The Journal of thoracic and cardiovascular surgery | 2019
Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics.
Abstract
BACKGROUND\nExtracellular vesicles (EVs) are promising therapeutics for cardiovascular disease, but poorly-timed delivery might hinder efficacy. We characterized the time-dependent response to endothelial progenitor cell (EPC)-EVs within an injectable shear-thinning hydrogel (STG+EV) post-myocardial infarction (MI) to identify when an optimal response is achieved.\n\n\nMETHODS\nThe angiogenic effects of prolonged hypoxia on cell response to EPC-EV therapy and EV uptake affinity were tested in\xa0vitro. A rat model of acute MI via left anterior descending artery ligation was created and STG+EV was delivered via intramyocardial injections into the infarct border zone at time points corresponding to phases of post-MI inflammation: 0\xa0hours (immediate), 3\xa0hours (acute inflammation), 4\xa0days (proliferative), and 2\xa0weeks (fibrosis). Hemodynamics 4\xa0weeks post-treatment were compared across treatment and control groups (phosphate buffered saline [PBS], shear-thinning gel). Scar thickness and ventricular diameter were assessed histologically. The primary hemodynamic end point was end systolic elastance. The secondary end point was scar thickness.\n\n\nRESULTS\nEPC-EVs incubated with chronically versus acutely hypoxic human umbilical vein endothelial cells resulted in a 2.56\xa0±\xa00.53 versus 1.65\xa0±\xa00.15-fold increase (P\xa0=\xa0.05) in a number of vascular meshes and higher uptake of EVs over 14\xa0hours. End systolic elastance improved with STG+EV therapy at 4\xa0days (0.54\xa0±\xa00.08) versus PBS or shear-thinning gel (0.26\xa0±\xa00.03 [P\xa0=\xa0.02]; 0.23\xa0±\xa00.02 [P = .01]). Preservation of ventricular diameter (6.20\xa0±\xa00.73\xa0mm vs 8.58\xa0±\xa00.38\xa0mm [P\xa0=\xa0.04]; 9.13\xa0±\xa00.25\xa0mm [P\xa0=\xa0.01]) and scar thickness (0.89\xa0±\xa00.05\xa0mm vs 0.62\xa0±\xa00.03\xa0mm [P\xa0<\xa0.0001] and 0.58\xa0±\xa00.05\xa0mm [P\xa0<\xa0.0001]) was significantly greater at 4\xa0days, compared wit PBS and shear-thinning gel controls.\n\n\nCONCLUSIONS\nDelivery of STG+EV 4\xa0days post-MI improved left ventricular contractility and preserved global ventricular geometry, compared with controls and immediate therapy post-MI. These findings suggest other cell-derived therapies can be optimized by strategic timing of therapeutic intervention.