募集到缺血性心肌中。然而，仍然存在主要挑战，包括在正常条件下CSC的CXCR4表达较低，即移植细胞的存活不良，这限制了体内干细胞的频率能力。我们提出了一系列体外实验和体内实验，以验证可通过调节CXCR4表达来增加缺氧预处理，并通过急性缺血性心肌中的细胞保护通过细胞增强细胞的存活。此外，重组腺相关病毒（RAAV）介导的SDF-1基因疗法可能使我们能够为慢性心肌缺血患者进行CSC移植。为了检验这些假设，我们提出了以下特定目的：（1）评估缺氧引起的心脏干细胞的归纳：CXCR4和HIF-11的作用在细胞募集和保留中。（2）确定缺氧前提是否可以增强CSC存活并表征该机制。（3）研究通过RAAV病毒介导的SDF-11基因治疗将CSC归为慢性缺血心肌的可能性。