Mesenchymal stem cell therapies for ARDS: translational promise and challenges.

Over the past decade, global investigations have rigorously assessed the safety and therapeutic potential of mesenchymal stem cells (MSCs) in managing acute respiratory distress syndrome (ARDS). MSCs, obtained from sources like bone marrow, adipose tissue, and umbilical cord, exert therapeutic effects in ARDS primarily through complex paracrine mechanisms, including anti-inflammatory, immunoregulatory, pro-reparative, antioxidant, antimicrobial, and mitochondrial transfer functions. Preclinical studies have consistently demonstrated significant therapeutic benefits. Clinical trials have further confirmed a favorable safety profile, with no significant infusion-related toxicity or serious adverse events observed even at higher doses (up to 10 × 10⁶ cells/kg) or following multiple administrations. Yet, while some early-phase clinical trials have not conclusively demonstrated a significant reduction in mortality among ARDS patients, multiple studies note diminished inflammatory biomarkers, enhanced markers of endothelial and epithelial repair (e.g., angiopoietin-2), and suggestive benefits in subgroups like younger patients or those receiving higher doses of viable cells. MSC-derived therapies, particularly extracellular vesicles and conditioned medium, represent promising "cell-free" strategies that may overcome limitations associated with live-cell therapy. Despite encouraging progress, clinical translation faces challenges, including optimizing cell sources, preparation, dosing, delivery, and developing robust potency assays. Future research should prioritize large, high-quality randomized trials to confirm efficacy across various ARDS etiologies and clinical phenotypes, evaluate repeat dosing, and explore innovative strategies such as gene modification, cellular preconditioning, and combination therapies. Collectively, MSCs and their derivatives hold substantial potential for ARDS treatment, though their widespread application requires further validation and a deeper understanding of their interactions with the complex ARDS microenvironment.