Long noncoding ribonucleic acid ENST00000517482 enhances mesenchymal stem cell therapy against acute lung injury

Abstract

Recent findings reveal that long non-coding RNA ENST00000517482 (ENST) protects mesenchymal stem cells (MSCs) from mitochondrial apoptosis via the microRNA-539/c-MYC axis, thereby enhancing their paracrine efficacy against lipopolysaccharide-induced acute lung injury (ALI) in vitro. Furthermore, ENST promotes autophagy through LC3B, autophagy related 7, and autophagy related 5, suggesting a dual role in MSC-mediated lung repair. However, translating these benefits to in vivo applications faces critical challenges. Autophagy, while protective in vitro, may exacerbate epithelial damage during ischemia-reperfusion or hyperoxic ALI if uncontrolled. Additionally, systemic MSC infusion suffers from poor pulmonary engraftment, limiting therapeutic efficiency. To overcome these barriers, future research should prioritize extracellular vehicle-based delivery of ENST-modified MSCs, combined with strategies to fine-tune autophagy via phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin or AMP-activated protein kinase/c-Jun-N-terminal kinase modulation. Rigorous validation in endotoxemia and ventilator-induced ALI models, with longitudinal assessment of autophagy and mitochondrial dynamics, will be essential to optimize this approach for clinical translation.

Keywords: Acute lung injury; AMP-activated protein kinase/c-Jun-N-terminal kinase; Autophagy; ENST00000517482; Extracellular vesicles; Mesenchymal stem cell; MicroRNA-539/c-MYC axis; Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin; Stem-cell therapy

Core Tip: Long non-coding RNA ENST00000517482 enhances the survival of mesenchymal stem cells by protecting mitochondria from apoptosis through the microRNA-539 and c-MYC signaling axis. While this mechanism strengthens stem cell paracrine effects in vitro, its simultaneous activation of autophagy poses potential risks of aggravating lung tissue injury in living organisms. Furthermore, conventional systemic infusion of mesenchymal stem cells results in limited therapeutic efficiency due to poor lung targeting. This article emphasizes the importance of controlling autophagy levels and adopting extracellular vesicle-based delivery systems as critical steps to translate ENST00000517482-mediated stem cell therapies into safe and effective treatments for acute lung injury.