Microvesicles from Adipose-derived Stem Cells for Ischemic Heart Repair

来自脂肪干细胞的微泡用于缺血性心脏修复

• 批准号: 9231486
• 负责人: Dong Liu
• 金额: $ 35.38万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231486
• 关键词: Adipocytes; Adipose tissue; Animal Model; Apoptosis; Area; Biological Assay; Blood capillaries; Calcified; Cardiac; Cell Proliferation; Cell Therapy; Cells; Chondrocytes; Clinical Research; Complement; Complex; Data; Disease; Dose; Dust; Endothelial Cells; Engineering; Epidemic; Funding; Gene Proteins; Giant Cells; Growth Factor; Histocompatibility Antigens; Homeostasis; In Situ; In Vitro; Intervention; Investigation; Ischemia; Life; Limb structure; Lipids; Maintenance; Mediating; Mediator of activation protein; Medical; Messenger RNA; MicroRNAs; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; NOD/SCID mouse; Operative Surgical Procedures; Osteocytes; Pathologic Processes; Pathway interactions; Phenotype; Physiologic Ossification; Physiological Processes; Play; Proteins; Randomized Controlled Clinical Trials; Reporting; Research Personnel; Research Proposals; Risk; Role; Route; Savings; Severe Combined Immunodeficiency; Signal Transduction; Stem cell transplant; Stem cells; Stress; Surface; Therapeutic; Tissues; Transplantation; Tumorigenicity; Vascular Endothelial Cell; angiogenesis; base; calcification; capillary; cardiac repair; clinical investigation; clinically significant; cytokine; density; exosome; experimental study; feeding; hypoxia inducible factor 1; in vivo; innovation; intercellular communication; matrigel; microvesicles; paracrine; particle; pre-clinical; preconditioning; public health relevance; repaired; response; stem; submicron; therapeutic angiogenesis; transdifferentiation; treatment strategy; tumor; tumorigenic

 DESCRIPTION (provided by applicant): The worldwide epidemic of ischemic heart diseases urgently requires innovative treatments in spite of the significant advances in medical, interventional and surgical therapy for these diseases. A microvesicle (MV)-based therapeutic angiogenesis is emerging for ischemic diseases because of tumorigenic concern of the stem cell approach. MVs are submicron particles that are released from cells, and contain a package of protein, mRNA, microRNA and bioactive lipid. In addition, MV has recently been recognized as a signaling transferring vehicle in intercellular communication. In our current pilot funding period, we have demonstrated that MVs from adipose-derived stem cells (ASCs), particularly from endothelial differentiation medium (EDM)-preconditioned ASCs, promote angiogenesis in vitro, ex vivo and in vivo (matrigel plugs). An underlying mechanism of the proangiogenesis may be the delivery of microRNA-31 via MVs from ASCs to vascular endothelial cells in which FIH1 (factor inhibiting HIF-1) is targeted and suppressed. In this application, our central hypothesis i that the transplantation of ASC-derived MVs promotes angiogenesis in ischemic heart myocardial infarction. We will complement this approach with broader efforts to continue to feed our pipeline of hypothesis-driven mechanistic experiments. Aim 1 is to determine the role of MVs released from EDM-preconditioned ASCs in promoting angiogenesis in the ischemic heart. The MVs will be administered after myocardial infarction (MI) in severe combined immunodeficiency (NOD SCID) mice. The cardiac function, cell proliferation and apoptosis, fibrotic area, and capillary density will subsequently be evaluated. Aim 2 is to investigate the role of miR-31 signaling in intercellular communication through the MVs. We will explore the activity of hypoxia inducible factor-1 (HIF-1), which has been reported to be inhibited by FIH1, and will broaden our understanding of the role of miR-31/FIH1/HIF-1 pathway in MV-transplanted ischemic myocardium. Aim 3 is to determine the effect of miR-31 in ASC-derived MVs on cardiac repair after MI. The effects of different dosing, timing and delivery routes of administration of MVs on cardiac repair after MI will be investigated. To increase the throughput of our investigation, miR-31 will be manipulated in EDM-preconditioned MV-donor ASCs or in MVs directly. At the conclusion of this research proposal we will have characterized the role of miR-31/FIH1/HIF1 pathway in MV- based therapy for ischemic heart diseases. Modulation of miRNA composition in vascular endothelial cells by delivering angiogenic miRNAs via MV may be an innovative strategy for the treatment of ischemic heart diseases.

 描述（由申请人提供）：尽管缺血性心脏病的医学、介入和外科治疗取得了重大进展，但缺血性心脏病的全球流行迫切需要创新的治疗方法，因为基于微泡（MV）的治疗性血管生成正在出现。 MV 是从细胞中释放的亚微米颗粒，含有蛋白质、mRNA、微小 RNA 和生物活性脂质。在我们当前的试点资助期间，我们已经证明来自脂肪干细胞（ASC）的MV，特别是来自内皮分化培养基（EDM）预处理的ASC，可以在体外、离体和体外促进血管生成。促血管生成的一个潜在机制可能是通过 MV 将 microRNA-31 从 ASC 传递到血管内皮细胞，其中 FIH1（因子）在本申请中，我们的中心假设是 ASC 衍生的 MV 的移植促进缺血性心脏心肌梗死中的血管生成，我们将通过更广泛的努力来补充这一方法，以继续满足我们的假设。目标 1 是确定 EDM 预处理的 ASC 释放的 MV 在促进缺血心脏血管生成中的作用。随后将评估严重联合免疫缺陷 (NOD SCID) 小鼠的心肌梗死 (MI) 的心脏功能、细胞增殖和凋亡、纤维化面积和毛细血管密度。目标 2 是研究 miR-31 信号传导在细胞间通讯中的作用。我们将通过 MV 探索缺氧诱导因子 1 (HIF-1) 的活性，据报道该因子可被 FIH1 抑制，并将拓宽我们对缺氧诱导因子 1 (HIF-1) 的理解。 miR-31/FIH1/HIF-1 通路在 MV 移植缺血心肌中的作用目的 3 是确定 ASC 来源的 MV 中 miR-31 对 MI 后心脏修复的影响。将研究 MV 给药途径对 MI 后心脏修复的影响 为了提高我们研究的通量，将在 EDM 预处理的 MV 供体中操作 miR-31。在本研究提案的结论中，我们将描述 miR-31/FIH1/HIF1 通路在基于 MV 的缺血性心脏病治疗中通过传递血管生成 miRNA 来调节血管内皮细胞中 miRNA 组成的作用。通过 MV 可能是治疗缺血性心脏病的创新策略。