Adult cardiomyocytes-derived EVs for the treatment of cardiac fibrosis

Marta Prieto-Vila ¹, Yusuke Yoshioka ¹, Naoya Kuriyama ^1,2

⁰Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan.

Journal of Extracellular Vesicles +

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June 28, 2024

View abstract on PubMed

Summary

Cardiomyocyte-derived extracellular vesicles (EVs) show promise for treating cardiac fibrosis. These EVs reduce fibroblast activation and extracellular matrix deposition, improving cardiac function in preclinical models.

Area Of Science

Cardiovascular Research
Cell Biology
Regenerative Medicine

Background

Cardiac fibrosis, characterized by fibroblast hyperactivation and excessive extracellular matrix deposition, impairs cardiac function and is a hallmark of cardiovascular diseases.
Cardiomyocyte-derived extracellular vesicles (CM-EVs) are crucial for maintaining myocardial homeostasis, but their function is disrupted in cardiac disease.

Purpose Of The Study

To investigate the therapeutic potential of healthy human adult CM-derived EVs for treating cardiac fibrosis.
To optimize the production of CM-EVs for therapeutic applications.

Main Methods

Human adult cardiomyocytes were cultured under optimized conditions using small molecules to maximize EV yield.
Extracellular vesicles (EVs) were isolated via ultracentrifugation and characterized.
The antifibrotic effects of CM-EVs were assessed in vitro using TGFβ-activated human cardiac fibroblasts and in vivo using an animal model of cardiac fibrosis.

Main Results

CM-EV treatment significantly decreased fibroblast activation markers and extracellular matrix accumulation in vitro.
EV cargo analysis revealed antifibrotic microRNAs; pathway analysis indicated reversion of activated fibroblast transcription and downregulation of pro-fibrotic signaling pathways (MAPK, mTOR, JAK/STAT, TGFβ, PI3K/Akt).
Intracardiac injection of CM-EVs in a cardiac fibrosis model reduced fibrosis, increased angiogenesis, and improved cardiac function.

Conclusions

Human adult CM-derived EVs possess potent antifibrotic properties, making them a promising cell-free therapeutic strategy for cardiac fibrosis.
Optimized CM-EV production and their specific cargo contribute to their therapeutic efficacy in preclinical models of cardiac fibrosis.

Keywords:

EVs cardiac fibrosis cardiovascular diseases cell‐free therapy extracellular vesicles microRNA