Sruti Bheri
BME PhD Defense Presentation

Date: 2022-12-06
Time: 12.00 PM - 2.00 PM (ET)
Location / Meeting Link: In-person: Emory Children's Center (ECC), Room 302. ; Virtual: https://emory.zoom.us/j/99629789387

Committee Members:
Michael E. Davis, PhD (Advisor); Manu Platt, PhD; Vahid Serpooshan, PhD; Julie Champion, PhD; Hee Cheol Cho, PhD


Title: Engineering small-extracellular vesicle-derived vehicles carrying optimized microRNA for cardiac repair after myocardial infarction

Abstract:
Myocardial infarction (MI) is one of the leading causes of morbidity and mortality worldwide. One promising therapy involves delivering small extracellular vesicles (sEVs). These sEVs are 30-150nm vesicles containing protein and/or nuclear cargo. Despite their reparative potential, sEV therapies have several issues due to their cellular origin, including variable sEV yield and uncontrolled and low-density cargo encapsulation. Synthetic sEV-mimics have been developed which allow optimized cargo loading but these have high toxicity, compromised membranes and poor uptake. Therefore, there is a need for cell-free vehicles with sEV-like membrane and uptake, which allow delivery of customized cargo. To address these needs, the aim of this study was (1) to develop an sEV-like vehicle (ELV) with select microRNA cargo for cardiac repair (2) to understand the role of sEV membrane on vesicle uptake and ELV functionality. We hypothesized that ELVs comprised of an sEV membrane and loaded with microRNA cargo will improve cardiac tissue repair after MI compared to sEVs alone and that membrane composition will affect ELV functionality. We successfully engineered ELVs using two different approaches. The ELVs were loaded with microRNA-126, an endothelial marker, and when administered to cardiac endothelial cells, improved angiogenesis compared to sEV treatment. We then injected microRNA-126+ELVs into a rat model of ischemia-reperfusion wherein the ELVs reduced infarct size, fibrosis and hypertrophy and increased angiogenic parameters. We then assessed the relationship between sEV membrane composition and uptake mechanism finding that sEV origin affects both composition and uptake. We tested this by engineering miR-126+ELVs from two cell types and found differences in their angiogenic and proliferative capacity. Taken together, this study demonstrates the value of engineering vehicles with sEV membranes and their potential to deliver selective cargo for cardiac repair after MI.