Large extracellular vesicles from induced pluripotent stem cell-marrow stem cells enhance limb angiogenesis via ERK/MAPK

<b>Aim:</b> This study aims to investigate the effects of large extracellular vesicles (EVs) induced by pluripotent stem cell-derived mesenchymal stem cells on lower limb ischemic disease and explore its potential mechanisms. <b>Materials &amp; methods:</b> The pathology of muscles was accessed by H&amp;E staining and immunofluorescence staining. <i>In vitro</i>, we conducted wound-healing assay, tube formation assay, RT qPCR, ELISA, RNA sequencing and proteomic analysis. <b>Results:</b> iMSCs-lEVs alleviated the injury of ischemic lower limb and promoted the recovery of lower limb function. <i>In vitro</i>, iMSCs-lEVs promoted the proliferation, migration, and angiogenesis of HMEC-1 cells by regulating the ERK/MAPK signing pathway. <b>Conclusion:</b> This study demonstrated that iMSCs-lEVs promoted endothelial cell angiogenesis via the ERK/MAPK signaling pathway, thereby improving function after lower limb ischemic injury. The therapeutic potential of large extracellular vesicles derived from induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs-lEVs) in promoting recovery after lower limb ischemia has rarely been investigated so far. Improving the functional status of endothelial cells may be effectively alleviate the symptoms of lower limb ischemia. iMSCs-lEVs could restore blood flow perfusion in ischemic tissues of mouse lower limbs and improved their function following ischemia. iMSCs-lEVs promoted endothelial cell proliferation, migration and tube formation by regulating the ERK/MAPK signaling pathway. These findings reveal the molecular mechanisms underlying the application of iMSCs-lEVs on mast cells and provide a novel therapeutic strategy for pain caused by tendinopathy.