Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA (original) (raw)
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Scientific Reports
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 expre...
The journal of sexual medicine, 2016
Muscle-derived stem cells (MDSCs) and other SCs implanted into the penile corpora cavernosa ameliorate erectile dysfunction in type 1 diabetic rat models by replenishing lost corporal smooth muscle cells (SMCs) and decreasing fibrosis. However, there are no conclusive data from models of type 2 diabetes (T2D) and obesity. To determine whether MDSCs from obese Zucker (OZ) rats with T2D at an early stage of diabetes (early diabetic SCs isolated and cultured in low-glucose medium [ED-SCs]) counteract corporal veno-occlusive dysfunction and corporal SMC loss or lipo-fibrosis when implanted in OZ rats at a late stage of diabetes and whether MDSCs from these OZ rats with late diabetes (late diabetic SCs isolated and cultured in high-glucose medium [LD-SC]) differ from ED-SCs in gene transcriptional phenotype and repair capacity. ED-SCs and LD-SCs were compared by DNA microarray assays, and ED-SCs were incubated in vitro under high-glucose conditions (ED-HG-SC). These three MDSC types were...
Open Access Macedonian Journal of Medical Sciences, 2021
This study investigated the therapeutic role of mesenchymal stem cells (MSCs) on erectile function in a diabetes mellitus erectile dysfunction (DMED) rat model by analyzing the expression of endothelial nitric oxide synthetase (eNOS), vascular endothelial growth factor (VEGF), and the 70 kilodalton heat shock proteins (HSP70). MSCs were isolated from umbilical cords (UCs), and their characteristics identified by flow cytometry and osteogenic differentiation analysis. Thirty 8-week-old rats were divided into four groups: sham, control, T1, and T2. After a 16 h fast, 24 rats were randomly selected and intraperitoneally injected with streptozotocin (STZ) to induce DM. At 8 weeks after STZ injection, rats with DMED were classified into four groups, sham, control group [DMED rats received 500 μL phosphate buffer saline (PBS)]; T1 [DMED rats treated with 500 μL PBS containing 1 × 106 UC-MSCs]; T2 [DMED rats treated with 500 μL PBS containing 2 × 106 UC-MSCs]. Eight weeks after MSCs admini...
Stem cell therapy and diabetic erectile dysfunction: A critical review
World Journal of Stem Cells, 2021
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the
Urologia Internationalis, 2021
Background and Objectives: Stem cell therapy is a novel treatment with regenerative ability that can treat erectile dysfunction (ED). This phase 1/2 clinical trial (NCT02945449) using 2 consecutive intracavernous (IC) injections of allogeneic Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) was studied for the first time in the treatment of diabetic patients with ED. The primary outcome was to assess the safety and tolerability, and the secondary outcome was to assess the efficacy of 2 consecutive IC injections of allogeneic WJ-MSCs in diabetic ED. Patients and Methods: Twenty-two diabetic patients with refractory ED were included. Two consecutive IC injections of allogeneic WJ-MSCs were performed. Tolerability was assessed immediately, and at 24 h, safety was evaluated for 12 months. Efficacy was assessed using International Index of Erectile Function-5 (IIEF-5), Erection Hardness Score (EHS), and Color Duplex Doppler Ultrasound for 12 months. Results: The procedure was wel...
International Journal of Molecular Sciences, 2022
Erectile dysfunction is a common complication associated with type 2 diabetes mellitus (T2DM) and after prostatectomy in relation to cancer. The regenerative effect of cultured adipose-derived stem cells (ASCs) for ED therapy has been documented in multiple preclinical trials as well as in recent Pase 1 trials in humans. However, some studies indicate that diabetes negatively affects the mesenchymal stem cell pool, implying that ASCs from T2DM patients could have impaired regenerative capacity. Here, we directly compared ASCs from age-matched diabetic Goto–Kakizaki (ASCGK) and non-diabetic wild type rats (ASCWT) with regard to their phenotypes, proteomes and ability to rescue ED in normal rats. Despite ASCGK exhibiting a slightly lower proliferation rate, ASCGK and ASCWT proteomes were more or less identical, and after injections to corpus cavernosum they were equally efficient in restoring erectile function in a rat ED model entailing bilateral nerve crush injury. Moreover, molecul...
The Journal of Sexual Medicine, 2012
Introduction. Men with diabetic erectile dysfunction (ED) often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. Aim. To examine whether and how freshly isolated stromal vascular fraction (SVF) promotes cavernous endothelial regeneration and restores erectile function in diabetic animals. Methods. Eight-week-old C57BL/6J mice were used. Diabetes was induced by intraperitoneal injection of streptozotocin. SVF was isolated from epididymal adipose tissues of green fluorescence protein transgenic mice. At 8 weeks after the induction of diabetes, the animals were divided into six groups: controls, diabetic mice, and diabetic mice treated with a single intracavernous injection of phosphate-buffered saline (PBS) or SVF (1 ¥ 10 4 cells, 1 ¥ 10 5 cells, or 2 ¥ 10 5 cells/20 mL, respectively). Main Outcome Measures. Two weeks later, erectile function was measured by cavernous nerve stimulation. The penis was stained with antibodies to CD31, CD34, phosphohistone H3, phospho-endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor-A (VEGF-A). We also performed Western blot for phospho-eNOS and eNOS, and determined cyclic guanosine monophosphate (cGMP) concentration in the corpus cavernosum tissue. Results. Significant improvement in erectile function was noted in diabetic mice treated with SVF at concentrations of 1 ¥ 10 5 and 2 ¥ 10 5 cells, which reached up to 82% of the control values. Local delivery of SVF significantly increased cavernous endothelial cell proliferation, eNOS phosphorylation, and cGMP expression compared with that in the untreated group and the PBS-treated diabetic group. Intracavernous injection of SVF increased cavernous VEGF-A expression and induced recruitment of CD34(+)CD31(-) progenitor cells. Some SVF underwent differentiation into cavernous endothelial cells. SVF-induced promotion of cavernous angiogenesis and erectile function was abolished in the presence of VEGF-Trap, a soluble VEGF-A neutralizing antibody. Conclusion. The results support the concept of cavernous endothelial regeneration by use of SVF as a curative therapy for diabetic ED.