Extracellular vesicles in cardiac repair and regeneration: Beyond stem-cell-based approaches

Abstract

The adult human heart poorly regenerate after injury due to the low self-renewal capability retained by adult cardiomyocytes. In the last two decades, several clinical studies have reported the ability of stem cells to induce cardiac regeneration. However, low cell integration and survival into the tissue has limited stem-cell-based clinical approaches. More recently, the release of paracrine mediators including extracellular vesicles (EV) has been recognized as the most relevant mechanism driving benefits upon cell-based therapy. In particular, EV have emerged as key mediators of cardiac repair after damage, in terms of reduction of apoptosis, resolution of inflammation and new blood vessel formation. Herein, mechanisms involved in cardiac damage and regeneration, and current applications of EV and their small non-coding RNAs (miRNAs) in regenerative medicine are discussed.

Keywords: cardiac repair; cell therapy; extracellular vesicles; inflammation; myocardial damage.

FIGURE 1

Regulation of inflammation in cardiac remodeling/fibrosis. Damaged or dead cardiomyocytes secrete DAMPs, which interact with PRRs to produce cytokines, including IL-l, IL-2, IFN-y, and TNF-α. These molecules promote immune cell recruitment in the heart, translating in myofibroblast activation and cardiac fibrosis. The figure was partly generated using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

FIGURE 2

Mechanisms involved in cardiac regeneration. Cardiomyogenesis and EV-mediated effects, such as angiogenesis, reduction of apoptosis and resolution of inflammation drive the damaged cardiac tissue towards healing. This figure was partly generated using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.