Embryonic stem cell-derived extracellular vesicle-mimetic nanovesicles rescue erectile function by enhancing penile neurovascular regeneration in the streptozotocin-induced diabetic mouse

Extracellular vesicles (EVs) have attracted particular interest in various fields of biology and medicine. However, one of the major hurdles in the clinical application of EV-based therapy is their low production yield. We recently developed cell-derived EV-mimetic nanovesicles (NVs) by extruding cells serially through filters with diminishing pore sizes (10, 5, and 1 mu m). Here, we demonstrate in diabetic mice that embryonic stem cell (ESC)-derived EV-mimetic NVs (ESC-NVs) completely restore erectile function (similar to 96% of control values) through enhanced penile angiogenesis and neural regeneration in vivo, whereas ESC partially restores erectile function (similar to 77% of control values). ESC-NVs promoted tube formation in primary cultured mouse cavernous endothelial cells and pericytes under high-glucose condition in vitro; and accelerated microvascular and neurite sprouting from aortic ring and major pelvic ganglion under high-glucose condition ex vivo, respectively. ESC-NVs enhanced the expression of angiogenic and neurotrophic factors (hepatocyte growth factor, angiopoietin-1, nerve growth factor, and neurotrophin-3), and activated cell survival and proliferative factors (Akt and ERK). Therefore, it will be a better strategy to use ESC-NVs than ESCs in patients with erectile dysfunction refractory to pharmacotherapy, although it remains to be solved for future clinical application of ESC.11Ysciescopu

Highlights of the São Paulo ISEV workshop on extracellular vesicles in cross-kingdom communication

In the past years, extracellular vesicles (EVs) have become an important field of research since EVs have been found to play a central role in biological processes. In pathogens, EVs are involved in several events during the host–pathogen interaction, including invasion, immunomodulation, and pathology as well as parasite–parasite communication. In this report, we summarised the role of EVs in infections caused by viruses, bacteria, fungi, protozoa, and helminths based on the talks and discussions carried out during the International Society for Extracellular Vesicles (ISEV) workshop held in São Paulo (November, 2016), Brazil, entitled Cross-organism Communication by Extracellular Vesicles: Hosts, Microbes and Parasites. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.11Ysciescopu

Extracellular vesicle mimetics: Novel alternatives to extracellular vesicle-based theranostics, drug delivery, and vaccines.

11135Nsciescopu

Bioinformatics tools for extracellular vesicles research

112scopu

Extracellular Vesicle-Mimetic Ghost Nanovesicles for Delivering Anti-Inflammatory Drugs to Mitigate Gram-Negative Bacterial Outer Membrane Vesicle-Induced Systemic Inflammatory Response Syndrome

Sepsis is one of the major causes of death in hospital patients and is represented by systemic inflammatory response syndrome (SIRS) associated with infection. Gram-negative bacteria including Escherichia coli can provoke sepsis by stimulating the immune systems. Outer membrane vesicles (OMVs), nanosized vesicular structures derived from Gram-negative bacteria, contain several pathogen-associated molecular patterns, and are demonstrated to mediate SIRS. Here, extracellular vesicle-mimetic ghost nanovesicles loaded with dexamethasone, an anti-inflammatory drug, are developed using alkaline solution, sonication, and buoyant density gradient ultracentrifugation. These ghost nanovesicles have comparable physical features with naturally released extracellular vesicles but have 200-fold higher production yields than extracellular vesicles. Importantly, these ghost nanovesicles are devoid of potentially unwanted luminal cargos, including cytosolic proteins and nucleic acids. By maintaining the same topology as the parental cells, these dexamethasone-loaded ghost nanovesicles derived from human U937 monocytes reduce the release of interleukin-8 from OMV-treated endothelial cells in vitro, and mitigate the symptoms of OMV-induced SIRS in vivo. This study sheds light on using extracellular vesicle-mimetic ghost nanovesicles to deliver therapeutics to treat diseases such as bacterial sepsis.11Nsciescopu

Pericyte-Derived Extracellular Vesicle-Mimetic Nanovesicles Restore Erectile Function by Enhancing Neurovascular Regeneration in a Mouse Model of Cavernous Nerve Injury

Background: Extracellular vesicle (EV)-mimetic nanovesicles (NVs) from embryonic stem cells have been observed to stimulate neurovascular regeneration in the streptozotocin-induced diabetic mouse. Pericytes play important roles in maintaining penile erection, yet no previous studies have explored the effects of pericyte-derived NVs (PC-NVs) in neurovascular regeneration in the context of erectile dysfunction. Aim: To investigate the potential effect of PC-NVs in neurovascular regeneration. Methods: PC-NVs were isolated from mouse cavernous pericytes, and neurovascular regeneration was evaluated in an in vitro study. Twelve-week-old C57BL/6J mice were used to prepare cavernous nerve injury model. Erectile function evaluation, histologic examination of the penis, and Western blots were assessed 2 weeks after model creation and PC-NVs treatment. Outcomes: The main outcomes of this study are PC-NVs characterization, intracavernous pressure, neurovascular regeneration in the penis, and in vitro functional evaluation. Results: The PC-NVs were extracted and characterized by cryotransmission electron microscopy and EV-positive (Alix, TSG101, CD81) and EV-negative (GM130) markers. In the in vivo studies, PC-NVs successfully improved erectile function in cavernous nerve injury mice (w82% of control values). Immunofluorescence staining showed significant increases in pericytes, endothelial cell, and neuronal contents. In the in vitro studies, PC-NVs significantly increased mouse cavernous endothelial cells tube formation, Schwann cell migration, and dorsal root ganglion and major pelvic ganglion neurite sprouting. Finally, Western blot analysis revealed that PC-NVs upregulated cell survival signaling (Akt and eNOS) and induced the expression of neurotrophic factors (brain-derived neurotrophic factor, neurotrophin-3, and nerve growth factor). Clinical Implications: PC-NVs may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases. Strengths & Limitations: We evaluated the effect of PC-NVs in vitro and in a mouse nerve injury model, cavernous nerve injury. Additional studies are necessary to determine the detailed mechanisms of neurovascular improvement. Further study is needed to test whether PC-NVs are also effective when given weeks or months after nerve injury. Conclusion: PC-NVs significantly improved erectile function by enhancing neurovascular regeneration. Local treatment with PC-NVs may represent a promising therapeutic strategy for the treatment of neurovascular diseases. Copyright (C) 2020, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.11Nsciescopu

Updating the MISEV minimal requirements for extracellular vesicle studies: building bridges to reproducibility

[No abstract available]11Nsciescopu