Harnessing Platelet-Endothelial Interactions for Stem Cell Delivery

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PROJECT SUMMARY Platelet-endothelial interactions play a vital role in diseases such atherosclerosis and ischemic injury such as myocardial infarction. Vascular injury/inflammation after MI can lead to platelet activation and trafficking, up- regulations of adhesion molecules, and production of reactive oxygen and nitrogen species in vasculatures. Despite in many cases platelet activation is harmful, recent studies indicate that after ischemic injury circulating stem cells (release from the bone marrow) rely on platelets to navigate into the injured heart for tissue repair. Platelets form co-aggregates with circulating stem cells in patients with myocardial infarction and thereby increase peripheral recruitment within the ischemic microcirculatory district and promote adhesion to the vascular lesion to promote healing. For the last decade, we have been working in the field of stem cell therapy for post-injury cardiac repair. One big challenge is to target infused stem cells to the cardiac injury site. Poor cell engraftment in the heart may at least partially explain the none-to-marginal efficacy of stem cell therapies for heart diseases so far. We hypothesize that expression of platelet binding motifs on stem cells can help them target to the injured heart. We devised a method of adding platelet binding motifs onto stem cells without genetically altering the cells. Instead, transient expression can be achieved by cell fusion mechanisms. We will first generate platelet membrane vesicles from live platelets and then decorate these vesicles onto the surface of therapeutic stem cells. This method is robust and simple. Under the auspice of this grant study, we aim to evaluate the cytotoxicity of this approach on stem cell functions and test the safety/efficacy of this approach to enhance endogenous and exogenous stem cell therapies in animal models of myocardium infarction.