Efficacy Of Cardiosphere-derived Cells Research Articles

Mechanistic and therapeutic distinctions between cardiosphere-derived cell and mesenchymal stem cell extracellular vesicle non-coding RNA

Cell therapy limits ischemic injury following myocardial infarction (MI) by preventing cell death, modulating the immune response, and promoting tissue regeneration. The therapeutic efficacy of cardiosphere-derived cells (CDCs) and mesenchymal stem cells (MSCs) is associated with extracellular vesicle (EV) release. Prior head-to-head comparisons have shown CDCs to be more effective than MSCs in MI models. Despite differences in cell origin, it is unclear why EVs from different adult stem cell populations elicit differences in therapeutic efficacy. Here, we compare EVs derived from multiple human MSC and CDC donors using diverse in vitro and in vivo assays. EV membrane protein and non-coding RNA composition are highly specific to the parent cell type; for example, miR-10b is enriched in MSC-EVs relative to CDC-EVs, while Y RNA fragments follow the opposite pattern. CDC-EVs enhance the Arg1/Nos2 ratio in macrophages in vitro and reduce MI size more than MSC-EVs and suppress inflammation during acute peritonitis in vivo. Thus, CDC-EVs are distinct from MSC-EVs, confer immunomodulation, and protect the host against ischemic myocardial injury and acute inflammation.

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

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.

P318Exosomes mediate myocardial regeneration of cardiac progenitor cells in a swine model of dilated cardiomyopathy

Abstract Introduction Stem cell therapy has been shown to improve cardiac function. The mechanisms of therapeutic efficacy are considered the secretion of paracrine factors but the details are still unknown. Hypothesis Exosomes are extracellular vesicles containing bioactive substances such as proteins, messenger RNAs and micro RNAs. We hypothesized that exosomes may be the main paracrine factors to mediate therapeutic efficacy of cardiosphere-derived cells (CDCs). Methods Farm pigs (30 kg, n=10) were treated by intracoronary administration of 10,000 microspheres (100–300 μm) into three vessels. Two weeks later, 9.0×106 CDCs pretreated by exosome inhibitor (EI; 20μM of GW4869) or DMSO as controls were selectively infused into three coronary arteries. Evaluation of ejection fraction (EF) was performed before cell infusion and 1 month after protocol treatment. Results Pigs developed diffuse hypokinetic heart failure (baseline EF 37.1%±2.1%) and randomly assigned into two groups (CDCs with EI: n=5, CDCs with DMSO: n=5). No serious adverse events were found during the CDCs infusion. Significant improvement of EF was observed in CDCs with DMSO group (37.1%±2.1% to 42.5%±3.0%; P=0.01), whereas no change was found in CDCs with EI group (37.1%±2.4% to 36.2%±2.9%; P=0.58). Myocardial fibrosis stained by picrosirius red was significantly reduced in CDCs with DMSO group compared with CDCs with EI group (9.5±3.6% versus 17.3±5.3%; P<0.01). Conclusions We confirmed the therapeutic efficacy of CDCs and these effects were mainly mediated by exosomes.