Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics

Research output: Contribution to journalArticle

Authors

  • Jennifer J. Chung
  • Jason Han
  • Leo L. Wang
  • Maria F. Arisi
  • Samir Zaman
  • Jonathan Gordon
  • Elizabeth Li
  • Samuel T. Kim
  • Zoe Tran
  • Carol W. Chen
  • Ann C. Gaffey
  • Jason A. Burdick
  • Pavan Atluri

External Institution(s)

  • University of Pennsylvania

Details

Original languageEnglish (US)
Pages (from-to)1825-1835.e2
JournalJournal of Thoracic and Cardiovascular Surgery
Volume159
Issue number5
StatusPublished - May 2020
Peer-reviewedYes

Abstract

Background: Extracellular 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. Methods: The angiogenic effects of prolonged hypoxia on cell response to EPC-EV therapy and EV uptake affinity were tested in vitro. 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 hours (immediate), 3 hours (acute inflammation), 4 days (proliferative), and 2 weeks (fibrosis). Hemodynamics 4 weeks 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. Results: EPC-EVs incubated with chronically versus acutely hypoxic human umbilical vein endothelial cells resulted in a 2.56 ± 0.53 versus 1.65 ± 0.15-fold increase (P = .05) in a number of vascular meshes and higher uptake of EVs over 14 hours. End systolic elastance improved with STG+EV therapy at 4 days (0.54 ± 0.08) versus PBS or shear-thinning gel (0.26 ± 0.03 [P = .02]; 0.23 ± 0.02 [P = .01]). Preservation of ventricular diameter (6.20 ± 0.73 mm vs 8.58 ± 0.38 mm [P = .04]; 9.13 ± 0.25 mm [P = .01]) and scar thickness (0.89 ± 0.05 mm vs 0.62 ± 0.03 mm [P < .0001] and 0.58 ± 0.05 mm [P < .0001]) was significantly greater at 4 days, compared wit PBS and shear-thinning gel controls. Conclusions: Delivery of STG+EV 4 days 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.

    Research areas

  • delayed therapy, extracellular vesicles, myocardial infarction, shear thinning gel

Citation formats

APA

Chung, J. J., Han, J., Wang, L. L., Arisi, M. F., Zaman, S., Gordon, J., ... Atluri, P. (2020). Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics. Journal of Thoracic and Cardiovascular Surgery, 159(5), 1825-1835.e2. https://doi.org/10.1016/j.jtcvs.2019.06.017

Harvard

Chung, JJ, Han, J, Wang, LL, Arisi, MF, Zaman, S, Gordon, J, Li, E, Kim, ST, Tran, Z, Chen, CW, Gaffey, AC, Burdick, JA & Atluri, P 2020, 'Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics', Journal of Thoracic and Cardiovascular Surgery, vol. 159, no. 5, pp. 1825-1835.e2. https://doi.org/10.1016/j.jtcvs.2019.06.017