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.