^{Glioblastoma Exosomes for Therapeutic Angiogenesis in Peripheral Ischemia}

Abstract

Peripheral ischemia as a result of occlusive vascular disease is a widespread problem in patients older than the age of 65. Angiogenic therapies that can induce microvascular growth have great potential for providing a long-lasting solution for patients with ischemia and would provide an appealing alternative to surgical and percutaneous interventions. However, many angiogenic therapies have seen poor efficacy in clinical trials, suggesting that patients with long-term peripheral ischemia have considerable therapeutic resistance to angiogenic stimuli. Glioblastoma is one of the most angiogenic tumor types, inducing robust vessel growth in the area surrounding the tumor. One major angiogenic mechanism used by the tumor cells to induce blood vessel growth is the production of exosomes and other extracellular vesicles that can carry pro-angiogenic and immunomodulatory signals. Here, we explored whether the pro-angiogenic aspects of glioblastoma-derived exosomes could be harnessed to promote angiogenesis and healing in the context of peripheral ischemic disease. We demonstrate that the exosomes derived from glioblastoma markedly enhance endothelial cell proliferation and increase endothelial tubule formation in vitro. An analysis of the microRNA expression using next generation sequencing identified that exosomes contained a high concentration of miR-221. In addition, we found that glioblastoma exosomes contained significant amounts of the proteoglycans glypican-1 and syndecan-4, which can serve as co-receptors for angiogenic factors, including fibroblast growth factor-2 (FGF-2). In a hindlimb ischemia model in mice, we found that the exosomes promoted enhanced revascularization in comparison to control alginate gels and FGF-2 treatment alone. Taken together, our results support the fact that glioblastoma-derived exosomes have powerful effects in increasing revascularization in the context of peripheral ischemia.

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

“…Coincidentally, EVs derived from monocytes containing miR-27a also play promoting role in the polarization of M2 macrophages [17]. Moreover, miR-27a that promotes proliferation and migration of glioblastoma cells is abundant in glioblastoma-EVs [18]. These works further support our statement that miR-27a-3p contained in glioblastoma-EVs could polarize M2 macrophage.…”

Natural Biomaterials for Cardiac Tissue Engineering: A Highly Biocompatible Solution

“…Exosomes loaded in alginate-based hydrogels might be considered in this area for preserving the exosomes in the wound site and acting as an extracellular matrix. Monteforte et al (201) reported the use of alginate hydrogels loaded with glioma-derived exosomes to enhance revascularization in peripheral ischemia. Alginate beads with exosomes induced angiogenesis in vivo showing their potential therapeutic effect for isquimia.…”

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme

“…The pro-angiogenic effect of GBM MVs was associated with several angiogenic proteins, such as vascular endothelial growth factor (VEGF), angiogenin, interleukin-6 (IL-6), IL-8, tissue factor (TF), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 [33,34,40,42,[105][106][107][108]. For instance, GSC-EVs loaded with VEGF initiate angiogenesis in brain endothelial cells, thus, supporting GSCs perivascular niche.…”

“…Likewise, EVs-delivered miR26a promotes angiogenesis of HBMECs by up-regulating VEGF, through the activation of the PI3K/Akt pathway, via PTEN inhibition [118]. Similarly, exosomal miR-221 from GSCs markedly enhances endothelial tube formation and proliferation [107]. Again, exosome-mediated transfer of long non-coding RNA POU3F3 (linc-POU3F3) from GSCs to brain ECs can promote angiogenesis.…”