Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy

Abstract

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)–mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…Moreover, these EV-primed fibroblasts, or the EVs themselves, were therapeutic in rat chronic MI, resulting in improved left ventricular ejection fraction, reduced scarring, and increased microvessel density [ 207 ]. Similar results were obtained after administration of human CDC EVs in porcine models of acute or chronic MI [ 208 ] or pediatric dilated cardiomyopathy [ 209 ]. Wnt/β-catenin signaling in the CDC was critical for the potency of CDC and proposed to enhance an antifibrotic EV miR-92- BMP pathway [ 210 ].…”

“…Overexpression of β-catenin and Gata4 in fibroblasts imparted therapeutic properties on the cells or their EVs as shown by, respectively, improved survival and heart function in mouse MI models or functional improvement and anti-fibrotic effects in the skeletal muscle of the mdx mouse model of Duchenne muscular dystrophy [ 210 ]. In the dilated cardiomyopathy model, the improvement in cardiac function and reduced fibrosis was attributed to the enrichment in CDC EVs of proangiogenic and cardioprotective miRs including miR-146a-5p which attenuated fibrosis by reducing inflammation and apoptosis through its targeting of TRAF6/Smad4/FOS [ 209 ]. CPC-derived exosomes also resulted in improvement of heart function and reduced apoptosis and fibrosis when administered to a mouse model of doxorubicin-induced dilated cardiomyopathy [ 211 ] and the therapeutic outcome was improved by conjugation of the exosomes with cardiac homing peptide which targets ischemic myocardium [ 212 ].…”

Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration

“…Several miRNAs such as miR-126-5p, miR-132-3p, miR-146a-5p, miR-181b, miR-210-3p, and miR-451a, known to induce antifibrotic, antiapoptotic, and proangiogenic properties, were found to be enriched in CDC exosomes from both human and swine compared to human cardiac fibroblast (HCF) exosomes. Pretreatment of CDCs with exosome inhibitor GW4869 abrogated the cardiac-protective functions of CDCs [ 35 ], confirming the role of their exosomes. The inhibition of specific pro-inflammatory and antiangiogenic miRNAs such miRNA 375 and miRNA 377 in bone marrow progenitor cells likely restricts the transfer of these miRNAs into the progenitor cell exosomes.…”

“…Moreover, sequencing human serum exosomes has revealed an abundance of circular RNAs within them [ 34 ]. A recent study demonstrated that swine cardiosphere-derived cells (CDCs) improved cardiac functions in a swine model of dilated cardiomyopathy (DCM), and this functional improvement was found to be associated with their miRNA composition [ 35 ]. Several miRNAs such as miR-126-5p, miR-132-3p, miR-146a-5p, miR-181b, miR-210-3p, and miR-451a, known to induce antifibrotic, antiapoptotic, and proangiogenic properties, were found to be enriched in CDC exosomes from both human and swine compared to human cardiac fibroblast (HCF) exosomes.…”

Exosomes Derived From miR-214-3p Overexpressing Mesenchymal Stem Cells Promote Myocardial Repair

“…The lipid membrane structure of exosomes is similar to that of liposomes. Thus, exosome can protect nucleic acids from degradation, and facilitate transport of miRNAs, mRNAs, and proteins to receptor cells with no virulence and adverse immunogenicity [14][15][16] . Genetic engineering of miRNA in exosomes can further enhance the protective effects on different diseases 17,18 .…”