# Hypoxia‐preconditioned MiotEVs from bone marrow mesenchymal stem cells inhibit myocardial infarction‐induced cardiac fibrosis

## TL;DR

Hypoxia-preconditioned mitochondrial extracellular vesicles from bone marrow stem cells reduce heart damage and fibrosis after a heart attack.

## Contribution

Hypoxia-BMSC MitoEVs are shown to inhibit cardiac fibrosis via QKI-mediated translational suppression and mitochondrial support.

## Key findings

- Hypoxia-BMSC MitoEVs inhibit TGF-β1-driven myofibroblast activation and restore mitochondrial function in vitro.
- Systemic delivery of Hypoxia-BMSC MitoEVs reduces cardiac fibrosis and improves heart function in a murine MI model.
- QKI is critical for MitoEV antifibrotic effects, acting via m7G-modified RNA interactions to suppress fibrotic mRNA translation.

## Abstract

Hypoxia‐preconditioned bone marrow mesenchymal stem cell‐derived mitochondrial extracellular vesicles (Hypoxia‐BMSC MitoEVs) emerged as a novel therapeutic candidate for myocardial infarction (MI)‐induced cardiac fibrosis. Here, we demonstrate that MitoEVs isolated from hypoxic BMSCs, rich in intact mitochondria and the RNA‐binding protein Quaking (QKI), potently inhibited TGF‐β1‐driven myofibroblast activation in vitro by suppressing α‐SMA and collagen expression while restoring mitochondrial oxidative phosphorylation and metabolic balance. In a murine MI model, systemic delivery of Hypoxia‐BMSC MitoEVs attenuated cardiac fibrosis, reduced infarct size, and improved left ventricular function. Pharmacological inhibition of mitochondrial ATP synthase in MitoEVs similarly diminished their therapeutic efficacy. Mechanistically, MitoEVs delivered QKI protein to cardiac fibroblasts, where it inhibited translation of fibrotic mRNAs via m7G‐modified RNA interactions. Genetic ablation of QKI in BMSCs abrogated MitoEV‐mediated antifibrotic effects both in vitro and in vivo, confirming QKI as a critical effector. These results suggested that both QKI‐driven translational suppression and mitochondrial bioenergetics underpin their antifibrotic action. These findings highlight Hypoxia‐BMSC MitoEVs as a therapeutic strategy to mitigate post‐MI fibrosis, warranting further exploration for clinical translation.