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Kots AY, Bian K. Regulation and Pharmacology of the Cyclic GMP and Nitric Oxide Pathway in Embryonic and Adult Stem Cells. Cells 2024; 13:2008. [PMID: 39682756 DOI: 10.3390/cells13232008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
This review summarizes recent advances in understanding the role of the nitric oxide (NO) and cyclic GMP (cGMP) pathway in stem cells. The levels of expression of various components of the pathway are changed during the differentiation of pluripotent embryonic stem cells. In undifferentiated stem cells, NO regulates self-renewal and survival predominantly through cGMP-independent mechanisms. Natriuretic peptides influence the growth of undifferentiated stem cells by activating particulate isoforms of guanylyl cyclases in a cGMP-mediated manner. The differentiation, recruitment, survival, migration, and homing of partially differentiated precursor cells of various types are sensitive to regulation by endogenous levels of NO and natriuretic peptides produced by stem cells, within surrounding tissues, and by the application of various pharmacological agents known to influence the cGMP pathway. Numerous drugs and formulations target various components of the cGMP pathway to influence the therapeutic efficacy of stem cell-based therapies. Thus, pharmacological manipulation of the cGMP pathway in stem cells can be potentially used to develop novel strategies in regenerative medicine.
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Affiliation(s)
- Alexander Y Kots
- Veteran Affairs Palo Alto Health Care System, US Department of Veteran Affairs, Palo Alto, CA 90304, USA
| | - Ka Bian
- Veteran Affairs Palo Alto Health Care System, US Department of Veteran Affairs, Palo Alto, CA 90304, USA
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Da Silva MHA, Medeiros JL, Costa WS, Sampaio FJB, De Souza DB. Effects of the dutasteride and sildenafil association in the penis of a benign prostatic hyperplasia animal model. Aging Male 2020; 23:1009-1015. [PMID: 31429633 DOI: 10.1080/13685538.2019.1653839] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE The aim of this study was to investigate whether concomitant treatment of dutasteride and sildenafil could prevent structural changes in the penis of a BPH rodent model. METHODS Thirty-two adult male rats were divided into the following groups: Ctrl, untreated control rats; BPH, untreated spontaneously hypertensive rats (SHRs); BPH + D, SHRs treated with dutasteride; and BPH + DS, SHRs treated with dutasteride and sildenafil. All treatments were performed during 40 days, following which the penises were collected for histomorphometrical analysis. The results were compared via one-way ANOVA with Bonferroni's post-test, considering p values <.05 as significant. RESULTS The smooth muscle density decreased by 28.6% and 21.4% in BPH + D and BPH + DS, respectively, when compared to the BPH group. The sinusoid space density reduced by 32.2% in BPH, when compared to the Ctrl group; this density was also reduced by 22.6% in BPH + D, when compared to the BPH group. The density of the elastic fibers increased 51.6% and 65.6% in BPH + D and BPH + DS, when compared to the BPH group. CONCLUSION Treatment with dutasteride promoted morphological changes in the corpus cavernous of this BPH model. Concomitant treatment with sildenafil did not prevent the morphological changes caused by dutasteride; on the contrary, it also promoted a further increase in elastic fibers.
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Affiliation(s)
| | | | - Waldemar S Costa
- Urogenital Research Unit, Rio De Janeiro State University, Rio De Janeiro, Brazil
| | | | - Diogo B De Souza
- Urogenital Research Unit, Rio De Janeiro State University, Rio De Janeiro, Brazil
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Cui K, Kang N, Banie L, Zhou T, Liu T, Wang B, Ruan Y, Peng D, Wang HS, Wang T, Wang G, Reed-Maldonado AB, Chen Z, Lin G, Lue TF. Microenergy acoustic pulses induced myogenesis of urethral striated muscle stem/progenitor cells. Transl Androl Urol 2019; 8:489-500. [PMID: 32133280 DOI: 10.21037/tau.2019.08.18] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Stress urinary incontinence (SUI) is a common disorder with high prevalence in women across their life span, but there are no non-surgical curative options for the condition. Stem cell-based therapy, especially endogenous stem cell therapy may be a potential treatment method for SUI. The aims of this study are to identify, isolate, and assay the function of urethral striated muscle derived stem/progenitor cells (uMDSCs) and to assess uMDSC response to microenergy acoustic pulses (MAP). Methods Urethral striated muscle was identified utilizing 3D imaging of solvent organs (3DISCO) and immunofluorescence (IF). uMDSCs were isolated and purified from Zucker Lean (ZL) (ZUC-LEAN) (ZUC-Leprfa 186) rats, with magnetic-activated cell sorting (MACS) and pre-plating methods. The stemness and differentiation potential of the uMDSCs were measured by cell proliferation, EdU, flow cytometry, IF, and Western blot. Results Comparison of the cell proliferation assays between MACS and pre-plating reveals the advantage of MACS over pre-plating. In addition, the study reveals that uMDSCs form myotubes when treated with MAP. Conclusions The uMDSCs within female rat urethral striated muscle could be a therapeutic target of MAP in managing SUI.
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Affiliation(s)
- Kai Cui
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.,Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ning Kang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Lia Banie
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tie Zhou
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.,Department of Urology, Shanghai Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Tianshu Liu
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Bohan Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Yajun Ruan
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Dongyi Peng
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Hsun Shuan Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tianyu Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Guifang Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Amanda B Reed-Maldonado
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Zhong Chen
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.,Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guiting Lin
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tom F Lue
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
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Successful Penile Replantation and the Role of Postreplantation Sildenafil Therapy: Report of 2 Cases and Literature Review. Sex Med 2019; 7:352-356. [PMID: 31235448 PMCID: PMC6728759 DOI: 10.1016/j.esxm.2019.05.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 04/27/2019] [Accepted: 05/02/2019] [Indexed: 12/15/2022] Open
Abstract
Penile amputation is a rare clinical emergency necessitating urgent urologic and microsurgical intervention. Microvascular replantation has become a conventional form of management, associated with significantly increased viability of the implanted tissue and a lower rate of complications. However, postreplantation treatment intended to promote early recovery of sexual function has been reported only seldomly. Here we report 2 cases of successful penile replantation with postreplantation daily sildenafil therapy. The patients were followed for 24 months and 8 months, respectively, from the date of repair. First intercourse was achieved at 92 days and 105 days, respectively. This is the first report of the use of phosphodiesterase type 5 inhibitors in postoperative care of penile replantation. Fu S, Zheng D, Xie M, et al. Successful Penile Replantation and the Role of Postreplantation Sildenafil Therapy: Report of 2 Cases and Literature Review. Sex Med 2019;7:352–356.
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Chronic administration of LIMK2 inhibitors alleviates cavernosal veno-occlusive dysfunction through suppression of cavernosal fibrosis in a rat model of erectile dysfunction after cavernosal nerve injury. PLoS One 2019; 14:e0213586. [PMID: 30870492 PMCID: PMC6417654 DOI: 10.1371/journal.pone.0213586] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 02/22/2019] [Indexed: 12/05/2022] Open
Abstract
We evaluated whether chronic administration of LIMK2-inhibitors could improve erectile function by alleviating CVOD through suppressing cavernosal fibrosis in a rat model of cavernosal nerve crush-injury (CNCI). Forty-two 12-week-old rats were equally categorized into the three groups: sham-surgery (S), CNCI (I), and CNCI treated with LIMK2-inhibitors (L). The L-group was treated with daily intraperitoneal injection of LIMK2-inhibitors (10.0 mg/kg) for 30-days after surgery. Erectile function was assessed using dynamic-infusion-cavernosometry (DIC). Penile tissue was processed for Masson’s-trichrome staining, Western-blotting, and double immunofluorescence. The I-group showed significantly higher maintenance and drop rates as well as lower papaverine response, compared to the S-group. Chronic inhibition of LIMK2 in the L-group significantly improved the DIC parameters compared to those in the I-group, although the parameters were not completely restored to normal control values. Also, the I-group showed a reduced smooth muscle (SM)-to-collagen ratio, decreased immunohistochemical staining for α-SM-actin, increased number of fibroblasts positive for phosphorylated Cofilin, increased LIMK2/Cofilin phosphorylation and increased protein expression of Collagen-1 or Fibronectin, compared to the S-group. The L-group showed significant improvements in SM/collagen ratio and the deposition of Collagen-1 or Fibronectin compared to the I-group, although not completely normalized. According to the densitometry and confocal microscopy results, the L-group showed restoration of LIMK2/Cofilin phosphorylation and amount of fibroblasts positive for phosphorylated Cofilin to the normal control value. In conclusion, chronic inhibition of LIMK2 can improve CVOD and ED by alleviating cavernosal fibrosis via normalizing the LIMK2/Cofilin pathway.
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Masouminia M, Gelfand R, Kovanecz I, Vernet D, Tsao J, Salas R, Castro K, Loni L, Rajfer J, Gonzalez-Cadavid NF. Dyslipidemia Is a Major Factor in Stem Cell Damage Induced by Uncontrolled Long-Term Type 2 Diabetes and Obesity in the Rat, as Suggested by the Effects on Stem Cell Culture. J Sex Med 2018; 15:1678-1697. [PMID: 30527052 PMCID: PMC6645779 DOI: 10.1016/j.jsxm.2018.09.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 09/04/2018] [Accepted: 09/28/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Previous work showed that muscle-derived stem cells (MDSCs) exposed long-term to the milieu of uncontrolled type 2 diabetes (UC-T2D) in male obese Zucker (OZ) rats, were unable to correct the associated erectile dysfunction and the underlying histopathology when implanted into the corpora cavernosa, and were also imprinted with a noxious gene global transcriptional signature (gene-GTS), suggesting that this may interfere with their use as autografts in stem cell therapy. AIM To ascertain the respective contributions of dyslipidemia and hyperglycemia to this MDSC damage, clarify its mechanism, and design a bioassay to identify the damaged stem cells. METHODS Early diabetes MDSCs and late diabetes MDSCs were respectively isolated from nearly normal young OZ rats and moderately hyperglycemic and severely dyslipidemic/obese aged rats with erectile dysfunction. Monolayer cultures of early diabetic MDSCs were incubated 4 days in DMEM/10% fetal calf serum + or - aged OZ or lean Zucker serum from non-diabetic lean Zucker rats (0.5-5%) or with soluble palmitic acid (PA) (0.5-2 mM), cholesterol (CHOL) (50-400 mg/dL), or glucose (10-25 mM). MAIN OUTCOME MEASURE Fat infiltration was estimated by Oil red O, apoptosis by TUNEL, protein expression by Western blots, and gene-GTS and microRNA (miR)-GTS were determined in these stem cells' RNA. RESULTS Aged OZ serum caused fat infiltration, apoptosis, myostatin overexpression, and impaired differentiation. Some of these changes, and also a proliferation decrease occurred with PA and CHOL. The gene-GTS changes by OZ serum did not resemble the in vivo changes, but some occurred with PA and CHOL. The miR-GTS changes by OZ serum, PA, and CHOL resembled most of the in vivo changes. Hyperglycemia did not replicate most alterations. CLINICAL IMPLICATIONS MDSCs may be damaged in long-term UC-T2D/obese patients and be ineffective in autologous human stem cell therapy, which may be prevented by excluding the damaged MDSCs. STRENGTH & LIMITATIONS The in vitro test of MDSCs is innovative and fast to define dyslipidemic factors inducing stem cell damage, its mechanism, prevention, and counteraction. Confirmation is required in other T2D/obesity rat models and stem cells (including human), as well as miR-GTS biomarker validation as a stem cell damage biomarker. CONCLUSION Serum from long-term UC-T2D/obese rats or dyslipidemic factors induces a noxious phenotype and miR-GTS on normal MDSCs, which may lead in vivo to the repair inefficacy of late diabetic MDSCs. This suggests that autograft therapy with MDSCs in long-term UT-T2D obese patients may be ineffective, albeit this may be predictable by prior stem cell miR-GTS tests. Masouminia M, Gelfand R, Kovanecz I, et al. Dyslipidemia Is a Major Factor in Stem Cell Damage Induced by Uncontrolled Long-Term Type 2 Diabetes and Obesity in the Rat, as Suggested by the Effects on Stem Cell Culture. J Sex Med 2018;15:1678-1697.
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Affiliation(s)
- Maryam Masouminia
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Robert Gelfand
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Istvan Kovanecz
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Dolores Vernet
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - James Tsao
- Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Ruben Salas
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Kenny Castro
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Leila Loni
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Jacob Rajfer
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Nestor F Gonzalez-Cadavid
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA.
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Milenkovic U, Albersen M, Castiglione F. The mechanisms and potential of stem cell therapy for penile fibrosis. Nat Rev Urol 2018; 16:79-97. [DOI: 10.1038/s41585-018-0109-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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The two phases of the clinical validation of preclinical translational mechanistic research on PDE5 inhibitors since Viagra's advent. A personal perspective. Int J Impot Res 2018; 31:57-60. [PMID: 30258189 DOI: 10.1038/s41443-018-0076-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 08/13/2018] [Indexed: 12/26/2022]
Abstract
The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie's disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis. Due to the extended half-life of the long-acting PDE5i, tadalafil, this new alternative encompasses preferentially daily administration, although shorter half-life PDE5i, like sildenafil and vardenafil work too, depending on the duration, dose, and frequency of their administration This novel use was initially supported by showing the antifibrotic/antioxidant effects of nitric oxide and cGMP, produced by the induction of iNOS, as a mechanism of defense against collagen deposition in the localized fibrotic plaque of PD in an avascular tissue, the tunica albuginea. Our studies on iNOS and the progressive diffuse fibrosis occurring in the smooth muscle in CVOD, led to proposing the CLTA of PDE5i for maintaining sustained cGMP levels both in PD and in CVOD in order to halt or regress the penile fibrosis. In CVOD, we showed that PDE5i protect the corporal smooth muscle and reduce myofibroblast activation and number, counteracting the underlying corporal tissue pathology that causes CVOD, and potentially ameliorating long-term CVOD or even curing it. This review is focused on this novel PDE5i anti-fibrotic therapeutic concept.
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Translational Perspective on the Role of Testosterone in Sexual Function and Dysfunction. J Sex Med 2017; 13:1183-98. [PMID: 27436075 DOI: 10.1016/j.jsxm.2016.06.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/13/2016] [Accepted: 06/09/2016] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The biological importance of testosterone is generally accepted by the medical community; however, controversy focuses on its relevance to sexual function and the sexual response, and our understanding of the extent of its role in this area is evolving. AIM To provide scientific evidence examining the role of testosterone at the cellular and molecular levels as it pertains to normal erectile physiology and the development of erectile dysfunction and to assist in guiding successful therapeutic interventions for androgen-dependent sexual dysfunction. METHODS In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current basic science literature examining the role of testosterone in sexual function and dysfunction. RESULTS Testosterone plays an important role in sexual function through multiple processes: physiologic (stimulates activity of nitric oxide synthase), developmental (establishes and maintains the structural and functional integrity of the penis), neural (development, maintenance, function, and plasticity of the cavernous nerve and pelvic ganglia), therapeutically for dysfunctional regulation (beneficial effect on aging, diabetes, and prostatectomy), and phosphodiesterase type 5 inhibition (testosterone supplement to counteract phosphodiesterase type 5 inhibitor resistance). CONCLUSION Despite controversies concerning testosterone with regard to sexual function, basic science studies provide incontrovertible evidence for a significant role of testosterone in sexual function and suggest that properly administered testosterone therapy is potentially advantageous for treating male sexual dysfunction.
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Kovanecz I, Vernet D, Masouminia M, Gelfand R, Loni L, Aboagye J, Tsao J, Rajfer J, Gonzalez-Cadavid NF. Implanted Muscle-Derived Stem Cells Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes, but Their Repair Capacity Is Impaired by Their Prior Exposure to the Diabetic Milieu. J Sex Med 2017; 13:786-97. [PMID: 27114192 DOI: 10.1016/j.jsxm.2016.02.168] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 02/02/2016] [Accepted: 02/17/2016] [Indexed: 12/20/2022]
Abstract
INTRODUCTION 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. AIM 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. METHODS 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 injected into the corpora cavernosa of OZ rats with late diabetes (OZ/ED, OZ/LD, and OZ/ED-HG rats, respectively). Untreated OZ and non-diabetic lean Zucker rats functioned as controls. Two months later, rats were subjected to cavernosometry and the penile shaft and corporal tissues were subjected to histopathology and DNA microarray assays. MAIN OUTCOME MEASURES In vivo erectile dysfunction assessment by Dynamic Infusion Cavernosometry followed by histopathology marker analysis of the penile tissues. RESULTS Implanted ED-SCs and ED-HG-SCs improved corporal veno-occlusive dysfunction, counteracted corporal decreases in the ratio of SMCs to collagen and fat infiltration in rats with long-term T2D, and upregulated neuronal and endothelial nitric oxide. LD-SCs acquired an inflammatory, pro-fibrotic, oxidative, and dyslipidemic transcriptional phenotype and failed to repair the corporal tissue. CONCLUSION MDSCs from pre-diabetic rats injected into the corpora cavernosa of rats with long-term T2D improve corporal veno-occlusive dysfunction and the underlying histopathology. In contrast, MDSCs from rats with long-term uncontrolled T2D are imprinted by the hyperglycemic and dyslipidemic milieu with a noxious phenotype associated with an impaired tissue repair capacity. SCs affected by diabetes could lack tissue repair efficacy as autografts and should be reprogrammed in vitro or substituted by SCs from allogenic non-diabetic sources.
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Affiliation(s)
- Istvan Kovanecz
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Dolores Vernet
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Maryam Masouminia
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - Robert Gelfand
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Leila Loni
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - James Aboagye
- Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
| | - James Tsao
- Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Jacob Rajfer
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Nestor F Gonzalez-Cadavid
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA.
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Kovanecz I, Masouminia M, Gelfand R, Vernet D, Rajfer J, Gonzalez-Cadavid NF. Myostatin, a profibrotic factor and the main inhibitor of striated muscle mass, is present in the penile and vascular smooth muscle. Int J Impot Res 2017; 29:194-201. [PMID: 28539643 DOI: 10.1038/ijir.2017.22] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 03/20/2017] [Accepted: 03/30/2017] [Indexed: 12/13/2022]
Abstract
Myostatin is present in striated myofibers but, except for myometrial cells, has not been reported within smooth muscle cells (SMC). We investigated in the rat whether myostatin is present in SMC within the penis and the vascular wall and, if so, whether it is transcriptionally expressed and associated with the loss of corporal SMC occurring in certain forms of erectile dysfunction (ED). Myostatin protein was detected by immunohistochemistry/fluorescence and western blots in the perineal striated muscles, and also in the SMC of the penile corpora, arteries and veins, and aorta. Myostatin was found in corporal SMC cultures, and its transcriptional expression (and its receptor) was shown there by DNA microarrays. Myostatin protein was measured by western blots in the penile shaft of rats subjected to bilateral cavernosal nerve resection (BCNR), that were left untreated, or treated (45 days) with muscle-derived stem cells (MDSC), or concurrent daily low-dose sildenafil. Myostatin was not increased by BCNR (compared with sham operated animals), but over expressed after treatment with MDSC. This was reduced by concurrent sildenafil. The presence of myostatin in corporal and vascular SMC, and its overexpression in the corpora by MDSC therapy, may have relevance for the stem cell treatment of corporal fibrosis and ED.
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Affiliation(s)
- I Kovanecz
- Division of Urology, Department of Surgery, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.,Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - M Masouminia
- Division of Urology, Department of Surgery, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - R Gelfand
- Division of Urology, Department of Surgery, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.,Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
| | - D Vernet
- Division of Urology, Department of Surgery, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.,Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
| | - J Rajfer
- Division of Urology, Department of Surgery, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.,Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - N F Gonzalez-Cadavid
- Division of Urology, Department of Surgery, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.,Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
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Tsao J, Kovanecz I, Awadalla N, Gelfand R, Sinha-Hikim I, White RA, Gonzalez-Cadavid NF. Muscle Derived Stem Cells Stimulate Muscle Myofiber Repair and Counteract Fat Infiltration in a Diabetic Mouse Model of Critical Limb Ischemia. ACTA ACUST UNITED AC 2016; 6. [PMID: 28217409 PMCID: PMC5313052 DOI: 10.4172/2157-7633.1000370] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Background Critical Limb Ischemia (CLI) affects patients with Type 2 Diabetes (T2D) and obesity, with high risk of amputation and post-surgical mortality, and no effective medical treatment. Stem cell therapy, mainly with bone marrow mesenchymal, adipose derived, endothelial, hematopoietic, and umbilical cord stem cells, is promising in CLI mouse and rat models and is in clinical trials. Their general focus is on angiogenic repair, with no reports on the alleviation of necrosis, lipofibrosis, and myofiber regeneration in the ischemic muscle, or the use of Muscle Derived Stem Cells (MDSC) alone or in combination with pharmacological adjuvants, in the context of CLI in T2D. Methods Using a T2D mouse model of CLI induced by severe unilateral femoral artery ligation, we tested: a) the repair efficacy of MDSC implanted into the ischemic muscle and the effects of concurrent intraperitoneal administration of a nitric oxide generator, molsidomine; and b) whether MDSC may partially counteract their own repair effects by stimulating the expression of myostatin, the main lipofibrotic agent in the muscle and inhibitor of muscle mass. Results MDSC: a) reduced mortality, and b) in the ischemic muscle, increased stem cell number and myofiber central nuclei, reduced fat infiltration, myofibroblast number, and myofiber apoptosis, and increased smooth muscle and endothelial cells, as well as neurotrophic factors. The content of myosin heavy chain 2 (MHC-2) myofibers was not restored and collagen was increased, in association with myostatin overexpression. Supplementation of MDSC with molsidomine failed to stimulate the beneficial effects of MDSC, except for some reduction in myostatin overexpression. Molsidomine given alone was rather ineffective, except for inhibiting apoptosis and myostatin overexpression. Conclusions MDSC improved CLI muscle repair, but molsidomine did not stimulate this process. The combination of MDSC with anti-myostatin approaches should be explored to restore myofiber MHC composition.
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Affiliation(s)
- J Tsao
- Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - I Kovanecz
- Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - N Awadalla
- Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - R Gelfand
- Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - I Sinha-Hikim
- Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - R A White
- Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA
| | - N F Gonzalez-Cadavid
- Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Abstract
PURPOSE OF REVIEW To summarize recent literature on basic stem cell research in erectile dysfunction in cavernous nerve injury, aging, diabetes, and Peyronie's disease and to provide a perspective on clinical translation of these cellular therapies. RECENT FINDINGS Stem cell research has been concentrated on mesenchymal stem (stromal) cells from bone marrow and adipose tissue. Application of both cell types has produced positive effects on erectile function in various animal models of erectile dysfunction. In acute animal models, such as cavernous nerve injury-induced erectile dysfunction and chemically induced Peyronie's disease, engraftment and differentiation have not been observed, and stem cells are believed to interact with the host tissue in a paracrine fashion, whereas in chronic disease models some evidence suggests both engraftment and paracrine factors may support improved function. Clinical trials are now investigating therapeutic efficacy of cellular therapy, whereas the first safety studies in humans have recently been published. SUMMARY Evidence from preclinical studies has established stem cells as a potential curative treatment for erectile dysfunction and early phase clinical trials are currently performed.
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Xin ZC, Xu YD, Lin G, Lue TF, Guo YL. Recruiting endogenous stem cells: a novel therapeutic approach for erectile dysfunction. Asian J Androl 2016; 18:10-5. [PMID: 25926601 PMCID: PMC4736335 DOI: 10.4103/1008-682x.150040] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Transplanted stem cells (SCs), owing to their regenerative capacity, represent one of the most promising methods to restore erectile dysfunction (ED). However, insufficient source, invasive procedures, ethical and regulatory issues hamper their use in clinical applications. The endogenous SCs/progenitor cells resident in organ and tissues play critical roles for organogenesis during development and for tissue homeostasis in adulthood. Even without any therapeutic intervention, human body has a robust self-healing capability to repair the damaged tissues or organs. Therefore, SCs-for-ED therapy should not be limited to a supply-side approach. The resident endogenous SCs existing in patients could also be a potential target for ED therapy. The aim of this review was to summarize contemporary evidence regarding: (1) SC niche and SC biological features in vitro; (2) localization and mobilization of endogenous SCs; (3) existing evidence of penile endogenous SCs and their possible mode of mobilization. We performed a search on PubMed for articles related to these aspects in a wide range of basic studies. Together, numerous evidences hold the promise that endogenous SCs would be a novel therapeutic approach for the therapy of ED.
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Affiliation(s)
- Zhong-Cheng Xin
- Andrology Center, Peking University First Hospital, Peking University, Beijing 100034, USA
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15
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Mahmood J, Shamah AA, Creed TM, Pavlovic R, Matsui H, Kimura M, Molitoris J, Shukla H, Jackson I, Vujaskovic Z. Radiation-induced erectile dysfunction: Recent advances and future directions. Adv Radiat Oncol 2016; 1:161-169. [PMID: 28740886 PMCID: PMC5514009 DOI: 10.1016/j.adro.2016.05.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 05/20/2016] [Accepted: 05/23/2016] [Indexed: 12/29/2022] Open
Abstract
Prostate cancer is one of the most prevalent cancers and the second leading cause of cancer-related deaths in men in the United States. A large number of patients undergo radiation therapy (RT) as a standard care of treatment; however, RT causes erectile dysfunction (radiation-induced erectile dysfunction; RiED) because of late side effects after RT that significantly affects quality of life of prostate cancer patients. Within 5 years of RT, approximately 50% of patients could develop RiED. Based on the past and current research findings and number of publications from our group, the precise mechanism of RiED is under exploration in detail. Recent investigations have shown prostate RT induces significant morphologic arterial damage with aberrant alterations in internal pudendal arterial tone. Prostatic RT also reduces motor function in the cavernous nerve which may attribute to axonal degeneration may contributing to RiED. Furthermore, the advances in radiogenomics such as radiation induced somatic mutation identification, copy number variation and genome-wide association studies has significantly facilitated identification of biomarkers that could be used to monitoring radiation-induced late toxicity and damage to the nerves; thus, genomic- and proteomic-based biomarkers could greatly improve treatment and minimize arterial tissue and nerve damage. Further, advanced technologies such as proton beam therapy that precisely target tumor and significantly reduce off-target damage to vital organs and healthy tissues. In this review, we summarize recent advances in RiED research and novel treatment modalities for RiED. We also discuss the possible molecular mechanism involved in the development of RiED in prostate cancer patients. Further, we discuss various readily available methods as well as novel strategies such as stem cell therapies, shockwave therapy, nerve grafting with tissue engineering, and nutritional supplementations might be used to mitigate or cure sexual dysfunction following radiation treatment.
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Affiliation(s)
- Javed Mahmood
- Division of Translational Radiation Sciences, Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Aksinija A Shamah
- Division of Translational Radiation Sciences, Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - T Michael Creed
- Division of Translational Radiation Sciences, Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Radmila Pavlovic
- Division of Translational Radiation Sciences, Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Hotaka Matsui
- The James Buchanan Brady Urological Institute, and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Masaki Kimura
- Department of Urology, School of Medicine, Teikyo University, Tokyo, Japan
| | - Jason Molitoris
- Division of Translational Radiation Sciences, Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Hem Shukla
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland
| | - Isabel Jackson
- Division of Translational Radiation Sciences, Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Zeljko Vujaskovic
- Division of Translational Radiation Sciences, Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland
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Shan H, Chen F, Zhang T, He S, Xu L, Wei A. Stem cell therapy for erectile dysfunction of cavernous nerve injury rats: a systematic review and meta-analysis. PLoS One 2015; 10:e0121428. [PMID: 25860455 PMCID: PMC4393097 DOI: 10.1371/journal.pone.0121428] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 02/13/2015] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Stem cell treatment is a novel therapeutic strategy for erectile dysfunction (ED) patients with bilateral cavernous nerve injury (CNI). The relative animal studies provide important clues to design pre-clinical studies and clinical studies further in the future. PURPOSE This study aims to evaluate the effects and influential factors of stem cell transplantation on ED rats with CNI. MATERIALS AND METHODS We searched PubMed and EBSCO databases published before April 30, 2014 for pre-clinical studies to evaluate the efficacy of stem cell transplantation in the treatment of ED rats with CNI. A systematic review and a planned subgroup analysis were performed to identify whether or not some certain influential factors could bring significant effects on stem cell treatment. RESULTS 12 studies with 319 rats were enrolled in this meta-analysis. Pooled analysis results confirmed the efficacy of stem cell transplantation. Subgroup analysis results showed that treatment effects were not related to CNI models, follow-up time, stem cell species, stem cell sources, markers and delivery approaches in the transplantation. Uncultured stem cells were poorly effective compared with cultured stem cells. Periprostatic implantation (PPI) with acellular scaffolds could promote cavernous nerve regeneration, but was less effective for smooth muscle cell recovery. Stem cells modified by NGF or BDNF combined with udenafil/bFGF seemed to be more effective than those modified by BDNF alone. CONCLUSION This meta-analysis shows that stem cell therapy can be performed to recover erectile function. Future studies should focus on nerve restoration and vascular cell recovery. The synergistic actions of multiple growth factors following stem cell transplantation should also be considered as beneficial strategies to obtain preferable effects.
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Affiliation(s)
- Haitao Shan
- Department of Urology, Hexian Memorial Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Fengzhi Chen
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tao Zhang
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuhua He
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Le Xu
- Department of Urology, Hexian Memorial Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Anyang Wei
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
- * E-mail:
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17
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Stem cell treatment of erectile dysfunction. Adv Drug Deliv Rev 2015; 82-83:137-44. [PMID: 25446142 DOI: 10.1016/j.addr.2014.11.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 09/09/2014] [Accepted: 11/08/2014] [Indexed: 12/31/2022]
Abstract
Erectile Dysfunction (ED) is a common disease that typically affects older men. While oral type-5 phosphodieserase inhibitors (PDE5Is) represent a successful first-line therapy, many patients do not respond to this treatment leading researchers to look for alternative treatment modalities. Stem cell (SC) therapy is a promising new frontier for the treatment of those patients and many studies demonstrated its therapeutic effects. In this article, using a Medline database search of all relevant articles, we present a summary of the scientific principles behind SCs and their use for treatment of ED. We discuss specifically the different types of SCs used in ED, the methods of delivery tested, and the methods attempted to enhance SC therapy effect. In addition, we review the current preclinical literature on SC therapy for ED and present a summary of its findings in addition to the single clinical trial published.
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Suzuki E, Nishimatsu H, Homma Y. Stem cell therapy for erectile dysfunction. World J Clin Urol 2014; 3:272-282. [DOI: 10.5410/wjcu.v3.i3.272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/03/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Erectile dysfunction (ED) is an important health problem that has commonly been clinically treated using phosphodiesterase type 5 inhibitors (PDE5Is). However, PDE5Is are less effective when the structure of the cavernous body has been severely injured, and thus regeneration is required. Stem cell therapy has been investigated as a possible means for regenerating the injured cavernous body. Stem cells are classified into embryonic stem cells and adult stem cells (ASCs), and the intracavernous injection of ASCs has been explored as a therapy in animal ED models. Bone marrow-derived mesenchymal stem cells and adipose tissue-derived stem cells are major sources of ASCs used for the treatment of ED, and accumulated evidence now suggests that ASCs are useful in the restoration of erectile function and the regeneration of the cavernous body. However, the mechanisms by which ASCs recover erectile function remain controversial. Some studies indicated that ASCs were differentiated into the vascular endothelial cells, vascular smooth muscle cells, and nerve cells that originally resided in the cavernous body, whereas other studies have suggested that ASCs improved erectile function via the secretion of anti-apoptotic and/or proangiogenic cytokines rather than differentiation into other cell types. In this paper, we reviewed the characteristics of stem cells used for the treatment of ED, and the possible mechanisms by which these cells exert their effects. We also discussed the problems to be solved before implementation in the clinical setting.
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19
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Zhang D, Wei G, Li P, Zhou X, Zhang Y. Urine-derived stem cells: A novel and versatile progenitor source for cell-based therapy and regenerative medicine. Genes Dis 2014; 1:8-17. [PMID: 25411659 PMCID: PMC4234168 DOI: 10.1016/j.gendis.2014.07.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Engineered functional organs or tissues, created with autologous somatic cells and seeded on biodegradable or hydrogel scaffolds, have been developed for use in individuals with tissue damage suffered from congenital disorders, infection, irradiation, or cancer. However, in those patients, abnormal cells obtained by biopsy from the compromised tissue could potentially contaminate the engineered tissues. Thus, an alternative cell source for construction of the neo-organ or functional recovery of the injured or diseased tissues would be useful. Recently, we have found stem cells existing in the urine. These cells are highly expandable, and have self-renewal capacity, paracrine properties, and multi-differentiation potential. As a novel cell source, urine-derived stem cells (USCs) provide advantages for cell therapy and tissue engineering applications in regeneration of various tissues, particularly in the genitourinary tract, because they originate from the urinary tract system. Importantly, USCs can be obtained via a non-invasive, simple, and low-cost approach and induced with high efficiency to differentiate into three dermal cell lineages.
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Affiliation(s)
- Deying Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China ; Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA
| | - Guanghui Wei
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Peng Li
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA ; Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiaobo Zhou
- Center for Bioinformatics and Systems Biology, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA
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Hu C, Wang F, Dong Y, Dai J. A novel method to establish a rat ED model using internal iliac artery ligation combined with hyperlipidemia. PLoS One 2014; 9:e102583. [PMID: 25047124 PMCID: PMC4105595 DOI: 10.1371/journal.pone.0102583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 06/20/2014] [Indexed: 11/29/2022] Open
Abstract
Objective To investigate a novel method, namely using bilateral internal iliac artery ligation combined with a high-fat diet (BCH), for establishing a rat model of erectile dysfunction (ED) that, compared to classical approaches, more closely mimics the chronic pathophysiology of human ED after acute ischemic insult. Materials and Methods Forty 4-month-old male Sprague Dawley rats were randomly placed into five groups (n = 8 per group): normal control (NC), bilateral internal iliac artery ligation (BIIAL), high-fat diet (HFD), BCH, and mock surgery (MS). All rats were induced for 12 weeks. Copulatory behavior, intracavernosal pressure (ICP), ICP/mean arterial pressure, hematoxylin-eosin staining, Masson's trichrome staining, serum lipid levels, and endothelial and neuronal nitric oxide synthase immunohistochemical staining of the cavernous smooth muscle and endothelium were assessed. Data were analyzed by SAS 8.0 for Windows. Results Serum total cholesterol and triglyceride levels were significantly higher in the HFD and BCH groups than the NC and MS groups. High density lipoprotein levels were significantly lower in the HFD and BCH groups than the NC and MS groups. The ICP values and mount and intromission numbers were significantly lower in the BIIAL, HFD, and BCH groups than in the NC and MS groups. ICP was significantly lower in the BCH group than in the BIIAL and HFD groups. Cavernous smooth muscle and endothelial damage increased in the HFD and BCH groups. Cavernous smooth muscle to collagen ratio, nNOS and eNOS staining decreased significantly in the BIIAL, HFD, and BCH groups compared to the NC and MS groups. Conclusions The novel BCH model mimics the chronic pathophysiology of ED in humans and avoids the drawbacks of traditional ED models.
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Affiliation(s)
- Chao Hu
- Departments of Urology, Affiliated Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Feixiang Wang
- Institute of Forensic Science, National Ministry of Justice, Shanghai Key Laboratory of Forensic Medicine, Shanghai, P.R. China
| | - Yehao Dong
- Departments of Urology, Affiliated Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Jican Dai
- Departments of Urology, Affiliated Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
- * E-mail:
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Hannan JL, Kutlu O, Stopak BL, Liu X, Castiglione F, Hedlund P, Burnett AL, Bivalacqua TJ. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats. J Sex Med 2014; 11:1442-51. [PMID: 24636283 PMCID: PMC4048646 DOI: 10.1111/jsm.12522] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. AIMS This study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. METHODS Five groups of rats (8-10 weeks, n = 10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250 mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-β1 (TGF-β1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (α-SMA) antibodies. MAIN OUTCOME MEASURES We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-β1 protein expression; penile fibrosis; penile α-SMA content. RESULTS There was a voltage-dependent decline (P < 0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (P < 0.05) 14 days after BCNI. There was a slight increase in TGF-β1 protein expression after BCNI. Histological analysis showed increased (P < 0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (P < 0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile α-SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (P < 0.05). CONCLUSION HDAC-induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy.
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Affiliation(s)
- Johanna L. Hannan
- The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Omer Kutlu
- Department of Urology, Karadeniz Technical University, Trabzon, Turkey
| | - Bernard L. Stopak
- The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Xiaopu Liu
- The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Fabio Castiglione
- Department of Urology, Urological Research Institute, San Raffaele Research Institute, Milan, Italy
| | - Petter Hedlund
- Department of Urology, Urological Research Institute, San Raffaele Research Institute, Milan, Italy
- Department of Clinical Pharmacology, Linköping University, Linköping, Sweden
| | - Arthur L. Burnett
- The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Trinity J. Bivalacqua
- The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
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22
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Meldrum DR, Burnett AL, Dorey G, Esposito K, Ignarro LJ. Erectile Hydraulics: Maximizing Inflow While Minimizing Outflow. J Sex Med 2014; 11:1208-20. [DOI: 10.1111/jsm.12457] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Abstract
Stem cell (SC) therapy for erectile dysfunction (ED) has been investigated in 35 published studies, with one being a small-scale clinical trial. Out of these 35 studies, 19 are concerned with cavernous nerve (CN) injury-associated ED while 10 with diabetes mellitus- (DM-) associated ED. Adipose-derived SCs (ADSCs) were employed in 18 studies while bone marrow SCs (BMSCs) in 9. Transplantation of SCs was done mostly by intracavernous (IC) injection, as seen in 25 studies. Allogeneic and xenogeneic transplantations have increasingly been performed but their immune-incompatibility issues were rarely discussed. More recent studies also tend to use combinatory therapies by modifying or supplementing SCs with angiogenic or neurotrophic genes or proteins. All studies reported better erectile function with SC transplantation, and the majority also reported improved muscle, endothelium, and/or nerve in the erectile tissue. However, differentiation or engraftment of transplanted SCs has rarely been observed; thus, paracrine action is generally believed to be responsible for SC’s therapeutic effects. But still, few studies actually investigated and none proved paracrine action as a therapeutic mechanism. Thus, based exclusively on functional outcome data shown in preclinical studies, two clinical trials are currently recruiting patients for treatment with IC injection of ADSC and BMSC, respectively.
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Kovanecz I, Gelfand R, Masouminia M, Gharib S, Segura D, Vernet D, Rajfer J, Li DK, Kannan K, Gonzalez-Cadavid NF. Oral Bisphenol A (BPA) given to rats at moderate doses is associated with erectile dysfunction, cavernosal lipofibrosis and alterations of global gene transcription. Int J Impot Res 2014; 26:67-75. [PMID: 24305612 PMCID: PMC4098849 DOI: 10.1038/ijir.2013.37] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 10/08/2013] [Accepted: 10/15/2013] [Indexed: 12/15/2022]
Abstract
Bisphenol A (BPA), a suspected reproductive biohazard and endocrine disruptor, released from plastics is associated with ED in occupationally exposed workers. However, in rats, despite the induction of hypogonadism, apoptosis of the penile corporal smooth muscle (SM), fat infiltration into the cavernosal tissue and changes in global gene expression with the intraperitoneal administration of high dose BPA, ED was not observed. We investigated whether BPA administered orally rather than intraperitoneally to rats for longer periods and lower doses will lead to ED. Main outcome measures are ED, histological, and biochemical markers in rat penile tissues. In all, 2.5-month-old rats were given drinking water daily without and with BPA at 1 and 0.1 mg kg(-1) per day. Two months later, erectile function was determined by cavernosometry and electrical field stimulation (EFS) and serum levels of testosterone (T), estradiol (E2) and BPA were measured. Penile tissue sections were assayed by Masson (SM/collagen), Oil Red O (fat), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) (apoptosis), immunohistochemistry for Oct4 (stem cells), and α-SM actin/calponin (SM and myofibroblasts), applying quantitative image analysis. Other markers were assayed by western blotting. DNA microarrays/microRNA (miR) assays defined transcription profiles. Orally administered BPA did not affect body weight, but (1) decreased serum T and E2; (2) reduced the EFS response and increased the drop rate; (3) increased within the corporal tissue the presence of fat, myofibroblasts and apoptosis; (4) lowered the contents of SM and stem cells, but not nerve terminals; and (5) caused alterations in the transcriptional profiles for both mRNA and miRs within the penile shaft. Long-term exposure of rats to oral BPA caused a moderate corporal veno-occlusive dysfunction (CVOD), possibly due to alterations within the corporal tissue that pose gene transcriptional changes related to inflammation, fibrosis and epithelial/mesenchymal transition (EMT).
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Affiliation(s)
- I Kovanecz
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - R Gelfand
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
- Division of Endocrinology, Charles Drew University of Medicine and Science, Los Angeles, CA
| | - M Masouminia
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
| | - S Gharib
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
| | - D Segura
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
| | - D Vernet
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
- Division of Endocrinology, Charles Drew University of Medicine and Science, Los Angeles, CA
| | - J Rajfer
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - DK Li
- Department of Health Research and Policy, Stanford University, Stanford, CA
- Division of Research, Kaiser Permanente
| | - K Kannan
- Wadsworth Center, New York State Department of Health, Albany, NY
| | - NF Gonzalez-Cadavid
- Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Division of Endocrinology, Charles Drew University of Medicine and Science, Los Angeles, CA
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Miyamoto K, Inoue S, Kobayashi K, Kajiwara M, Teishima J, Matsubara A. Rat cavernous nerve reconstruction with CD133+ cells derived from human bone marrow. J Sex Med 2014; 11:1148-58. [PMID: 24576198 DOI: 10.1111/jsm.12485] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Erectile dysfunction remains a major complication after surgery of pelvic organs, especially after radical prostatectomy. AIM The aim of this study was to assess the effect of endothelial progenitor cells on the regeneration of cavernous nerves in a rat injury model. METHODS A 2 mm length of the right and left cavernous nerves of 8-week-old male nude rats were excised. Alginate gel sponge sheets supplemented with 1 × 10(4) CD133+ cells derived from human bone marrow were then placed over the gaps on both sides (CD group). The same experiments were performed on sham-operated rats (SH group), rats with only the nerve excision (EX group), and rats with alginate gel sheets placed on the injured nerves (AL group). MAIN OUTCOME MEASURES Immunofluorescence staining and molecular evaluation were performed 4 days later. Functional and histological evaluations were performed 12 weeks later. RESULTS The intracavernous pressure elicited by electrical stimulation and the neuronal nitric oxide synthase-positive area in surrounding tissues of the prostate was significantly greater in the CD group. Immunofluorescence microscopy showed that CD133+ cells were assimilated as vascular endothelial cells, and the real-time polymerase chain reaction showed upregulation of nerve growth factor and vascular endothelial growth factor in the alginate gel sponge sheets of the CD group. CONCLUSIONS Transplantation of CD133+ cells accelerated the functional and histological recovery in this cavernous nerve injury model, and the recovery mechanism is thought to be angiogenesis and upregulation of growth factors. CD133+ cells could be an optional treatment for cavernous nerve injury after prostatectomy in clinical settings.
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Affiliation(s)
- Katsutoshi Miyamoto
- Department of Urology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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Kovanecz I, Gelfand R, Masouminia M, Gharib S, Segura D, Vernet D, Rajfer J, Li DK, Liao CY, Kannan K, Gonzalez-Cadavid NF. Chronic high dose intraperitoneal bisphenol A (BPA) induces substantial histological and gene expression alterations in rat penile tissue without impairing erectile function. J Sex Med 2013; 10:2952-66. [PMID: 24134786 PMCID: PMC4038545 DOI: 10.1111/jsm.12336] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Bisphenol A (BPA), released from plastics and dental sealants, is a suspected endocrine disruptor and reproductive toxicant. In occupationally exposed workers, BPA has been associated with erectile dysfunction (ED). AIMS To determine whether long-term exposure to high doses of BPA in the rat affects serum levels of testosterone (T) and estradiol (E2), and induces corporal histopathology and resultant ED. METHODS Young rats were injected intraperitoneal (IP) injection daily with BPA at 25 mg/kg/day or vehicle (n = 8/group). Erectile function was measured at 3 months by cavernosometry and electrical field stimulation (EFS). BPA was assayed in serum, urine, and penile tissue, and serum T and E2 were determined. Quantitative Masson trichrome, terminal deoxynucleotidyl transferase dUTP nick end labeling, Oil Red O, immunohistochemistry for calponin, α-smooth muscle actin, and Oct 4 were applied to penile tissue sections. Protein markers were assessed by Western blots and 2-D minigels, and RNA by DNA microarrays. MAIN OUTCOME MEASURES Erectile function, histological, and biochemical markers in corporal tissue. RESULTS In the BPA-treated rats, total and free BPA levels were increased in the serum, urine, and penile tissue while serum T and E2 levels were reduced. In addition, the corpora cavernosa demonstrated a reduction in smooth muscle (SM) content, SM/collagen ratio, together with an increase in myofibroblasts, fat deposits, and apoptosis, but no significant change in collagen content or stem cells (nuclear/perinuclear Oct 4). In the penile shaft, BPA induced a downregulation of Nanog (stem cells), neuronal nitric oxide synthase (nitrergic terminals), and vascular endothelial growth factor (angiogenesis), with genes related to SM tone and cytoskeleton upregulated 5- to 50-fold, accompanied by changes in the multiple protein profile. However, both cavernosometry and EFS were unaltered by BPA. CONCLUSIONS While rats treated chronically with a high IP dose of BPA developed hypogonadism and a corporal histo- and molecular-pathology usually associated with ED, no changes were detected in erectile function as measured by EFS and cavernosometry. Further studies using alternate routes of BPA administration with various doses and length of exposure are needed to expand these findings.
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Affiliation(s)
- Istvan Kovanecz
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Robert Gelfand
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Division of Endocrinology, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Maryam Masouminia
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Sahir Gharib
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Denesse Segura
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Dolores Vernet
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Jacob Rajfer
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - De-Kun Li
- Division of Research, Kaiser Permanente, Oakland, CA, USA
- Department of Health Research and Policy, Stanford University, Stanford, CA, USA
| | - Chun Yang Liao
- New York State Department of Health, Wadsworth Center, Albany, NY, USA
| | | | - Nestor F. Gonzalez-Cadavid
- Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Division of Endocrinology, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
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Decaluwé K, Pauwels B, Boydens C, Van de Voorde J. Treatment of erectile dysfunction: new targets and strategies from recent research. Pharmacol Biochem Behav 2013; 121:146-57. [PMID: 24291648 DOI: 10.1016/j.pbb.2013.11.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 11/18/2013] [Indexed: 12/15/2022]
Abstract
In recent years, research on penile erection has increasingly been centered on the molecular mechanisms involved. Major progress has been made in the field and at present a whole number of neurotransmitters, chemical effectors, growth factors, second-messenger molecules, ions, intercellular proteins, and hormones have been characterized as components of the complex process of erection. This knowledge has led to the discovery of several new therapeutic targets and multiple medical approaches for the treatment of erectile dysfunction (ED). This review focuses on the progress made in this field within the last few years.
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Affiliation(s)
- K Decaluwé
- Department of Pharmacology, Ghent University, Ghent, Belgium
| | - B Pauwels
- Department of Pharmacology, Ghent University, Ghent, Belgium
| | - C Boydens
- Department of Pharmacology, Ghent University, Ghent, Belgium
| | - J Van de Voorde
- Department of Pharmacology, Ghent University, Ghent, Belgium.
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Ryu JK, Kim DH, Song KM, Yi T, Suh JK, Song SU. Intracavernous delivery of clonal mesenchymal stem cells restores erectile function in a mouse model of cavernous nerve injury. J Sex Med 2013; 11:411-23. [PMID: 24251583 DOI: 10.1111/jsm.12380] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Recently, much attention has focused on stem cell therapy; bone marrow-derived stem cells (BMSCs) are one of the most studied mesenchymal stem cells used in the field of erectile dysfunction (ED). However, a major limitation for the clinical application of stem cell therapy is the heterogeneous nature of the isolated cells, which may cause different treatment outcomes. AIM We investigated the effectiveness of mouse clonal BMSCs obtained from a single colony by using subfractionation culturing method (SCM) for erectile function in a mouse model of cavernous nerve injury (CNI). METHODS Twelve-week-old C57BL/6J mice were divided into four groups: sham operation group, bilateral CNI group receiving a single intracavernous (IC) injection of phosphate-buffered saline (20 μL) or clonal BMSCs (3 × 10(5) cells/20 μL), and receiving a single intraperitoneal (IP) injection of clonal BMSCs (3 × 10(5) cells/20 μL). MAIN OUTCOME MEASURES The clonal BMSC line was analyzed for cell-surface epitopes by using fluorescence-activated cell sorting and for differentiation potential. Two weeks after CNI and treatment, erectile function was measured by electrically stimulating the cavernous nerve. The penis was harvested for histologic examinations and Western blot analysis. RESULTS Clonal BMSCs expressed cell surface markers for mesenchymal stem cells and were capable of differentiating into several lineages, including adipogenic, osteogenic, and chondrogenic cells. Both IC and IP injections of clonal BMSCs significantly restored cavernous endothelial and smooth muscle content, and penile nNOS and neurofilament content in CNI mice. IC injection of clonal BMSCs induced significant recovery of erectile function, which reached 90-100% of the sham control values, whereas IP injection of clonal BMSCs partially restored erectile function. CONCLUSION We established a homogeneous population of mouse clonal BMSCs using SCM; clonal BMSCs successfully restored erectile function in CNI mice. The homogeneous nature of clonal mesenchymal stem cells may allow their clinical applications.
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Affiliation(s)
- Ji-Kan Ryu
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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Lin CS, Xin Z, Dai J, Huang YC, Lue TF. Stem-cell therapy for erectile dysfunction. Expert Opin Biol Ther 2013; 13:1585-97. [PMID: 24090162 DOI: 10.1517/14712598.2013.847085] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Stem cells (SCs) have been investigated for the treatment of erectile dysfunction (ED). AREAS COVERED This review covers key disease targets and all 33 preclinical studies, including their use of SC types, animal models, transplantation routes, and outcome assessment methods. EXPERT OPINION In the past one and half years there have been more stem-cell-for-erectile-dysfunction studies than the prior 8 years combined. These new studies tend to use combinatory treatment approaches by modifying or supplementing SCs with angiogenic or neurotrophic genes or proteins. However, when considering all risks and benefits, these combinatory approaches do not seem more advantageous than single-SC approaches. Another trend is the choice of transplantation routes other than the standard intracavernous (IC) injection. However, with the exception of intravenous injection, these new transplantation approaches are more cumbersome than IC injection and yet offer no evidence of producing better outcomes. In contrast to these variations, a consensus among these studies is the suggestion that paracrine action, as opposed to cellular differentiation, is the principal therapeutic mechanism. In conclusion, IC injection of a single SC type should be the choice protocol for initial clinical trials, and this is clearly the case with two clinical trials that are currently recruiting patients.
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Affiliation(s)
- Ching-Shwun Lin
- University of California, School of Medicine, Department of Urology, Knuppe Molecular Urology Laboratory , San Francisco, CA 94143-0738 , USA +1 415 476 3800 ; +1 415 476 3803 ;
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Tsao J, Vernet DA, Gelfand R, Kovanecz I, Nolazco G, Bruhn KW, Gonzalez-Cadavid NF. Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle. Stem Cell Res Ther 2013; 4:4. [PMID: 23295128 PMCID: PMC3706886 DOI: 10.1186/scrt152] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 01/03/2013] [Indexed: 01/07/2023] Open
Abstract
Introduction Stimulating the commitment of implanted dystrophin+ muscle-derived stem cells (MDSCs) into myogenic, as opposed to lipofibrogenic lineages, is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). Methods To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSCs from wild-type (WT) and myostatin knockout (Mst KO) mice under various modulators, the expression of key stem cell and myogenic genes, and the capacity of these MDSCs to repair the injured gastrocnemius in aged dystrophic mdx mice with exacerbated lipofibrosis. Results Surprisingly, the potent in vitro myotube formation by WT MDSCs was refractory to modulators of myostatin expression or activity, and the Mst KO MDSCs failed to form myotubes under various conditions, despite both MDSC expressing Oct 4 and various stem cell genes and differentiating into nonmyogenic lineages. The genetic inactivation of myostatin in MDSCs was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSCs implanted into the injured gastrocnemius of aged mdx mice significantly improved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro behavior, Mst KO MDSCs in vivo also significantly improved myofiber repair, but had few effects on lipofibrotic degeneration. Conclusions Although WT MDSCs are very myogenic in culture and stimulate muscle repair after injury in the aged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro, but the myogenic capacity is recovered in vivo under the influence of the myostatin+ host-tissue environment, presumably by reactivation of key genes originally silenced in the Mst KO MDSCs.
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