C166 EVs potentiate miR cardiac reprogramming via miR-148a-3p

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Therapy

Background:

• Direct reprogramming of cardiac fibroblasts into cardiomyocytes offers a promising strategy for cardiac repair.
• Current delivery methods for reprogramming factors face challenges in efficacy and efficiency.
• Extracellular vesicles (EVs) are being explored as novel delivery vehicles for therapeutic molecules.

Purpose of the Study:

• To investigate C166-derived EVs as delivery agents for microRNA (miRNA) combinations for cardiac fibroblast reprogramming.
• To evaluate the efficacy of EV-mediated delivery in improving cardiac function in a myocardial infarction model.
• To identify novel miRNAs within EVs that enhance reprogramming efficiency.

Main Methods:

• Screening of delivery agents for miRNA combinations.
• In vitro and in vivo studies using C166-derived EVs for miRNA delivery.
• Assessment of cardiomyocyte conversion, fibrosis, and cardiac function in a myocardial infarction mouse model.
• Identification and functional validation of specific miRNAs and their targets.

Main Results:

• C166-derived EVs effectively delivered miRNA combinations both in vitro and in vivo.
• EV-mediated delivery resulted in significant cardiac fibroblast to cardiomyocyte conversion (approximately 20%) in vivo.
• Treatment reduced fibrosis and improved cardiac function in a myocardial infarction model.
• EV-mediated delivery showed enhanced reprogramming efficacy compared to lipid-based transfection.
• MiR-148a-3p, found within C166 EVs, was identified as a key factor enhancing reprogramming by targeting Mdfic.
• Mdfic was confirmed as a repressor of cardiomyocyte-specific gene expression.

Conclusions:

• C166-derived EVs represent an effective delivery system for reprogramming factors in cardiac fibroblasts.
• EV-mediated delivery of miRNA combinations promotes cardiac repair and improves cardiac function post-myocardial infarction.
• MiR-148a-3p within C166 EVs is a novel enhancer of cardiomyocyte reprogramming by suppressing Mdfic.