Endothelial cells induce degradation of ECM through enhanced secretion of MMP14 carried on extracellular vesicles in venous malformation.

Venous malformations (VMs), featuring localized dilated veins, are the most common developmental vascular anomalies. Aberrantly organized perivascular extracellular matrix (ECM) is one of the prominent pathological hallmarks of VMs, accounting for vascular dysfunction. Although previous studies have revealed various proteins involved in ECM remodeling, the detailed pattern and molecular mechanisms underlying the endothelium-ECM interplay have not been fully elucidated. Our previous studies revealed drastically elevated extracellular vesicle (EV) secretion in VM lesions. Here, we identified increased EV-carried MMP14 in lesion fluids of VMs and culture medium of TIE2-L914F mutant endothelial cells (ECs), along with stronger ECM degradation. Knockdown of RAB27A, a required regulator for vesicle docking and fusion, led to decreased secretion of EV-carried MMP14 in vitro. Histochemical analysis further demonstrated a highly positive correlation between RAB27A in the endothelium and MMP14 in the perivascular environment. Therefore, our results proved that RAB27A-regulated secretion of EV-MMP14, as a new pattern of endothelium-ECM interplay, contributed to the development of VMs by promoting ECM degradation.

Deciphering the Heterogeneity Landscape of Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles for Precise Selection in Translational Medicine.

Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) have been considered promising therapeutics for disease treatments. However, MSC-EVs harvested from different tissues present unique biological features reflective of their origins. The heterogeneity of MSC-EVs constitutes an important barrier to their precise application in clinical translation that may probably lead to uncertain therapeutic effects. To give hints for future clinical translation, five MSCs are employed, whose derived EVs are most intensively utilized, namely bone marrow mesenchymal stem/stromal cells (BMMSCs), umbilical cord stem/stromal cells (UCSCs), adipose-derived stem/stromal cells (ASCs), dermal stem/stromal cells (DSCs) and dental pulp stem/stromal cells (DPSCs) and the heterogeneity landscape of the corresponding MSC-EVs are documented. Overall, the basic parameters, stability, and biosafety of different MSC-EVs are indiscriminate. Strikingly, UCSC-EVs exhibit distinguishing productivity. UCSC-EVs as well as DPSC-EVs present better drug loading/delivery capacity. In addition, the heterogeneity of different MSC-EVs in cargo diversity, cellular affinity, organ biodistribution, and therapeutic effects may cue the rational selection in different disease treatments. Through a combined assessment, a rational strategy is combined for selecting MSC-EVs in future clinics. Offering a panoramic view of MSC-EVs harvested from different tissues, the current study may provide guidelines for the precise selection of MSC-EVs in next-generation therapeutics.