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

描述(申请人提供)：干细胞移植和治疗性基因传递在心血管治疗中显示出希望。我们推测，同时动员驻留的心脏干细胞(CSCs)和骨髓干细胞(BMSCs)并将它们归巢到梗死心肌中将是一种有效的心肌再生策略。这项研究的基本原理是探索CSCs和BMSCs的不同特性，以及不同细胞因子在心肌梗死后心肌再生中的不同作用机制。我们预计，高表达肝细胞生长因子(HGF)、基质细胞衍生因子-11(SDF-11)和胰岛素样生长因子(IGF-1)的转基因SCA-1+细胞移植将在心脏形成良好的趋化梯度。局部发育的HGF和SDF-11梯度将有利于CSCs和BMSCs的动员和归巢。此外，SDF-11将为趋化因子受体CXCR4阳性的BMSCs提供足够长的持续时间的保留信号，以确保它们参与并致力于修复过程。IGF-1过表达将刺激IGF-1/IGF-1R配体-受体系统激活PI3K/Akt信号，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，进一步促进修复过程。主要假设将在三个具体目标下进行研究。AIM-1旨在开发细胞因子的趋化梯度，以利于CSCs和BMSCs在梗塞心脏中的同时动员和募集。AIM-2将阐明动员的细胞的血管生成和肌肉生成的命运和功能益处。AIM-3将通过预适应或通过基因修饰延长细胞因子的表达来确定干细胞启动细胞因子的作用，以促进移植后干细胞的存活。我们预计CSCs和BMSCs的同时动员和细胞因子的启动将增加它们的植入并上调生存因子，从而防止心肌梗死后的细胞凋亡和坏死。基于我们的多模式治疗方法的预期益处，拟议的研究将显示同时动员BMSCs和常驻CSCs的意义。因此，从这些研究中获得的信息可能会导致心血管病理管理的新的治疗方法。简介：骨髓来源的干细胞和常驻的心脏干细胞在心肌修复方面显示出了希望。我们的建议是基于通过多种细胞因子治疗同时动员这两种干细胞群体。

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.