Interleukin-10 Deficiency Alters Endothelial Progenitor Cell -Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment.

Rationale: Systemic inflammation compromises the reparative properties of Endothelial Progenitor Cell (EPC) and their exosomes on myocardial repair, while the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of Interleukin-10 (IL-10) deficient-EPC-derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity. Methods and Results: Using interleukin-10 (IL-10) knockout (KO) mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild type EPC and IL-10KO-EPC. In a mouse model of myocardial infarction (MI) WT-EPC-Exo treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size and promoted post-MI neovascularization, while IL-10KO-EPC-Exo treatment showed diminished and opposite effects. Mass spectrometry analysis revealed WT-EPC-Exo and IL-10KO-EPC-Exo contain different protein expression pattern. Amongst differentially expressed proteins, Integrin Linked Kinase (ILK) was highly enriched in both IL-10KO-EPC-Exo as well as TNFα treated Mouse Cardiac Endothelial Cell derived exosomes (MCEC+TNFα-Exo). ILK enriched exosomes activated NFκB pathway and NFkB-dependent gene transcription in recipient endothelial cells and this effect was partly attenuated though ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10KO-EPC-Exo significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size and enhanced post-MI neovascularization in MI mouse model. Conclusions: IL-10 deficiency/inflammation alters EPC derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes and ILK-mediated activation of NFĸB pathway in recipient cells while ILK knockdown in exosomes attenuates NFĸB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alters stem cell-exosome mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.