# KLF5 Regulation of Exosome-Derived miR-152-3p From Bone Marrow Stem Cells Improves Ventricular Arrhythmia After Myocardial Infarction

## TL;DR

This study shows that enhancing KLF5 in bone marrow stem cells helps reduce heart damage and arrhythmias after a heart attack by improving cell communication and reducing fibrosis.

## Contribution

The study reveals that KLF5 enhances BMSCs' cardioprotective effects via exosome-derived miR-152-3p transfer to cardiac fibroblasts.

## Key findings

- KLF5-overexpressing BMSCs reduced ventricular fibrosis and arrhythmias in mice after MI.
- BMSCs inhibited fibroblast activation and altered potassium currents through paracrine effects.
- KLF5 facilitated miR-152-3p transfer from BMSCs to fibroblasts, improving cardiac function.

## Abstract

Cardiac fibroblasts (CFs) are activated into cardiac myofibroblasts (CMFs) in myocardial infarction (MI) and promote fibrosis, playing a crucial role in deteriorating cardiac function and inducing fatal arrhythmias. Transplantation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a promising therapeutic approach for ischemic heart diseases, including MI. Recent studies have indicated that BMSCs can modulate the survival, differentiation, and antifibrotic activity of CFs. Kruppel-like factor 5 (KLF5) is a significant transcription factor involved in maintaining stem cell properties. In this study, we aimed to investigate whether overexpression of KLF5 could enhance the cardioprotective characteristics of BMSCs, particularly in terms of mitigating structural and electrical remodeling. Our in vivo experiments revealed that transplantation of KLF5-overexpressing BMSCs in mice with MI led to a substantial reduction in ventricular fibrosis and the occurrence of ventricular arrhythmias (VAs). In vitro coculture experiments demonstrated that BMSCs could inhibit CFs activation and cytoskeleton protein bundling induced by hypoxia through paracrine effects, resulting in reduced expression of α-SMA and Collagen I. Furthermore, coculturing BMSCs significantly reduced the expression of connexin 43, alleviated hypoxia, increased the expression of inward-rectifier K+ current (Kir), and decreased voltage-dependent K+ (Kv) currents. Mechanistically, KLF5 enhanced the effects of BMSCs by facilitating the transfer of miR-152-3 p from BMSCs-derived exosomes to CFs. Overall, our findings show that BMSCs transplantation promotes the recovery of cardiac function and reduces the incidence of arrhythmias by inhibiting CFs activation and modulating CFs Kir current remodeling. Additionally, overexpression of KLF5 enhances the cardioprotective effects of BMSCs.