Fools Rush In: Delayed Delivery of a Shear-Thinning Hydrogel and Endothelial Progenitor Cell - Derived Exosomal Therapy Improves Hemodynamics Following Myocardial Infarction
Jennifer J. Chung, Jason Han, Leo L. Wang, Maria F. Arisi, Samir Zaman, Jonathan Gordon, Elizabeth Li, Carol W. Chen, Ann C. Gaffey, Jason Burdick, Pavan Atluri
University of Pennsylvania, Philadelphia, PA
OBJECTIVES: Stem cells and their derivatives continue to show promise for therapeutic use following myocardial infarction (MI), but major clinically translatable breakthroughs may be hindered by a lack of optimally-timed intervention. We have previously demonstrated that endothelial progenitor cell-derived exosomes (XO) encapsulated within an injectable shear-thinning hydrogel (STG) produce robust functional improvements when delivered immediately after MI. The STG allows precise targeting of XOs into ischemic myocardium and sustained release of particles over time. We aim to characterize the response to STG+XO therapy at different points along the post-MI inflammatory timeline to identify the time at which therapy will produce the optimal response with maximum angiogenesis, preservation of ventricular geometry, and functional improvements.
METHODS: Exosomes isolated from male Wistar rat EPCs were suspended in STG. Acute MI was induced in male Wistar rats via left anterior descending artery ligation. Animals were assigned to one of 4 treatment timepoints corresponding to known phases of inflammation and remodeling post-MI - 0 hours (immediate), 3 hours (acute inflammation), 4 days (proliferative), and 2 weeks (fibrosis). Intramyocardial STG+XO injections into the ischemic borderzone were performed at the designated times, and compared to control (PBS @ t=0). In vitro experiments were performed with rat aortic endothelial cells (RAEC) incubated in serum collected at each timepoint, to represent the inflammatory milieu present at time of therapy. Following XO administration to RAECs in each serum condition, proliferation, uptake of XOs into RAECs, and angiogenesis was measured. In vivo delivery of STG+XO at each timepoint was followed by invasive hemodynamic assessment via pressure-volume catheter 4 weeks post-MI. Histologic analysis of scar thickness was assessed with Masson's trichrome. Primary hemodynamic endpoints were dp/dt and end systolic elastance (Ees), a volume-independent measure of contractility. The secondary endpoint was ventricular remodeling and dilatation, as represented by scar thickness.
RESULTS: In vitro experiments suggest highest relative uptake of XOs by endothelial cells at 4 days vs at 0h, 3h, or 2 weeks. Hemodynamics were significantly improved with STG+XO therapy delivered at 4 days vs control with regards to both dp/dt (5789±386.2mmHg/s vs 2634±348.2; p<0.0001) and Ees (0.58±0.12mmHg/uL vs 0.29±0.03; p=0.04). Furthermore, dp/dt in the 4 day group was significantly higher than in the 0h group (5789±386.2mmHg/s vs 3766±279.3; p=0.008). Preservation of ventricular geometry and scar thickness was significantly greater in the 4d group compared to control (37.99±4.2 vs 26.27±5.7 units, p=0.03).
CONCLUSIONS: Delayed delivery of STG+XO therapy at 4 days post-MI improves LV contractility and preserves global ventricular geometry with reduced thinning and dilatation of the infarcted tissue, compared to PBS controls and therapy at the time of acute MI. These findings have vast implications for potentially optimizing the effects of other cell-derived therapies via strategic timing of therapeutic intervention.
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