MESENCHYMAL STEM CELLS IN THE PREVENTION OF THROMBOSIS AND NEOINTIMAL HYPERPLASIA

间充质干细胞预防血栓形成和新生内膜增生

• 批准号: 8402772
• 负责人: Devendra K. Agrawal
• 金额: $ 5.13万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402772
• 关键词: Angiography; Angioplasty; Apoptosis; Area; Atherosclerosis; Autologous; Balloon Angioplasty; Blood; Blood Platelets; Blood Vessels; Caliber; Cardiology; Cardiovascular system; Cell Differentiation process; Cell Proliferation; Cell Therapy; Cellular biology; Clinical; Coronary; Coronary Angiography; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; Data; Deposition; Development; Down-Regulation; Drug Controls; Endothelial Cells; Engineering; Family suidae; Fibrinogen; Functional disorder; Gene Expression; Gene Transduction Agent; Genes; Goals; Growth; Heart; Histology; Human; Hyperlipidemia; Hyperplasia; In Vitro; Inflammatory; Injury; Insulin-Like Growth Factor I; Interferons; Interleukin-12; Investigation; Laboratories; Legal patent; Lipids; Mediator of activation protein; Mesenchymal Stem Cells; Metals; Mitogens; Modeling; Molecular Biology; Optics; Outcome; PTEN gene; Pathology; Patients; Percutaneous Transluminal Coronary Angioplasty; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Positioning Attribute; Prevention; Procedures; Receptor Cell; Research; Resolution; Role; Signal Transduction; Signaling Molecule; Site; Smooth Muscle Myocytes; Stem cells; Stenosis; Stents; Symptoms; TNF gene; Testing; Therapeutic; Thick; Thrombosis; Transduction Gene; Transgenes; Translating; Ulcer; Vascular Diseases; Vascular Endothelial Growth Factors; cell growth; cytokine; gene therapy; in vivo; intercellular communication; intima media; novel; overexpression; phase 1 study; prevent; receptor expression; repaired; response to injury; restenosis; shear stress; stem cell differentiation; tomography; transgene expression; vector; vector control

DESCRIPTION (provided by applicant): Drug-eluting stents cause less intimal hyperplasia and less late luminal loss, but inhibit re- endothelialization of the stented segment making it more susceptible to thrombosis. Thus, there is trade-off between restenosis and late stent thrombosis requiring longer periods of anti-platelet therapy. Clearly, a better therapeutic approach that can prevent intimal hyperplasia and induce re-endothelialization would be useful to provide long-term symptom-free control of coronary artery disease without the need for prolonged anti- platelet therapy. Since PTEN modulates cell signaling and cell growth, PTEN transgene overexpression in arterial smooth muscle cells would prevent the development of neointimal hyperplasia. In addition, thrombosis could be prevented by the repair of endothelial cells with mesenchymal stem cells (MSCs) which have been primed to differentiate into endothelial cells. We hypothesize that the delivery of MSCs and PTEN transgene locally to the site of angioplasty and stent injury prevents thrombosis and the development of neointimal hyperplasia. Down-regulation of Wnt/2 catenin signaling in MSCs promotes endothelial cell differentiation and re-endothelialization. This hypothesis has been supported by our data demonstrating that vascular endothelial growth factor (VGEF)-primed MSCs differentiate into endothelial cells and PTEN overexpression inhibits proliferation of arterial smooth muscle cells. We will do these studies in a well-established and routinely used in our laboratory the swine model of hyperlipidemia and atherosclerosis with angioplasty and in-stent restenosis. Aim 1: Test the hypothesis that overexpression of PTEN transgene with MSCs at the site of balloon angioplasty in atherosclerotic coronary artery prevents thrombosis and the development of neointimal hyperplasia. Aim 2: Test the hypothesis that overexpression of PTEN transgene with MSCs at the site of bare metal stenting in atherosclerotic coronary artery prevents thrombosis and in-stent restenosis and this would be superior to the effect of drug-eluting stent alone. Aim 3: Test the hypothesis that down-regulation of Wnt/2-catenin signaling promotes MSC differentiation to endothelial cells at the injury site in coronary arteries. We will examine the role of Wnt/¿-catenin signaling molecules, particularly ¿-catenin, LRP5 and Kremen1, as the underlying mechanism of MSCs differentiation into ECs and re-endothelialization both in vitro and in vivo in swine coronary arteries. These studies would position us to translate our investigation into a clinical phase 1 study for the use of PTEN-engineered autologous MSCs for the treatment of the complications due to coronary interventional procedures, and PTCA with PTEN-engineered autologous MSCs might eliminate the need of stents in coronary artery disease.

描述（由申请人提供）：药物洗脱支架引起较少的内膜增生和较少的晚期管腔损失，但抑制支架段的再内皮化，使其更容易形成血栓。因此，再狭窄和晚期支架内血栓形成之间存在权衡，需要更长时间的抗血小板治疗。显然，能够预防内膜增生并诱导再内皮化的更好的治疗方法将有助于提供冠状动脉疾病的长期无症状控制，而不需要长期的抗血小板治疗。由于 PTEN 调节细胞信号传导和细胞生长，动脉平滑肌细胞中 PTEN 转基因过度表达将阻止新内膜增生的发展。此外，可以通过用已准备好分化为内皮细胞的间充质干细胞（MSC）修复内皮细胞来预防血栓形成。我们假设将 MSC 和 PTEN 转基因局部递送至血管成形术和支架损伤部位可防止血栓形成和新内膜增生的发展。 MSC 中 Wnt/2 连环蛋白信号传导的下调可促进内皮细胞分化和再内皮化。这一假设得到了我们的数据的支持，该数据表明血管内皮生长因子（VGEF）引发的 MSC 分化为内皮细胞，并且 PTEN 过度表达抑制动脉平滑肌细胞的增殖。我们将在我们实验室常规使用的高脂血症和动脉粥样硬化猪模型中进行这些研究，并进行血管成形术和支架内再狭窄。目标 1：检验以下假设：在动脉粥样硬化冠状动脉球囊血管成形术部位用 MSC 过度表达 PTEN 转基因可防止血栓形成和新内膜增生的发展。目标2：检验以下假设：在动脉粥样硬化冠状动脉裸金属支架置入部位用MSC过度表达PTEN转基因可预防血栓形成和支架内再狭窄，并且这将优于单独的药物洗脱支架的效果。目标 3：检验 Wnt/2-catenin 信号传导下调可促进冠状动脉损伤部位的 MSC 分化为内皮细胞的假设。我们将研究 Wnt/¿-连环蛋白信号分子，特别是 Ф-连环蛋白、LRP5 和 Kremen1，作为猪冠状动脉体外和体内 MSC 分化为 EC 和再内皮化的潜在机制。这些研究将使我们能够将我们的研究转化为临床 1 期研究，使用 PTEN 工程化的自体 MSC 来治疗冠状动脉介入手术引起的并发症，并且使用 PTEN 工程化的自体 MSC 进行 PTCA 可能会消除冠状动脉疾病中支架的需要。