Simltaneous recruitment of cardiac and bone marrow stem cells for cardiac repair

同时招募心脏和骨髓干细胞进行心脏修复

• 批准号: 8055000
• 负责人: KHAWAJA H HAIDER
• 金额: $ 39万
• 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: 2008-04-10 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055000
• 关键词: ABCB1 gene; Accounting; Antigens; Apoptosis; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; CD44 gene; CXCR4 gene; Cardiac; Cardiovascular Pathology; Cardiovascular system; Cell Differentiation process; Cell Survival; Cell Therapy; Cell Transplants; Cells; Cytokine Signaling; Dimensions; Effectiveness; Elements; Engraftment; Ensure; Exposure to; Gene Delivery; Genes; Glossary; Healed; Heart; Hematopoietic Stem Cell Mobilization; Hepatocyte Growth Factor; Homing; Immigration; Individual; Infarction; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Ischemia; Ischemic Preconditioning; Lead; Ligands; Modification; Molecular; Muscle; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Necrosis; Pathway interactions; Process; Property; Proteins; Role; Signal Pathway; Signal Transduction; Site; Somatomedins; Stem cell transplant; Stem cells; Stromal Cells; System; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenes; Transplantation; Treatment Efficacy; Vascular blood supply; angiogenesis; base; chemokine receptor; cytokine; cytokine therapy; gene therapy; genetically modified cells; healing; heart cell; hemodynamics; improved; in vivo; indexing; injured; myogenesis; novel strategies; novel therapeutic intervention; overexpression; paracrine; preconditioning; prevent; receptor; regenerative; repaired; response; stem cell differentiation; stem cell population; therapeutic gene

DESCRIPTION (provided by applicant): Stem cell transplantation and therapeutic gene delivery have shown promise in cardiovascular therapeutics. We hypothesized that concomitant mobilization of the resident cardiac stem cells (CSCs) and bone marrow stem cells (BMSCs) and their homing into the infarcted myocardium will be an effective strategy for myocardial regeneration. The rationale for this study is to exploit the diverse properties of CSCs and BMSCs, and varying mechanisms of action of different cytokines in myocardial regeneration following infarction. We anticipate that transplantation of Sca-1+ cells genetically modified to overexpress hepatocyte growth factor (HGF), stromal cell derived factor-11 (SDF-11) and insulin-like growth factor (IGF-1) will develop favorable chemotactic gradient in the heart. The locally developed gradient of HGF and SDF-11 will favor mobilization and homing-in of CSCs and BMSCs. Additionally, SDF-11 will provide retention signals for the chemokine receptor CXCR4 positive BMSCs for long enough time duration to ensure their participation and commitment to the repair process. IGF-1 overexpression will stimulate IGF-1/IGF-1R ligand-receptor system to activate PI3K/Akt signaling to promote proliferation and differentiation of these cells. The mobilized and transplanted stem cells will further contribute to the repair process by the release of trophic factors to exert paracrine effects. The main hypothesis will be studied in three specific Aims. Aim-1 is intended to develop chemotactic gradient of cytokines to favor simultaneous mobilization and recruitment of CSCs and BMSCs in the infarcted heart. Aim-2 will elucidate the angiogenic and myogenic fate and functional benefits of the mobilized cells. Aim-3 will determine the role of cytokine priming of stem cells by preconditioning or by gene modification for protracted cytokines expression to promote their survival after transplantation. We anticipate that simultaneous mobilization of CSCs and BMSCs together with cytokine priming will augment their engraftment and upregulate survival factors thus preventing apoptosis and necrosis in the infarcted myocardium. Based on the anticipated beneficial effects of our multimodal therapeutic approach, the proposed study will show the significance of simultaneous mobilization of BMSCs and resident CSCs. The information thus obtained from these studies will likely lead to new therapeutic approaches for management of cardiovascular pathologies. NARRATIVE: Bone marrow derived stem cells and resident cardiac stem cells have shown promise in myocardial repair. Our proposal is based on concomitant mobilization of both these stem cell populations by multiple cytokine therapy.

描述（由申请人提供）：干细胞移植和治疗基因递送在心血管疗法中显示出希望。我们假设驻留心脏干细胞（CSC）和骨髓干细胞（BMSC）及其将其归为梗塞心肌是心肌再生的有效策略。这项研究的基本原理是利用CSC和BMSC的各种特性，以及梗塞后心肌再生中不同细胞因子的作用机理的不同机制。我们预计，对过表达肝细胞生长因子（HGF），基质细胞得出的因子-11（SDF-11）和胰岛素样生长因子（IGF-1）的过表达肝细胞生长因子（HGF）的移植将在心脏中发展出有利的趋化性梯度。 HGF和SDF-11的本地开发的梯度将有利于动员和CSC和BMSC的归居。此外，SDF-11将在足够长的时间内为趋化因子受体CXCR4阳性BMSC提供保留信号，以确保其参与和对维修过程的承诺。 IGF-1过表达将刺激IGF-1/IGF-1R配体受体系统激活PI3K/AKT信号传导，以促进这些细胞的增殖和分化。动员和移植的干细胞将通过释放营养因子发挥旁分泌作用进一步有助于修复过程。主要假设将以三个特定目的进行研究。 AIM-1旨在发展细胞因子的趋化梯度，以同时动员和募集梗塞心脏中CSC和BMSC。 AIM-2将阐明动员细胞的血管生成和肌原性命运以及功能益处。 AIM-3将通过预处理或通过基因修饰进行旷日持久的细胞因子表达来确定干细胞的细胞因子启动的作用，以促进其移植后其存活。我们预计，同时动员CSC和BMSC以及细胞因子启动将增加其植入并上调生存因子，从而阻止梗死心肌的细胞凋亡和坏死。基于我们多模式治疗方法的预期有益作用，拟议的研究将表明同时动员BMSC和常驻CSC的重要性。从这些研究中获得的信息可能会导致用于管理心血管病理的新治疗方法。叙事：骨髓衍生的干细胞和常驻心脏干细胞在心肌修复中表现出了希望。我们的建议基于通过多种细胞因子疗法伴随动员这些干细胞群体的动员。