Eur J Clin Invest. 2026 May;56(5):
e70212
BACKGROUND: Human amniotic membrane mesenchymal stem cells (hAMSCs) hold strong cardioprotective potential, yet their mechanisms of action remain largely elusive.
METHODS AND RESULTS: C57BL/6 mice were subjected to cardiac ischemia/reperfusion (I/R) and received intravenous (IV) 2 × 105 hAMSCs at 2, 7 or 14 days post-reperfusion. Cardiac function and MIAT/miR-150/HOXA4 signalling were assessed. Mice treated 2 days post-I/R markedly improved LVEF and reduced myocardial necrosis and fibrosis by Day 21. Minimal hAMSC engraftment, evidenced by SSEA-4 immunostaining, suggests paracrine rather than direct cellular effects. Guided by GWAS implicating miRNAs in myocardial infarction, we identified miR-150 as a key effector, finding that hAMSC upregulated cardiac miR-150 and suppressed HOXA4, a profibrotic target in ischemic myocardium. In parallel, hAMSC treatment reduced cardiac MIAT, a lncRNA that sequesters miR-150, uncovering a mechanism of cardioprotection via MIAT downregulation post-reperfusion. Notably, CRISPR-Cas9 miR-150-silenced hAMSC exhibited severely impaired cardioprotective effects compared to wild-type cells, confirming the functional role of miR-150. miR-150 was identified as a key extracellular vesicle (EV) cargo released by hAMSC under hypoxic conditions, both in vitro and in hAMSC-injected I/R mice. Strickingly, administration of miR-150-enriched EVs to mice recapitulated the therapeutic benefits of hAMSC, underscoring miR-150-5p as central mediator of hAMSC-iduced cardioprotection.
CONCLUSIONS: hAMSCs promote cardioprotection following I/R via the MIAT/miR-150-5p/HOXA4 axis, in which miR-150-5p plays a central role. These findings provide loss-of-function evidence about the therapeutic potential of hAMSC-derived EVs as a novel cell-free exosome-based strategy for the treatment of acute myocardial infarction.
Keywords: HOXA4; MIAT; acute myocardial infarction; cardioprotection; extracellular vesicles; human amniotic mesenchymal stem cells; ischemia/reperfusion; miR‐150‐5p