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, ?brotic 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.
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. This proposal will investigate the therapeutic potential and molecular mechanisms of stem cell-released microvesicles for ischemic heart diseases.