Lack of cardiac benefit after intramyocardial or intravenous injection of mesenchymal stem cell-derived extracellular vesicles supports the need for optimized cardiac delivery

Aim: To determine the differences in improvement in cardiac function by intramyocardial (IM) vs. intravenous (IV) injection of human bone mesenchymal stem cell-derived extracellular vesicles (HBMSC-EV) after acute MI. Methods: FVB mice underwent acute MI via left anterior descending coronary artery ligation and subsequent injection of: (1) IM saline control; (2) IM HBMSC-EV; (3) IV saline control; and (4) IV HBMSC-EV. Cardiac function was evaluated with weekly postoperative echocardiography. On postoperative day 28, the mice were euthanized, and the heart, lungs, liver, spleen, and kidneys were harvested. Given previous studies showing HBMSC-EV hepatic uptake after IV injection, the liver was evaluated for changes in inflammation, fibrosis, and proliferation. Results: On postoperative day 28, there were no significant differences in left ventricular ejection fraction (P = 0.6151), fractional shortening (P = 0.1135), or anterior border zone fibrosis (P = 0.6333) in any of the experimental groups. Interestingly, there was a strong trend demonstrating improvement in infarct size on fibrosis staining, which did not reach significance (P = 0.05620). There were no differences in hepatic inflammation, fibrosis, and proliferation. Conclusions: Although there was a trend in the improvement in infarct size, a single-dose administration of neither IM nor IV injection of HBMSC-EV resulted in significant improvement in post-MI cardiac function. A major limitation of this study is the lack of trials determining the optimal dose of HBMSC-EV needed in this model. However, the current study demonstrates that future studies are required to either optimize administration or bioengineer HBMSC-EV with cardiac-homing properties.