Abstract Body (Do not enter title and authors here): Background: Recently we reported the development of a novel lab-grown human 3D extracellular matrix (ECM) from cultured human mesenchymal stem cells (MSCs) to mitigate product variability, immunogenicity, and preserve ECM function/architecture.
Hypothesis: We hypothesized that intramyocardial (IM) but not systemic intravenous (IV) administration of ECM will localize to myocardium and improve post-MI cardiac function by altering local protein expression and coronary angiogenesis.
Goals/Aims: Determine whether IM and IV administration of fluorophore-labeled ECM localize in post-MI myocardium and induce improvement in cardiac function in vivo.
Methods/Approach: ECM particles (Dia ~200 microns) were suspended at 63,400 particles per mL. For biodistribution, ECM particles were conjugated to the fluorophore, TL680, and mice underwent either 10uL IM or 100uL tail vein (TV) injections with ECM +/- TL680 followed by quantification of end organ epifluorescence by IVIS imaging. WT mice (8-10 weeks, both sexes) underwent LAD coronary artery ligation and IM injection of 10 uL ECM (n=10) or 10 uL of saline (n=10). Echocardiographic analysis of post-op day (POD) 3, 7, 14, 21, and 28, and cardiac IHC and immunofluorescent studies were performed. For proteomic analysis, solubility-fractionated tissues from ischemic and contralateral perfused sections of hearts were analyzed using LC-MS/MS (n=3).
Results: Biodistribution study showed localized epifluorescence in the heart after IM injection, but no significant peripheral end organ epifluorescence in the IM ECM+TL680 cohort (p>0.05) or in TV ECM+TL680 cohort (p>0.05). Significant reduction in infarct size (p=0.04) and increased fractional shortening (p<0.05), with a trend towards improved ejection fraction in IM ECM group were observed. Capillary density in ischemic myocardium of ECM group was increased compared to control (p=0.01), with a trend towards increased arteriolar density (p=0.12). Proteomic analysis of mouse hearts (n=3) showed significant changes associated with ECM affecting contractility, ECM organization, cellular adhesion, and metabolism.
Conclusion: IM injected ECM particles remain localized to the injection site and significantly reduced infarct size and improved coronary angiogenesis and cardiac function post-MI. Proteome changes linked to the ECM matrisome included cellular contractility and metabolism in ECM-injected hearts. These findings suggest that 3D ECM represent a promising therapy for MI.