Abstract 16549: Single Cell Encapsulation Primes Explant-Derived Cardiac Stem Cells to Adopt an Invasive/Migratory Phenotype
Background: Single cell encapsulation of explant-derived cardiac stem cells (EDCs) boosts therapeutic regeneration by abrogating detachment induced cell death and vascular clearance of cocooned cells. Here, we test the hypothesis that encapsulation instructs cells to adopt an invasive/migratory phenotype favoring mobilization and increased myocardial function after transplantation into the injured heart.
Methods/Results: Human EDCs were encapsulated within agarose cocoons of variable density (2 vs. 3.5% agarose) supplemented with extracellular matrix (fibrinogen and fibronectin). Multiplex analysis demonstrated that encapsulation alone promoted greater expression of matrix metalloproteinases (MMP1, MMP10 and EMMPRIN; p<0.01 vs. non-encapsulated EDCs) while increasing capsule density enhanced the secretion of fibroblast growth factor and hepatocyte growth factor by 501±90 fold (p=0.002 vs. 2% agarose capsules, n=4) and by 75±17 fold (p=0.02 vs. 2% agarose capsules, n=4), respectively. In vitro kinetic profiling revealed that encapsulation within 3.5% agarose capsules delayed the half time of cell emergence from the capsule from 16±2 hours to 42±12 hours (p=0.02 vs. 2% agarose capsules; n=3). Once cells escaped the capsules, real time profiling demonstrated that increasing capsule density primed cells to migrate 3.8±0.3 fold faster across a porous membrane (p=0.0001 vs. 2% agarose capsules, n=4). Transplant of EDCs encapsulated in 2% agarose into the myocardium of immunodeficient mice 1 week after infarction increased the 4-week post infarct ejection fraction from 32.9±1.3% to 37.4±0.5% as compared to non-cocooned EDCs (p=0.008, n=6 per treatment group). Although encapsulation increased long term retention of transplanted cells by 6±2 fold (p=0.04 vs. suspended EDCs), increasing capsule density did not boost the long term cell retention (p=0.7 vs. 2% encapsulation) despite providing a marked increase in myocardial function (4-week post infarct ejection fraction: 47.6±1.5%, p=0.0001 vs 2% agarose, n=8).
Conclusion: Encapsulation within dense cocoons enhances the migratory/invasive nature of EDCs to promote indirect repair of damaged myocardium.
Author Disclosures: P. Kanda: None. D.J. Stewart: None. D.R. Davis: None.
- © 2016 by American Heart Association, Inc.