Abstract
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 μm). Here, we demonstrate in diabetic mice that embryonic stem cell (ESC)-derived EV-mimetic NVs (ESC-NVs) completely restore erectile function (~96% of control values) through enhanced penile angiogenesis and neural regeneration in vivo, whereas ESC partially restores erectile function (~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.
Highlights
Extracellular vesicles (EVs) have attracted particular interest in various fields of biology and medicine
Recent study has demonstrated in diabetic rats that intracavernous injection of adipose-derived EVs isolated by ultracentrifugation of culture supernatant restored erectile function by increasing cavernous endothelial content and by decreasing cavernous fibrosis
We examined the proangiogenic or neurotrophic effects of embryonic stem cell (ESC)-NVs in primary cultured mouse cavernous endothelial cells (MCEC) and pericytes (MCP) in vitro; in cultured aortic ring and major pelvic ganglion (MPG) ex vivo; and in diabetic mice in vivo
Summary
Extracellular vesicles (EVs) have attracted particular interest in various fields of biology and medicine. We recently developed cell-derived EV-mimetic nanovesicles (NVs) by extruding cells serially through filters with diminishing pore sizes (10, 5, and 1 μm). One of the major hurdles in the clinical application of EV-based therapy is the low production yield of EVs and the difficulty of purification[10] To overcome these limitations, our colleagues recently developed cell-derived EV-mimetic nanovesicles (NVs) by extruding cells serially through filters with diminishing pore sizes (10, 5, and 1 μm). Our colleagues recently developed cell-derived EV-mimetic nanovesicles (NVs) by extruding cells serially through filters with diminishing pore sizes (10, 5, and 1 μm) These cell-derived EV-mimetic NVs have similar characteristics with the natural EVs, but have 100-fold higher production yield[18,19]
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