In a mouse model of myocardial infarction, IL-10 deficiency altered EPC-derived exosome reparative effects by upregulating ILK, whereas ILK knockdown in exosomes rescued their reparative function.
Does ILK knockdown in IL-10 knockout EPC-derived exosomes rescue their reparative dysfunction in a mouse model of myocardial infarction?
IL-10 deficiency impairs the reparative effects of EPC-derived exosomes on myocardial repair via ILK enrichment, and targeted ILK knockdown rescues this dysfunction, identifying ILK as a potential therapeutic target for exosome-based cardiac therapies.
Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of IL-10 (interleukin-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 IL-10 knockout mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild-type EPC and IL-10 knockout EPC. In a mouse model of myocardial infarction (MI), wild-type EPC-derived exosome treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size, and promoted post-MI neovascularization, whereas IL-10 knockout EPC-derived exosome treatment showed diminished and opposite effects. Mass spectrometry analysis revealed wild-type EPC-derived exosome and IL-10 knockout EPC-derived exosome contain different protein expression pattern. Among differentially expressed proteins, ILK (integrin-linked kinase) was highly enriched in both IL-10 knockout EPC-derived exosome as well as TNFα (tumor necrosis factor-α)-treated mouse cardiac endothelial cell–derived exosomes (TNFα inflamed mouse cardiac endothelial cell–derived exosome). ILK-enriched exosomes activated NF-κB (nuclear factor κB) pathway and NF-κB–dependent gene transcription in recipient endothelial cells and this effect was partly attenuated through ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10 knockout EPC-derived exosome 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 NF-κB pathway in recipient cells, whereas ILK knockdown in exosomes attenuates NF-κB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alter stem cell-exosome–mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.
Yue et al. (Mon,) conducted a other in Myocardial infarction (mouse model). ILK knockdown in IL-10 knockout EPC-derived exosomes vs. Wild-type EPC-derived exosomes / IL-10 knockout EPC-derived exosomes was evaluated on Left ventricle cardiac function, MI scar size, and post-MI neovascularization. In a mouse model of myocardial infarction, IL-10 deficiency altered EPC-derived exosome reparative effects by upregulating ILK, whereas ILK knockdown in exosomes rescued their reparative function.