Activated Stat5 trafficking Via Endothelial Cell-derived Extracellular Vesicles Controls IL-3 Pro-angiogenic Paracrine Action

Abstract

Soluble factors and cell-derived extracellular vesicles (EVs) control vascular cell fate during inflammation. The present study investigates the impact of Interleukin 3 (IL-3) on EV release by endothelial cells (ECs), the mechanisms involved in EV release and paracrine actions. We found that IL-3 increases EV release, which is prevented by IL-3Ralpha blockade. EVs released upon IL-3 stimulation were able to induce pro-angiogenic signals as shown by chromatin immunoprecipitation (ChIP) assay performed on the promoter region of cyclin D1 and tridimensional tube-like structure formation. We herein demonstrate that these effects rely on the transfer of miR-126-3p, pre-miR-126 and, more importantly, of activated signal transduction and activator of transcription 5 (pSTAT5) from IL-3-EV cargo into recipient ECs. We show, using the dominant negative form (ΔN)STAT5 and an activated STAT5 (1*6STAT5) constructs, that STAT5 drives IL-3-mediated EV release, miR-126-3p and pSTAT5 content. Finally, using EVs recovered from ΔNSTAT5 expressing ECs, we provide evidence that miR-126-3p and pSTAT5 trafficking is relevant for IL-3-mediated paracrine pro-angiogenic signals. These results indicate that IL-3 regulates EC-EV release, cargo and IL-3 angiogenic paracrine action via STAT5. Moreover, these results provide evidence that EC-derived IL-3-EVs can serve as pro-angiogenic clinical delivery wound healing devices.

Stem Cell-Derived, microRNA-Carrying Extracellular Vesicles: A Novel Approach to Interfering with Mesangial Cell Collagen Production in a Hyperglycaemic Setting

“…5×10 5 cells/well of MCs were incubated with a transcriptional inhibitor, α-amanitin [31], either in the absence or in the presence of EVs that had either been pre-treated with RNAse or not. Total RNA from MCs, was subjected to qRT-PCR for miR expression.…”

Microvesicles shed from bortezomib-treated or lenalidomide-treated human myeloma cells inhibit angiogenesis in�vitro

“…Selective supportive conditions of the bone marrow (BM) microenvironment, especially BM angiogenesis (26), are involved in the development of MM. Microvesicles (MVs), also called microparticles, range in size from 100 to 1000 nm in diameter, are formed by the outward blebbing of the plasma membrane and are known as important players in the cell-to-cell communication that occurs in normal physiology and in pathological conditions such as the angiogenic process (10)(11)(12)(13)(14). A recent study has shown that MM-derived MVs (MM MVs) are internalized by endothelial cells and promote angiogenesis (14) in vitro and in vivo.…”

“…Microvesicles (MVs), a type of extracellular vesicles (EVs), are also called shedding vesicles or microparticles (MPs) and have emerged as important players in cell-to-cell communication (6)(7)(8). MVs can load and transmit bioactive molecules to target cells (9)(10)(11) and induce different signaling cascades (10,12,13). A previous study found that MVs derived from MM cells (MM MVs) can be internalized by endothelial cells and promote angiogenesis (14).…”

Exosomes play roles in sequential processes of tumor metastasis

“…Some non‐TDEs with potential pro‐angiogenic functions are also involved in angiogenesis within pre‐metastatic niche. These non‐TDEs are usually secreted by several tumor‐associated stromal cells, like tumor‐associated macrophages, platelets, endothelial cells, etc …”

“…These non-TDEs are usually secreted by several tumor-associated stromal cells, like tumor-associated macrophages, platelets, endothelial cells, etc. 80 Lymphangiogenesis is actively involved in the premetastatic niche. Lymphatic vessels may serve as initial routes for tumor lymphatic dissemination.…”