功能化细胞团簇响应低切应力微环境促进血管损伤修复的研究

Low shear stress microenvironment plays a key role in endothelial injury and the development of atherosclerosis vascular diseases. Endothelial progenitor cell (EPC) represents one of the most promising cell-based strategies for the repair of endothelial injury. However, how to enhance the repair capacity of EPC and targeted homing to the sites of injured endothelium is so far an unsolved scientific problem. Flow Chamber device will be used to evaluate the influence of shear stress on the CXCR4-CXCR7/PGC-1α pathway and the relationship between mitochondrial energetic metabolism, oxidative stress and shear stress. EPC cluster responsive to low shear stress microenvironment will be used to promote targeted homing to endothelial injury sites. In vitro low shear stress device and in vivo carotid artery stenosis animal model will be applied to evaluate the microenvironment-dependent targeted enrichment of EPC cluster and single cell discharge by multi-disciplinary measurement methods including molecular imaging technique. Consequently, the efficiency of EPC-based repair for the endothelial damage will be remarkably improved via up-regulating functional activities and homing capacities of EPC. Our present study for the first time demonstrates that CXCR4-CXCR7/PGC-1α signaling pathway is the novel molecular mechanism of shear stress-upregulated EPC repair capacity. Also, we provide data to show that vascular mechanical microenvironment can be used as the salutary factor to contribute to increase in EPC-mediated repair power for the vascular injury. The current investigation will offer new strategies and laboratory evidences for the prevention and treatment of atherosclerotic vascular diseases.

血管低切应力微环境是导致内皮损伤进而触发血管疾病发生发展的关键机制，内皮祖细胞（EPC）疗法是修复血管损伤的常用手段，如何提高EPC的修复能力及加快其在损伤部位的靶向归巢是目前细胞再生疗法亟待解决的科学难题。本课题采用Flow Chamber切应力装置，研究切应力调控CXCR4-CXCR7/PGC-1α信号通路对EPC线粒体能量代谢和氧化应激的影响及其与加快血管损伤修复的关系；构建低切应力响应性纳米EPC团簇，基于体外低切应力装置和在体颈动脉狭窄模型，采用分子影像学等多学科手段，评估EPC团簇的微环境响应性靶向富集及细胞释放，阐明利用低切应力加快EPC归巢与提高血管损伤修复效率的作用。本课题首次提出CXCR4-CXCR7/PGC-1α信号是切应力调控EPC修复能力的新机制，揭示以血管力学微环境驱动的EPC靶向修复血管损伤新模式的调控机理，为细胞再生疗法防治缺血性血管病提供新策略和实验依据。

血管低切应力微环境是导致内皮损伤进而触发血管疾病发生发展的关键机制，内皮祖细胞（EPC）疗法是修复血管损伤的常用手段，如何提高EPC的修复能力及加快其在损伤部位的靶向归巢是目前细胞再生疗法亟待解决的科学难题。为了解决这些科学问题，在本项目的资助下，我们从生物力学、内皮祖细胞（EPC）、线粒体三个方面探讨了血管低切应力微环境在血管内皮损伤中的作用，揭示了CXCR4-CXCR7多信号网络对 EPC及其线粒体功能的影响，阐明了CXCR4-CXCR7多信号网络在干细胞修复血管损伤中的重要作用；同时，利用纳米颗粒的靶向传输作用，构建了纳米-DNA传输体系、纳米-siRNA传输体系、纳米药物、纳米-干细胞传输体系，通过生物力学、纳米医学、细胞工程学及影像学相结合的综合技术手段，实现了纳米技术在血管损伤修复领域的转化，为缺血性血管病的防治提供了新策略与实验依据；此外，我们还在微针药物传输体系方面也进行了探索。总体而言，本项目按初定的研究内容进行深入探索，获得一系列研究成果，发表高水平SCI论文25篇、申请5项专利、获得广东省科技进步一等奖、培养硕士及博士研究生20余名，已达到预期设定的研究目标。