Objective: The study aimed to explore the effects of B cell lymphoma-2 (Bcl-2)-modified bone marrow-derived mesenchymal stem cells (BMSCs) transplantation for the treatment of diabetes mellitus-induced erectile dysfunction (DMED) in a rat model. Methods: The DMED rat model was successfully established. Thirty-six DMED rats were assigned into the Bcl-2-BMSCs, null-BMSCs, BMSCs and phosphate buffered saline (PBS) groups. Meanwhile, 9 normal rats injected with PBS were taken as the normal control group. Results: In the Bcl-2-BMSCs group, the average times of erection, rate of erection, peak intra-cavernous pressure (ICP) and peak ICP/mean arterial pressure were higher than those in the null-BMSCs, BMSCs and PBS groups, but were lower than those in the normal control group. In the Bcl-2-BMSCs group, capillary vessels and Bcl-2 mRNA and protein expressions were similar to those in the normal control group, while they were higher than those in other groups. Conclusion: These findings indicate that Bcl-2-modified BMSC transplantation could improve erectile function in DMED rats.

Keywords:
Transplantation, B cell lymphoma-2, Bone marrow derived mesenchymal stem cells, Erectile dysfunction, Diabetes mellitus, Gene modification
1.
Otunctemur A, et al: Lipoprotein-associated phospholipase A2 levels are associated with erectile dysfunction in patients without known coronary artery disease. Andrologia 2015;47:706-710.
2.
Yang G, Pan C, Lu J: Prevalence of erectile dysfunction among Chinese men with type 2 diabetes mellitus. Int J Impot Res 2010;22:310-317.
3.
Bivalacqua TJ, et al: Dysregulation of cGMP-dependent protein kinase 1 (PKG-1) impairs erectile function in diabetic rats: influence of in vivo gene therapy of PKG1alpha. BJU Int 2007;99:1488-1494.
4.
Corona G, et al: The use of phosphodiesterase 5 inhibitors with concomitant medications. J Endocrinol Invest 2008;31:799-808.
5.
García-Perdomo HA, Echeverría-García F, Tobías A: Effectiveness of phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction in patients with spinal cord trauma: systematic review and meta-analysis. Urol Int 2016, Epub ahead of print.
6.
Hatzichristou D, et al: Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med 2008;25:138-146.
7.
Fonseca V, et al: Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia 2004;47:1914-1923.
8.
Wan ZH, et al: Calpain inhibition improves erectile function in a rat model of cavernous nerve injury. Urol Int 2015;95:233-239.
9.
Kim JH, Lee HJ, Song YS: Mesenchymal stem cell-based gene therapy for erectile dysfunction. Int J Impot Res 2016;28:81-87.
10.
Qiu X, et al: Combined strategy of mesenchymal stem cell injection with vascular endothelial growth factor gene therapy for the treatment of diabetes-associated erectile dysfunction. J Androl 2012;33:37-44.
11.
Moodley Y: Evidence for human lung stem cells. N Engl J Med 2011;365:464; author reply 465-466.
12.
McFarlin K, et al: Bone marrow-derived mesenchymal stromal cells accelerate wound healing in the rat. Wound Repair Regen 2006;14:471-478.
13.
Frisch J, et al: Determination of the chondrogenic differentiation processes in human bone marrow-derived mesenchymal stem cells genetically modified to overexpress transforming growth factor-β via recombinant adeno-associated viral vectors. Hum Gene Ther 2014;25:1050-1060.
14.
Jiang W, et al: Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study. Pflugers Arch 2006;453:43-52.
15.
Youle RJ, Strasser A: The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9:47-59.
16.
Li W, et al: Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells 2007;25:2118-2127.
17.
Kirshenbaum LA, de Moissac D: The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 1997;96:1580-1585.
18.
Murphy AN, et al: Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Natl Acad Sci U S A 1996;93:9893-9898.
19.
Nuñez G, et al: Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol 1990;144:3602-3610.
20.
Kendirci M, et al: Transplantation of nonhematopoietic adult bone marrow stem/progenitor cells isolated by p75 nerve growth factor receptor into the penis rescues erectile function in a rat model of cavernous nerve injury. J Urol 2010;184:1560-1566.
21.
Heaton JP, Varrin SJ, Morales A: The characterization of a bio-assay of erectile function in a rat model. J Urol 1991;145:1099-1102.
22.
Zhang Y, Wang W: Effects of bone marrow mesenchymal stem cell transplantation on light-damaged retina. Invest Ophthalmol Vis Sci 2010;51:3742-3748.
23.
Melman A, et al: The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo. J Urol 2003;170:285-290.
24.
Kim YK, et al: MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis. Histopathology 2015;67:520-528.
25.
Tarhan F, et al: Apoptosis of corpus cavernosum in patients with organic erectile dysfunction. World J Urol 2009;27:235-240.
26.
Yohannes E, et al: Molecular targets for diabetes mellitus-associated erectile dysfunction. Mol Cell Proteomics 2010;9:565-578.
27.
Qiu X, et al: Intracavernous transplantation of bone marrow-derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats. J Sex Med 2011;8:427-436.
28.
Nolazco G, et al: Effect of muscle-derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat. BJU Int 2008;101:1156-1164.
29.
Rehman J, et al: Intracavernous pressure responses to physical and electrical stimulation of the cavernous nerve in rats. Urology 1998;51:640-644.
30.
Oswald J, et al: Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 2004;22:377-384.
31.
Jiang Y, et al: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-49.
32.
Song YS, et al: Potential differentiation of human mesenchymal stem cell transplanted in rat corpus cavernosum toward endothelial or smooth muscle cells. Int J Impot Res 2007;19:378-385.
33.
Bivalacqua TJ, et al: Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction. Am J Physiol Heart Circ Physiol 2007;292:H1278-H1290.
34.
Czabotar PE, et al: Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014;15:49-63.
35.
Seftel AD, et al: Loss of TGFbeta, apoptosis, and Bcl-2 in erectile dysfunction and upregulation of p53 and HIF-1alpha in diabetes-associated erectile dysfunction. Mol Urol 1999;3:103-107.
36.
Liu N, et al: Effects of transplantation with bone marrow-derived mesenchymal stem cells modified by Survivin on experimental stroke in rats. J Transl Med 2011;9:105.
37.
Gheisari Y, et al: Genetic modification of mesenchymal stem cells to overexpress CXCR4 and CXCR7 does not improve the homing and therapeutic potentials of these cells in experimental acute kidney injury. Stem Cells Dev 2012;21:2969-2980.
38.
Wen Z, et al: Repair mechanisms of bone marrow mesenchymal stem cells in myocardial infarction. J Cell Mol Med 2011;15:1032-1043.
39.
Henry GD, et al: Intracavernosal injections of vascular endothelial growth factor protects endothelial dependent corpora cavernosal smooth muscle relaxation in the hypercholesterolemic rabbit: a preliminary study. Int J Impot Res 2000;12:334-339.
40.
Ryu JK, et al: Combined angiopoietin-1 and vascular endothelial growth factor gene transfer restores cavernous angiogenesis and erectile function in a rat model of hypercholesterolemia. Mol Ther 2006;13:705-715.
41.
Byrne RR, et al: Vascular endothelial growth factor restores corporeal smooth muscle function in vitro. J Urol 2001;165:1310-1315.
42.
Iervolino A, et al: Bcl-2 overexpression in human melanoma cells increases angiogenesis through VEGF mRNA stabilization and HIF-1-mediated transcriptional activity. FASEB J 2002;16:1453-1455.
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2016
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