Hypoxia and cardiac stem cell homing

缺氧与心脏干细胞归巢

基本信息

批准号：
7575241
负责人：
YAO LIANG TANG
金额：
$ 6.24万
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 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575241
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

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）可被视为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) 在通过 SDF-1 与 CXC 趋化因子受体 4 (CXCR4) 结合将循环 BM 衍生干细胞 (BMSC) 招募到缺血心肌以进行心脏修复方面发挥着关键作用。除了外源性干细胞之外，越来越多的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）可用于成人心脏的自我更新。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 增殖和自我更新不足而无法快速重建心脏中的 CSC 群体，以及有限且短暂的内源归巢信号（例如 SDF- 11）诱发心肌缺血。我们建议通过在体外从心脏分离和扩增 CSC，将它们在 MI 后全身输注回体内，并使用 SDF-11/CXCR4 信号通路将它们招募到缺血心肌，来补充用于心脏修复的干细胞库。然而，主要挑战仍然存在，包括正常条件下CSCs的CXCR4表达水平较低，移植细胞的存活率较差，这限制了干细胞在体内的修复能力。我们提出了一系列体外实验和体内实验来验证缺氧预处理可用于通过调节CXCR4表达来增加CSC归巢，并通过急性缺血心肌中的细胞保护来增强归巢细胞的存活。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。为了检验这些假设，我们提出以下具体目标：（1）评估缺氧诱导的心脏干细胞归巢：CXCR4和HIF-11在细胞招募和保留中的作用。 (2) 确定缺氧预处理是否可以提高归巢CSC的存活率并表征其机制。 (3)探讨rAAV病毒介导的SDF-11基因治疗将CSC归巢至慢性缺血心肌的可能性。