Intracavernous Delivery of Freshly Isolated Stromal Vascular Fraction Rescues Erectile Function by Enhancing Endothelial Regeneration in the Streptozotocin-Induced Diabetic Mouse

Abstract

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 × 104 cells, 1 × 105 cells, or 2 × 105 cells/20 µL, 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 × 105 and 2 × 105 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.

Potential application of adipose tissue-derived stem cells for urological Disease

“…An important mechanism appeared to be secretion of angiogenic factors from SVF. Similar tests conducted by Das et al [88] and Ryu et al [89] in models of diabetic ED additionally found improved erectile function and recovery of pathological changes in SVF treated groups. Our previous work also illustrated the beneficial effect of immediate and delayed intracavernous injection of uncultured autologous SVF, penile injection of ADSCs or ADSC derived lysate in CNI model [90,91].…”

First Transplantation of Isolated Murine Follicles in Alginate

“…Two hypotheses can thus be drawn: either stromal cells are able to differentiate into endothelial cells or endothelial cells are recruited to the grafting site by stromal cells. Both scenarios have already been described [33][34][35][36], and we believe these phenomena may contribute to the development of new ovarian tissue, as blood vessels containing red blood cells, a sign of normal functioning, were also seen within the alginate matrix after only 1 week of grafting. Moreover, the number of vessels per surface unit was also similar to our previous study [12], in which more endothelial cells were grafted.…”

45 Comparative study of autologous stromal vascular fraction and adipose-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury

“…Because of these limitations, ED research using uncultured/heterogeneous SVF has accelerated [18][19][20][21], and several clinical trials are underway to examine the efficacy and safety of the use of SVF to treat ED [16,17]. However, no study has reported side-by-side comparisons of the effects of different types of adipose tissue-derived cells on ED [13].…”

“…However, few preclinical studies have assessed the efficacy and safety of such treatment for ED [18][19][20][21]. Moreover, no systematic study has compared the use of different cell types derived from adipose tissue.…”