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Yin GN, Ryu JK. Role of pericytes in regulating penile angiogenesis and nerve regeneration. Asian J Androl 2025; 27:13-19. [PMID: 39162179 PMCID: PMC11784945 DOI: 10.4103/aja202455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 05/19/2024] [Indexed: 08/21/2024] Open
Abstract
ABSTRACT Pericytes are multifunctional mural cells that surround the abluminal wall of endothelial cells and are associated with vascular development, vascular permeability, and angiogenesis. Additionally, pericytes demonstrate stem cell-like properties and contribute to neuroinflammatory processes. Pericytes have been extensively studied in the central nervous system. However, specific mechanisms underlying its involvement in various physiological and pathological conditions, especially in erectile dysfunction (ED), remain poorly understood. Advancements in in vitro and in vitro techniques, such as single-cell RNA sequencing, are expanding our understanding of pericytes. Recent studies have shown that pericyte dysfunction is considered an important factor in the pathogenesis of vascular and neurological ED. Therefore, this study aims to analyze the specific role of pericytes in ED, focusing on diabetic and neurogenic ED. This article provides a comprehensive review of research findings on PubMed from 2000 to 2023, concerning pericyte dysfunction in the process of ED, offering valuable insights, and suggesting directions for further research.
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Affiliation(s)
- Guo Nan Yin
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Korea
| | - Ji-Kan Ryu
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Korea
- Program in Biomedical Science and Engineering, Inha University, Incheon 22212, Korea
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Ma J, Chen Y, Si Y, Qian J, Wang C, Jin J, He Q. The multifaceted nature of diabetic erectile dysfunction: uncovering the intricate mechanisms and treatment strategies. Front Endocrinol (Lausanne) 2024; 15:1460033. [PMID: 39583965 PMCID: PMC11581859 DOI: 10.3389/fendo.2024.1460033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 10/07/2024] [Indexed: 11/26/2024] Open
Abstract
Background One of the most common complications of diabetes mellitus is diabetic erectile dysfunction (DMED), a condition that has grown more common in recent years and has a significant impact on patients' daily lives. The complicated pathophysiological changes of DMED, involving vascular, neurological, muscular, and endocrine variables, have not been well addressed by any one treatment technique, and no widely approved treatment strategy has been developed. Aim The objective of this study was to thoroughly examine the complex nature of the pathogenic mechanism of DMED and discover new therapeutic approaches that could improve DMED symptoms. Methods Studies and review articles from the past 10 years were considered. Results The pathogenesis of DMED encompasses vascular dysfunction, endothelial cell damage, cavernous smooth muscle defects, neurological dysfunction, endocrine/metabolic factors, leukomalacia fibrosis, and psychosocial factors, elucidating complex interplay among the mechanisms underlying DMED. It underscores the need of integrating traditional herbal medicine, energy-based medicine treatments, and advanced techniques like stem cell and gene therapy to enhance therapeutic outcomes. Furthermore, it expresses optimism on the therapeutic potential of new nanobiomaterials in DMED. Conclusion Through integrating a complete description of DMED etiology and current therapy methods, this work offers a helpful resource for researchers, doctors, and patients dealing with this difficult condition.
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Affiliation(s)
- Jianxiong Ma
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yihao Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yuhe Si
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiahua Qian
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Chenxi Wang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Juan Jin
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Qiang He
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Chakra MA, Bailly H, Klampke F, Boaz J, Jida M, Yassine AA, McElree IM, Moussa M. An update on the use of stem cell therapy for erectile dysfunction. Asian J Urol 2024; 11:530-544. [PMID: 39534008 PMCID: PMC11551375 DOI: 10.1016/j.ajur.2023.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 07/24/2023] [Indexed: 11/16/2024] Open
Abstract
Objective This systematic review aimed to analyze animal and human trial data to better understand the efficacy of stem cell therapy (SCT) for erectile dysfunction (ED) and the obstacles that may hinder its application in this field. Methods We searched electronic databases, including PubMed and Scopus, for published studies with the Medical Subject Heading terms of "erectile dysfunction" (AND) "stem cell therapy" (OR) "erectile dysfunction" (AND) "clinical trial of stem cell therapy" (OR) "stem cell therapy" (AND) "sexual dysfunction". The search was limited to English-language journals and full papers only. The initial search resulted in 450 articles, of which 90 relevant to our aims were included in the analysis. Results ED is a multifactorial disease. Current treatment options rely on pharmacotherapy as well as surgical options. Patients may have side effects or unsatisfactory results following the use of these treatment options. SCT may restore pathophysiological changes leading to ED rather than treating the symptoms. It has been evaluated in animal models and shown promising results in humans. Results confirm that SCT does improve erectile function in animals with different types of SC use. In humans, evidence showed promising results, but the trials were heterogeneous and limited mainly by a lack of randomization and the small sample size. Many challenges could limit future research in this field, including ethical dilemmas, regulation, patient recruitment, the cost of therapy, and the lack of a standardized SCT regimen. Repairing and possibly replacing diseased cells, tissue, or organs and eventually retrieving normal function should always be the goals of any therapy, and this can only be guaranteed by SCT. Conclusion SCT is a potential and successful treatment for ED, particularly in patients who are resistant to the classic therapy. SCT may promote nerve regeneration and vascular cell regeneration, not only symptomatic treatment.
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Affiliation(s)
| | - Hugo Bailly
- Department of Urology, Vivantes Klinikum, Berlin, Germany
| | - Fabian Klampke
- Department of Urology, Vivantes Klinikum, Berlin, Germany
| | - Johann Boaz
- Department of Urology, Royal Liverpool University Hospital, Liverpool, UK
| | | | - Ahmad Abou Yassine
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY, USA
| | - Ian M. McElree
- Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Mohamad Moussa
- Department of Urology, Lebanese University, Beirut, Lebanon
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Ahmed SM, Elkhenany HA, Ahmed TA, Ghoneim NI, Elkodous MA, Mohamed RH, Magdeldin S, Osama A, Anwar AM, Gabr MM, El-Badri N. Diabetic microenvironment deteriorates the regenerative capacities of adipose mesenchymal stromal cells. Diabetol Metab Syndr 2024; 16:131. [PMID: 38880916 PMCID: PMC11181634 DOI: 10.1186/s13098-024-01365-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/29/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND Type 2 diabetes is an endocrine disorder characterized by compromised insulin sensitivity that eventually leads to overt disease. Adipose stem cells (ASCs) showed promising potency in improving type 2 diabetes and its complications through their immunomodulatory and differentiation capabilities. However, the hyperglycaemia of the diabetic microenvironment may exert a detrimental effect on the functionality of ASCs. Herein, we investigate ASC homeostasis and regenerative potential in the diabetic milieu. METHODS We conducted data collection and functional enrichment analysis to investigate the differential gene expression profile of MSCs in the diabetic microenvironment. Next, ASCs were cultured in a medium containing diabetic serum (DS) or normal non-diabetic serum (NS) for six days and one-month periods. Proteomic analysis was carried out, and ASCs were then evaluated for apoptosis, changes in the expression of surface markers and DNA repair genes, intracellular oxidative stress, and differentiation capacity. The crosstalk between the ASCs and the diabetic microenvironment was determined by the expression of pro and anti-inflammatory cytokines and cytokine receptors. RESULTS The enrichment of MSCs differentially expressed genes in diabetes points to an alteration in oxidative stress regulating pathways in MSCs. Next, proteomic analysis of ASCs in DS revealed differentially expressed proteins that are related to enhanced cellular apoptosis, DNA damage and oxidative stress, altered immunomodulatory and differentiation potential. Our experiments confirmed these data and showed that ASCs cultured in DS suffered apoptosis, intracellular oxidative stress, and defective DNA repair. Under diabetic conditions, ASCs also showed compromised osteogenic, adipogenic, and angiogenic differentiation capacities. Both pro- and anti-inflammatory cytokine expression were significantly altered by culture of ASCs in DS denoting defective immunomodulatory potential. Interestingly, ASCs showed induction of antioxidative stress genes and proteins such as SIRT1, TERF1, Clusterin and PKM2. CONCLUSION We propose that this deterioration in the regenerative function of ASCs is partially mediated by the induced oxidative stress and the diabetic inflammatory milieu. The induction of antioxidative stress factors in ASCs may indicate an adaptation mechanism to the increased oxidative stress in the diabetic microenvironment.
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Affiliation(s)
- Sara M Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Hoda A Elkhenany
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
- Department of surgery, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt
| | - Toka A Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Nehal I Ghoneim
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Mohamed Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Rania Hassan Mohamed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Sameh Magdeldin
- Proteomic and Metabolomics Research Program, Basic Research Department, Children's Cancer Hospital, Cairo, Egypt
- Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Aya Osama
- Proteomic and Metabolomics Research Program, Basic Research Department, Children's Cancer Hospital, Cairo, Egypt
| | - Ali Mostafa Anwar
- Proteomic and Metabolomics Research Program, Basic Research Department, Children's Cancer Hospital, Cairo, Egypt
| | - Mahmoud M Gabr
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt.
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Sheikh Zayed District, Giza 12588, 6th of October City, Egypt.
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Wang W, Liu Y, Zhu ZB, Pang K, Wang JK, Gu J, Li ZB, Wang J, Shi ZD, Han CH. Research Advances in Stem Cell Therapy for Erectile Dysfunction. BioDrugs 2024; 38:353-367. [PMID: 38520608 PMCID: PMC11055746 DOI: 10.1007/s40259-024-00650-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2024] [Indexed: 03/25/2024]
Abstract
Erectile dysfunction (ED) is a common clinical condition that mainly affects men aged over 40 years. Various causes contribute to the progression of ED, including pelvic nerve injury, diabetes, metabolic syndrome, age, Peyronie's disease, smoking, and psychological disorders. Current treatments for ED are limited to symptom relief and do not address the root cause. Stem cells, with their powerful ability to proliferate and differentiate, are a promising approach for the treatment of male ED and are gradually gaining widespread attention. Current uses for treating ED have been studied primarily in experimental animals, with most studies observing improvements in erectile quality as well as improvements in erectile tissue. However, research on stem cell therapy for human ED is still limited. This article summarizes the recent literature on basic stem cell research on ED, including cavernous nerve injury, aging, diabetes, and sclerosing penile disease, and describes mechanisms of action and therapeutic effects of various stem cell therapies in experimental animals. Stem cells are also believed to interact with host tissue in a paracrine manner, and improved function can be supported through both implantation and paracrine factors. To date, stem cells have shown some preliminary promising results in animal and human models of ED.
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Affiliation(s)
- Wei Wang
- School of Medicine, Southeast University, Nanjing, China
| | - Ying Liu
- Department of Central Laboratory, Xuzhou Central Hospital, Xuzhou, China
| | - Zuo-Bin Zhu
- Xuzhou Engineering Research Center of Medical Genetics and Transformation, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, China
| | - Kun Pang
- Department of Urology, Xuzhou Central Hospital, Xuzhou, China
| | - Jing-Kai Wang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Jun Gu
- The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, China
| | - Zhen-Bei Li
- Department of Reproductive Medicine, Xuzhou Central Hospital, Xuzhou, China
| | - Jian Wang
- Department of Urology, Xuzhou Central Hospital, Xuzhou, China
| | - Zhen-Duo Shi
- Department of Urology, Xuzhou Central Hospital, Xuzhou, China.
| | - Cong-Hui Han
- School of Medicine, Southeast University, Nanjing, China.
- Department of Urology, Xuzhou Central Hospital, Xuzhou, China.
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Argiolas A, Argiolas FM, Argiolas G, Melis MR. Erectile Dysfunction: Treatments, Advances and New Therapeutic Strategies. Brain Sci 2023; 13:802. [PMID: 37239274 PMCID: PMC10216368 DOI: 10.3390/brainsci13050802] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/08/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Erectile dysfunction (ED) is the inability to get and maintain an adequate penile erection for satisfactory sexual intercourse. Due to its negative impacts on men's life quality and increase during aging (40% of men between 40 and 70 years), ED has always attracted researchers of different disciplines, from urology, andrology and neuropharmacology to regenerative medicine, and vascular and prosthesis implant surgery. Locally and/or centrally acting drugs are used to treat ED, e.g., phosphodiesterase 5 inhibitors (first in the list) given orally, and phentolamine, prostaglandin E1 and papaverine injected intracavernously. Preclinical data also show that dopamine D4 receptor agonists, oxytocin and α-MSH analogues may have a role in ED treatment. However, since pro-erectile drugs are given on demand and are not always efficacious, new strategies are being tested for long lasting cures of ED. These include regenerative therapies, e.g., stem cells, plasma-enriched platelets and extracorporeal shock wave treatments to cure damaged erectile tissues. Although fascinating, these therapies are laborious, expensive and not easily reproducible. This leaves old vacuum erection devices and penile prostheses as the only way to get an artificial erection and sexual intercourse with intractable ED, with penile prosthesis used only by accurately selected patients.
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Affiliation(s)
- Antonio Argiolas
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy; (F.M.A.); (M.R.M.)
| | - Francesco Mario Argiolas
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy; (F.M.A.); (M.R.M.)
| | - Giacomo Argiolas
- General Medicine Unit, Hospital San Michele, ARNAS“G. Brotzu”, Piazzale Ricchi 1, 09100 Cagliari, Italy;
| | - Maria Rosaria Melis
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy; (F.M.A.); (M.R.M.)
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Zou H, Zhang X, Chen W, Tao Y, Li B, Liu H, Wang R, Zhao J. Vascular endothelium is the basic way for stem cells to treat erectile dysfunction: a bibliometric study. Cell Death Discov 2023; 9:143. [PMID: 37127677 PMCID: PMC10151332 DOI: 10.1038/s41420-023-01443-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/29/2023] [Accepted: 04/20/2023] [Indexed: 05/03/2023] Open
Abstract
Vascular endothelial is considered to be a key factor in the pathogenesis of erectile dysfunction (ED). The purpose is to reveal the research trend of the field of ED and vascular endothelium. In addition, the goal is to discover the role and mechanism of vascular endothelium in ED. Bibliometrics and visualization methods based on CiteSpace were selected. We conducted the co-authorship analysis of countries, institutions and authors, co-occurrence analysis of keywords, and co-citation analysis of literature and authors through CiteSpace 6.1.R3. 1431 articles from Web of Science Core Collection (WOSCC) were included in the analysis from 1991 to 2022. We found some influential and cutting-edge nodes in each map, including countries, institutions, authors, articles, etc. Stem cell, therapy, oxidative stress, cavernous nerve injury, radical prostatectomy, fibrosis, erectile function, mesenchymal stem cell, and apoptosis may be hot keywords. In conclusion, the efficacy and mechanisms of stem cells and their derivatives in the treatment of diabetes (DM) ED and cavernous nerve injury (CNI) ED are the future research trends. Stem cells therapy for ED is a hot spot in this field, which side notes that stem cells may work mainly through improving endothelial function. Vascular endothelial cells and VEGF may repair nerve and cavernous smooth muscle directly or indirectly, and finally polish up erectile function.
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Affiliation(s)
- Hede Zou
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuesong Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenkang Chen
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Tao
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Bolin Li
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hanfei Liu
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Ruikun Wang
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Jiayou Zhao
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China.
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Zhu Y, Jiang T, Yao C, Zhang J, Sun C, Chen S, Chen M. Effects of stem cell-derived exosome therapy on erectile dysfunction: a systematic review and meta-analysis of preclinical studies. Sex Med 2023; 11:qfac019. [PMID: 36910707 PMCID: PMC9978599 DOI: 10.1093/sexmed/qfac019] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/01/2022] [Accepted: 12/11/2022] [Indexed: 03/06/2023] Open
Abstract
Introduction Erectile dysfunction (ED) is a common disease among elderly men, and novel therapy methods are needed for drug-refractory ED. As an extracellular vesicle, stem cell-derived exosomes displayed erectile function improvement in rat ED models in some preclinical studies. However, the therapeutic efficacy has not been comprehensively evaluated. Aim To study the therapeutic effects of stem cell-derived exosomes on ED in preclinical studies and to investigate the potential mechanisms responsible for the efficacy. Methods The systematic literature search was conducted in Web of Science, PubMed, and Embase to retrieve studies utilizing stem cell-derived exosomes for ED treatment. We extracted data of intracavernous pressure/mean artery pressure (ICP/MAP), and cavernosum structural changes in rat ED models before and after stem cell-derived exosome therapy. RevMan 5.3 was used to perform meta-analyses of ICP/MAP and cavernosum microstructural changes. Publication bias was assessed with the Egger test and funnel plot by Stata 15.0 (StataCorp). Main Outcome Measures Outcomes included ICP/MAP, smooth muscle, and endothelial markers-such as the ratio of smooth muscle to collagen and the expression of α-SMA (alpha smooth muscle actin), CD31 (cluster of differentiation 31), nNOS and eNOS (neuronal and endothelial nitric oxide synthase), TGF-β1 (transforming growth factor β1), and caspase 3 protein-to evaluate erectile function and microstructural changes. Forest plots of effect sizes were performed. Results Of 146 studies retrieved, 11 studies were eligible. Pooled analysis showed that stem cell-derived exosomes ameliorated damaged ICP/MAP (standardized mean difference, 3.68; 95% CI, 2.64-4.72; P < .001) and structural changes, including the ratio of smooth muscle to collagen and the expression of α-SMA, CD31, nNOS, eNOS, TGF-β1, and caspase 3 protein. Subgroup analysis indicated that exosome type and ED model type made no difference to curative effects. Conclusion This meta-analysis suggests the therapeutic efficacy of stem cell-derived exosomes for ED. Exosomes may restore erectile function by optimizing cavernosum microstructures.
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Affiliation(s)
| | | | | | - Jiawei Zhang
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, 210009, China
- Institute of Urology, Medical College, Southeast University, Nanjing, 210009, China
| | - Chao Sun
- Corresponding authors: Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China. . Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China. . Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China.
| | - Shuqiu Chen
- Corresponding authors: Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China. . Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China. . Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China.
| | - Ming Chen
- Corresponding authors: Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China. . Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China. . Department of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, China.
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Shan S, Li Q, Criswell T, Atala A, Zhang Y. Stem cell therapy combined with controlled release of growth factors for the treatment of sphincter dysfunction. Cell Biosci 2023; 13:56. [PMID: 36927578 PMCID: PMC10018873 DOI: 10.1186/s13578-023-01009-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Sphincter dysfunction often occurs at the end of tubule organs such as the urethra, anus, or gastroesophageal sphincters. It is the primary consequence of neuromuscular impairment caused by trauma, inflammation, and aging. Despite intensive efforts to recover sphincter function, pharmacological treatments have not achieved significant improvement. Cell- or growth factor-based therapy is a promising approach for neuromuscular regeneration and the recovery of sphincter function. However, a decrease in cell retention and viability, or the short half-life and rapid degradation of growth factors after implantation, remain obstacles to the translation of these therapies to the clinic. Natural biomaterials provide unique tools for controlled growth factor delivery, which leads to better outcomes for sphincter function recovery in vivo when stem cells and growth factors are co-administrated, in comparison to the delivery of single therapies. In this review, we discuss the role of stem cells combined with the controlled release of growth factors, the methods used for delivery, their potential therapeutic role in neuromuscular repair, and the outcomes of preclinical studies using combination therapy, with the hope of providing new therapeutic strategies to treat incontinence or sphincter dysfunction of the urethra, anus, or gastroesophageal tissues, respectively.
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Affiliation(s)
- Shengzhou Shan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Tracy Criswell
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, 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, 27157, USA.
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10
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Meng F, Liao X, Chen H, Deng S, Wang L, Zhao M, Li H, Liu D, Gao G, Li H, Wang J. Bibliometric and visualization analysis of literature relating to diabetic erectile dysfunction. Front Endocrinol (Lausanne) 2022; 13:1091999. [PMID: 36568113 PMCID: PMC9780376 DOI: 10.3389/fendo.2022.1091999] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction Diabetic erectile dysfunction (DMED) refers to erectile dysfunction secondary to diabetes. Erectile dysfunction is characterized by a persistent inability to achieve and maintain an erection sufficient to permit satisfactory sexual activity. Methods Based on the Web of Science core collection database, we firstly analyzed the quantity and quality of publications in the field of DMED, secondly profiled the publishing groups in terms of country, institution, author's publication and cooperation network, and finally sorted out and summarized the hot topics of research. Results From 2001 to 2022, a total of 1,403 articles relating to this topic were published in 359 journals. They represent the global research status, potential hotspots, and future research directions. The number of DMED-related publications and citations has steadily increased over the few past decades. Academic institutions from Europe and the United States have played a leading role in DMED research. The country, institution, journal, and author with the most publications were the United States (294), INHA University (39), the Journal of Sexual Medicine (156), and Ryu, Ji-Kan (29), respectively. The most common keywords were erectile dysfunction (796), men (256), diabetes (254), diabetes mellitus (239), prevalence (180), corpus cavernosum (171), dysfunction (155), mellitus (154), nitric-oxide synthase (153), and expression (140). The main keyword-based research topics and hotspots in the DMED field were oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis. Discussion The terms oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis will be at the forefront of DMED-related research.
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Affiliation(s)
- Fanchao Meng
- Urology Surgery, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoxing Liao
- Urology Surgery, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Haimin Chen
- Department of Nephroendocrinology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Sheng Deng
- Department of Andrology, Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Lu Wang
- Department of Surgery, Beijing Xuanwu Traditional Chinese Medicine Hospital, Beijing, China
| | - Mengjie Zhao
- Urology Surgery, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Haibin Li
- Urology Surgery, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Dong Liu
- Urology Surgery, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Guojing Gao
- Urology Surgery, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Haisong Li
- Department of Andrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jisheng Wang
- Department of Andrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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11
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Zhuang J, Gao P, Chen H, Fang Z, Zheng J, Zhu D, Hou J. Extracellular vesicles from human urine-derived stem cells merged in hyaluronic acid ameliorate erectile dysfunction in type 2 diabetic rats by glans administration. Andrology 2022; 10:1673-1686. [PMID: 36161709 DOI: 10.1111/andr.13293] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/17/2022] [Accepted: 08/27/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND The high prevalence of erectile dysfunction (ED) in patients with type 2 diabetes mellitus (DM2) is a challenging clinical problem. Researches on extracellular vesicles from urine-derived stem cells (USC-EVs) have shown that they have significant therapeutic effects in a variety of diseases by injection including ED. Hyaluronic acid (HA) is especially useful for delivering bioactive molecules. This study investigated the effects and related mechanisms of local administration of human USC-EVs combined with HA (USC-EVs-HA) on a rat model of DM2ED. METHODS UCSs were extracted from human urine samples and identified for preparation of the corresponding USC-EVs. The effects of high glucose and USC-EVs on human umbilical vein endothelial cells (HUVECs) were assessed in vitro using a CCK-8 assay to determine cell proliferation and pick the most appropriate concentration for subsequent experiments. Scratch and tube formation assays were performed to assess the function of HUVECs. Quantitative real-time polymerase chain reaction (PCR) was used to detect the expression of genes such as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (BAX), and superoxide dismutase-2 (SOD2). HA, USC-EVs, and USC-EVs-HA were prepared at concentrations and then administered topically to DM2ED rats multiple times. Intracavernous pressure and mean arterial pressure were measured to assess erectile function in rats. Masson, Tunel, Immunohistochemistry, and Western blot analysis were performed to assess the fibrosis and endothelial function in corpus cavernosum, respectively. RESULTS Compared with the control group, the proliferation, migration ability, and tube-forming ability of HUVECs decreased in high glucose environment, while USC-EVs could optimize the function of HUVECs, reverse the expression of apoptotic genes, and enhance the antioxidant capacity. USC-EVs-HA showed improvement in ED compared to the HA and USC-EVs groups, and the 10-dose group was better than the 5-dose group. Histologically, the USC-EVs-HA group significantly improved apoptosis, angiogenesis, and smooth muscle regeneration in the corpus cavernosum compared to the HA group. CONCLUSIONS The topical application of USC-EVs-HA in the treatment of DM2ED rats has been proved effective. The potential mechanism might to promote the proliferation of endothelial cells and smooth muscle in the corpus cavernosum, which leads to the remodeling of erectile function. And multiple dosing at intervals may make the effect more pronounced.
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Affiliation(s)
- Jingming Zhuang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Peng Gao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Haoran Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zujun Fang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jie Zheng
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Daqian Zhu
- Department of Psychology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Jiangang Hou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
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12
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Xu W, Sun T, Wang J, Wang T, Wang S, Liu J, Li H. GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis. Antioxidants (Basel) 2022; 11:antiox11101896. [PMID: 36290619 PMCID: PMC9598206 DOI: 10.3390/antiox11101896] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.
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Affiliation(s)
- Wenchao Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Taotao Sun
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiaxin Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Correspondence: (J.L.); (H.L.)
| | - Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Correspondence: (J.L.); (H.L.)
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13
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Feng H, Liu Q, Deng Z, Li H, Zhang H, Song J, Liu X, Liu J, Wen B, Wang T. Human umbilical cord mesenchymal stem cells ameliorate erectile dysfunction in rats with diabetes mellitus through the attenuation of ferroptosis. Stem Cell Res Ther 2022; 13:450. [PMID: 36064453 PMCID: PMC9444126 DOI: 10.1186/s13287-022-03147-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/18/2022] [Indexed: 11/15/2022] Open
Abstract
Background Erectile dysfunction (ED), as one of the most prevalent consequences in male diabetic patients, has a serious impact on men's physical and mental health, and the treatment effect of diabetic mellitus erectile dysfunction (DMED) is often worse. Therefore, the development of a novel therapeutic approach is urgent. As stem cells with high differentiation potential, human umbilical cord mesenchymal stem cells (HUCMSCs) have been widely used in the treatment of diseases in other systems, and are expected to be a promising strategy for the treatment of DMED. In this study, we investigated the role of HUCMSCs in managing erectile function in rat models of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and compared the effects of two different injection methods. Methods T1DM and T2DM ED rats were given labelled HUCMSCs by corpus cavernosum injection and tail vein injection, respectively. ICP and MAP were monitored simultaneously by electrical stimulation four weeks after injection to indicate the erectile function of rats. To track the development and colonisation capabilities of stem cells, we performed EdU assay with penile tissue. The histological changes of the penis were observed by hematoxylin–eosin staining, and Masson’s trichrome staining was conducted to evaluate the smooth muscle content and the degree of fibrosis in the rat penis. Then, we employed specific kits to measure the level of NO, cGMP, MDA, SOD and Fe in penis. Electron transmission microscopy was implemented to observe morphology of mitochondria. Besides, western blot and immunofluorescence staining were performed to demonstrate the expression of ferroptosis-related genes. Results We found that HUCMSCs improved erectile function in T1DM and T2DM ED rats, with no difference in efficacy between corpus cavernosum injection and tail vein injection. The EdU assay revealed that only a tiny percentage of HUCMSCs colonised the corpus cavernosum, while smooth muscle in the penis expanded and collagen decreased following HUCMSC injection. Moreover, the levels of oxidative stress in the penis of the rats given HUCMSCs were dramatically reduced, as was the tissue iron content. HUCMSCs normalised mitochondrial morphology within corpus cavernosum smooth muscle cells (CCSMCs), which were characteristically altered by high glucose. Furthermore, the expression of ferroptosis inhibitory genes SLC7A11 and GPX4 was obviously elevated in CCSMCs after stem cell management, but the abundances of ACSL4, LPCAT3 and ALOX15 showed the polar opposite tendency. Conclusions HUCMSCs can effectively and safely alleviate erectile dysfunction in T1DM and T2DM ED rats, while restoring erectile function by attenuating diabetes-induced ferroptosis in CCSMCs. Additionally, this study provides significant evidence for the development of HUCMSCs as a viable therapeutic strategy for DMED. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03147-w.
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Affiliation(s)
- Huan Feng
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qi Liu
- Department of Urology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China
| | - Zhiyao Deng
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, Guangdong, China
| | - Hao Li
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huajie Zhang
- Department of Urology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China
| | - Jingyu Song
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaming Liu
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jihong Liu
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bo Wen
- Department of Urology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China.
| | - Tao Wang
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. .,Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, Guangdong, China.
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14
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He L, Yu T, Xiao Y, Huang Y, Guan Y, Zhao F, Ma L. Co-overexpression of VEGF and Smad7 improved the therapeutic effects of adipose-derived stem cells on neurogenic erectile dysfunction in the rat model. Andrologia 2022; 54:e14538. [PMID: 35912795 DOI: 10.1111/and.14538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/23/2022] [Accepted: 07/11/2022] [Indexed: 11/29/2022] Open
Abstract
Cavernous nerve injury is the main cause of erectile dysfunction (ED) after radical prostatectomy (RP). In our previous study, injection of adipose-derived stem cells (ADSCs) into the cavernosum can repair damaged cavernosum nerves and ED can be restored to a certain extent. In order to improve these therapeutic effects, we evaluated the efficacy of ADSCs co-modified with VEGF and Smad7 in a rat model. SD rats were randomly divided into six groups: a sham surgery group, and the five bilateral cavernous nerve injury (BCNI) groups were injected with ADSC or ADSCs genetically modified by VEGF (ADSC-V), Smad7 (ADSC-S), or VEGF&Smad7 (ADSC-V&S) or phosphate-buffered saline (PBS). The results indicated that the erectile function of the ADSC-V, ADSC-S, and ADSC-V&S groups was significantly recovered, and the erectile function of the ADSC-V&S group was more distinctly recovered as compared to the other groups. The same results are shown in the expression of neuronal nitric oxide synthase and the smooth muscle/collagen ratio of penile tissue comparing the ADSC-V&S group to the ADSC-V and ADSC-S group. These experimental data suggest that ADSCs co-overexpressed with VEGF and Smad7 can significantly improve erectile function after BCNI. This study provides new therapeutic thoughts for ED following RP.
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Affiliation(s)
- Lei He
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China.,Medical College, Nantong University, Nantong, China
| | - Tiannan Yu
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China.,Medical College, Nantong University, Nantong, China
| | - Ying Xiao
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China.,Medical College, Nantong University, Nantong, China
| | - Yeqing Huang
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yangbo Guan
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China
| | - Fan Zhao
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China
| | - Limin Ma
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China
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15
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Yao C, Zhang X, Yu Z, Jing J, Sun C, Chen M. Effects of Stem Cell Therapy on Diabetic Mellitus Erectile Dysfunction: A Systematic Review and Meta-analysis. J Sex Med 2022; 19:21-36. [PMID: 36963981 DOI: 10.1016/j.jsxm.2021.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/25/2021] [Accepted: 10/06/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Stem cell is considered a potential therapy for treating erectile dysfunction (ED), including diabetic mellitus erectile dysfunction (DMED), which was investigated in some preclinical studies. Several trials introduced stem cell into clinical practice, but divergences emerged. AIM To further investigate the therapeutic effects of stem cell on DMED in preclinical studies and investigate some possible factors that influence curative effects. METHODS The literature research was conducted in Web of Science and PubMed to retrieve studies utilizing stem cell to treat DMED. Revman 5.3 was used to perform subgroup analysis of intracavernosal pressure/mean artery pressure (ICP/MAP) and structural changes. Publication bias was assessed with Egger's test, funnel plot, and sensitivity analysis by Stata 15.0. OUTCOMES The ICP/MAP and structural changes before and after stem cell treatment. RESULTS Of 2,115 studies retrieved, 23 studies are eligible. Plus 10 studies from a meta-analysis published in 2016, 33 studies were enrolled. Pooled analysis showed that stem cell ameliorates damaged ICP/MAP (WMD 0.26; 95% CI 0.23-0.29; P < .001) and structural changes induced by diabetes. Subgroup analysis indicated that adipose-derived mesenchymal stem cell (ADSC) may have better efficacy than bone marrow-derived mesenchymal stem cell (BMSC) (χ2= 4.21, P = .04; ADSC WMD 0.28, 95% CI [0.24-0.32] vs BMSC WMD 0.22 95% CI [0.17-0.26]). Transplantation type, diabetes type, and cell number make no difference to curative effects. Gene modification and therapy combination proved promising in improving the therapeutic effects of stem cell. CLINICAL TRANSLATION The evidence reminded that ADSC may be prior to BMSC in clinical trials and autotransplantation is probably not compulsory in the clinical practice of stem cell. STRENGTHS AND LIMITATIONS The study number and sample size are large enough. However, high degree of heterogeneity remains after subgroup analysis. CONCLUSION This meta-analysis suggests the efficacy of stem cell therapy for DMED and the possible superiority of ADSC over BMSC in erection restoration and structure renovation.
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Affiliation(s)
- Chi Yao
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China
- Institute of Urology, Medical College, Southeast University, Nanjing, China
| | - Xiangyu Zhang
- Institute of Urology, Medical College, Southeast University, Nanjing, China
| | - Zhikang Yu
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China
- Institute of Urology, Medical College, Southeast University, Nanjing, China
| | - Jibo Jing
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China
- Institute of Urology, Medical College, Southeast University, Nanjing, China
| | - Chao Sun
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Ming Chen
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China
- Zhongda Hospital Lishui branch, Southeast University, Nanjing, China
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16
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Luo DS, Li YQ, Deng ZQ, Liu GH. Progress and prospect of stem cell therapy for diabetic erectile dysfunction. World J Diabetes 2021; 12:2000-2010. [PMID: 35047115 PMCID: PMC8696650 DOI: 10.4239/wjd.v12.i12.2000] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/18/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic erectile dysfunction (DED) is a common complication of diabetes mellitus, significantly impairing the quality of life of patients. The conventional clinical treatment still has limitations. Stem cells (SCs), as a type of cells with multidirectional or directional differentiation capability and sustainable self-renewal potential, are widely used in regenerative medicine and tissue engineering. With the continuous update of regenerative medicine theory and the success of animal experiments, SCs as a treatment for male erectile dysfunction, especially DED, have attracted widespread attention because of curable possibility. This review focus on the current progress in the clinical application of SC treatment for DED. Moreover, we summarize the development prospects of SCs in the field of DMED therapy.
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Affiliation(s)
- Dao-Sheng Luo
- Department of Urology, Dongguan People’s Hospital, Dongguan 523000, Guangdong Province, China
| | - Yan-Qing Li
- Reproductive Centre, Sun Yat-Sen University, The Sixth Affiliated Hospital, Guangzhou 510000, Guangdong Province, China
| | - Zhi-Quan Deng
- Department of Urology, Dongguan People’s Hospital, Dongguan 523000, Guangdong Province, China
| | - Gui-Hua Liu
- Reproductive Centre, Sun Yat-Sen University, The Sixth Affiliated Hospital, Guangzhou 510000, Guangdong Province, China
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17
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Pakpahan C, Ibrahim R, William W, Faizah Z, Juniastuti J, Lusida MI, Oceandy D. Stem cell therapy and diabetic erectile dysfunction: A critical review. World J Stem Cells 2021; 13:1549-1563. [PMID: 34786157 PMCID: PMC8567456 DOI: 10.4252/wjsc.v13.i10.1549] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.
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Affiliation(s)
- Cennikon Pakpahan
- Department of Biomedical Sciences, Universitas Airlangga, Surabaya 60132, Indonesia
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
| | - Raditya Ibrahim
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
| | - William William
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
- Department of Medical Biology, School of Medicine and Health Sciences Atma Jaya Catholic University of Indonesia, Jakarta 14440, Indonesia
| | - Zakiyatul Faizah
- Department of Biomedical Sciences, Universitas Airlangga, Surabaya 60132, Indonesia
| | | | - Maria I Lusida
- Institute for Tropical Disease, Universitas Airlangga, Surabaya 60132, Indonesia
| | - Delvac Oceandy
- Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom
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18
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Yu B, Qin F, Wei S, Wu C, Ma M, Yuan J. Prolonged isoflurane anesthesia-induced acidosis decreases penile intracavernous pressure in rats. Andrology 2021; 10:143-153. [PMID: 34333872 DOI: 10.1111/andr.13085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 07/07/2021] [Accepted: 07/23/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Intracavernous pressure measurement following cavernous nerve electrostimulation has been extensively adopted for the evaluation of erectile function in animals. However, the effect of measurement time and acidosis during anesthesia is still lacking. OBJECTIVE To explore the effect of measurement time and acidosis during anesthesia. MATERIALS AND METHODS Fifty-six male Sprague-Dawley rats were used and anesthetized by a spontaneous inhalation of isoflurane. In the first step, rats were randomly divided into four groups: a control group and three time-delayed measurement groups (intracavernous pressure measurement beginning at 15, 30, and 45 min after cavernous nerve exposure). In the second step, rats were randomly divided into three groups: a control group and two time-delayed measurement groups. Two intravenous fluid support strategies were used in time-delayed measurement groups: a normal saline solution and an isotonic Na2 CO3 solution. RESULTS Isoflurane-anesthetized rats developed systemic acidosis that worsens with time during intracavernous pressure measurement, which results in a significant decrease in the maximum intracavernous pressure value, intracavernous pressure/mean arterial pressure ratio, and total intracavernous pressure measured. The Na2 CO3 infusion could effectively correct acidosis. The decrease in intracavernous pressure was related to the reduced nitric oxide synthase activity, decreased cyclic guanosine monophosphate concentration, and reactive oxygen species activation in rat penis under acidosis conditions. DISCUSSION AND CONCLUSION Prolonged isoflurane anesthesia-induced acidosis markedly depresses the erectile response to cavernous nerve electrostimulation in rats. In this situation, it is recommended to supplement with a Na2 CO3 infusion to maintain a normal acid-base balance.
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Affiliation(s)
- Botao Yu
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, China.,Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Feng Qin
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Shanzun Wei
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, China.,Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Changjing Wu
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Ma
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, China.,Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jiuhong Yuan
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, China.,Department of Urology, West China Hospital, Sichuan University, Chengdu, China
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19
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Lian C, Huang Q, Zhong X, He Z, Liu B, Zeng H, Xu N, Yang Z, Liao C, Fu Z, Guo H. Pentraxin 3 secreted by human adipose-derived stem cells promotes dopaminergic neuron repair in Parkinson's disease via the inhibition of apoptosis. FASEB J 2021; 35:e21748. [PMID: 34152016 DOI: 10.1096/fj.202100408rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/02/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022]
Abstract
Although adipose-derived human mesenchymal stem cell (hADSC) transplantation has recently emerged as a promising therapeutic modality for Parkinson's disease (PD), its underlying mechanism of action has not been fully elucidated. This study evaluated the therapeutic effects of stereotaxic injection of hADSCs in the striatum of the 6-OHDA-induced mouse model. Furthermore, an in vitro PD model was constructed using tissue-organized brain slices. The therapeutic effect was also evaluated using a co-culture of the hADSCs and 6-OHDA-treated brain slice. The analysis of hADSC exocrine proteins using RNA-sequencing, human protein cytokine arrays, and label-free quantitative proteomics identified key extracellular factors in the hADSC secretion environment. The degeneration and apoptosis of the dopaminergic neurons were measured in the PD samples in vivo and in vitro, and the beneficial effects were evaluated using quantitative reverse transcription-polymerase chain reaction, western blotting, Fluoro-Jade C, TUNEL assay, and immunofluorescence analysis. This study found that hADSCs protected the dopaminergic neurons in the in vivo and vitro models. We identified Pentraxin 3 (PTX3) as a key extracellular factor in the hADSC secretion environment. Moreover, we found that human recombinant PTX3 (rhPTX3) treatment could rescue the pathophysiological behavior of the PD mice in vivo, prevent dopaminergic neuronal death, and increase neuronal terminals in the ventral tegmental area + substantia nigra pars compacta and striatum in the PD brain slices in vitro. Furthermore, testing of the pro-apoptotic markers in the PD mouse brain following rhPTX3 treatment revealed that rhPTX3 can prevent apoptosis and degeneration of the dopaminergic neurons. This study discovered that PTX3, a hADSC-secreted protein, potentially protected the dopaminergic neurons against apoptosis and degeneration during PD progression and improved motor performance in PD mice, indicating the possible mechanism of action of hADSC replacement therapy for PD. Thus, our study discovered potential translational implications for the development of PTX3-based therapeutics for PD.
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Affiliation(s)
- Changlin Lian
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qiongzhen Huang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiangyang Zhong
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhenyan He
- Department of Neurosurgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Boyang Liu
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Huijun Zeng
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ningbo Xu
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhao Yang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chenxin Liao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhao Fu
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hongbo Guo
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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20
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Irdam GA, Febriyani, Rasyid N, Taher A. A systematic review of intracavernosal injection of mesenchymal stem cells for diabetic erectile dysfunction. MEDICAL JOURNAL OF INDONESIA 2021. [DOI: 10.13181/mji.oa.204475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
BACKGROUND As current erectile dysfunction (ED) treatments are limited, other treatment such as stem cells should be explored. Hence, this study aimed to review the sources, method of administration, and therapeutic effect of mesenchymal stem cells (MSCs) for diabetic ED treatment.
METHODS All relevant articles regarding the use of MSCs for diabetic ED were searched in PubMed and Google Scholar databases from December 15, 2019 to January 1, 2020 published in the past 10 years. The keywords were “mesenchymal stem cells” and “diabetic ED”. The selection and critical appraisal of the studies were discussed. Diabetic ED was evaluated for functional and structural outcome. Functional outcome in animal studies was assessed by intracavernosal pressure/mean arterial pressure (ICP/MAP) ratio, meanwhile the structural outcome was done microscopically. In human study, the assessments were done using international index of erectile function score (IIEF-5) to erection hardness score and penile Doppler ultrasonography.
RESULTS There were 10 animal studies and 3 human studies. The studies used MSCs from adipose (n = 6), bone marrow (n = 4), placenta (n = 1), umbilical cord (n = 1), and muscle tissue (n = 1). The MSCs were administrated through intracavernosal injection in all studies. In all animal studies, functional outcome was improved, shown in higher ICP/MAP ratio. Microscopically, there were an increase of cavernosal endothelial cells, vascular endothelial growth factor, nitric oxide synthase, and smooth muscle cells. In human studies, IIEF-5 and erection hardness score were improved. Peak systolic velocity was also higher.
CONCLUSIONS MSCs may be a promising therapy for diabetic ED; however, long-term safety concerns still need further investigations.
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21
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Wu JH, Wang DY, Sheng L, Qian WQ, Xia SJ, Jiang Q. Human umbilical cord Wharton's jelly-derived mesenchymal stem cell transplantation could improve diabetic intracavernosal pressure. Asian J Androl 2021; 24:171-175. [PMID: 33975986 PMCID: PMC8887109 DOI: 10.4103/aja.aja_33_21] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Mesenchymal stem cells (MSCs) secrete various cytokines with angiogenic and neuroprotective effects. This study aimed to assess the effects of human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on diabetes-related intracavernosal pressure (ICP) impairment in rats. hWJ-MSCs were isolated from human umbilical cord Wharton's jelly and transplanted into the corpus cavernosum of streptozotocin (STZ)-induced diabetic rats by unilateral injection. The erectile function was evaluated at 4 weeks, as well as the expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS), and insulin-like growth factor 1 (IGF1). STZ-induced diabetic rats showed impaired ICP, which was significantly improved by hWJ-MSC treatment. VEGF, eNOS, IGF1, and bFGF expression levels were higher in hWJ-MSC injection sites than those in control ones in STZ-induced diabetic rats. These results suggest that hWJ-MSC transplantation might improve diabetic erectile dysfunction through increased production of paracrine growth factors, highlighting a novel potential therapeutic option for erectile dysfunction.
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Affiliation(s)
- Jian-Hong Wu
- Department of Urology, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, China.,Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Dong-Ya Wang
- Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Lu Sheng
- Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Wei-Qing Qian
- Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Shu-Jie Xia
- Department of Urology, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, China.,Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Qi Jiang
- Department of Urology, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, China.,Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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22
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Chen X, Yang Q, Xie Y, Deng C, Liu G, Zhang X. Comparative study of different transplantation methods of adipose tissue-derived stem cells in the treatment of erectile dysfunction caused by cavernous nerve injury. Andrologia 2021; 53:e13950. [PMID: 33600019 DOI: 10.1111/and.13950] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/09/2020] [Accepted: 12/12/2020] [Indexed: 11/26/2022] Open
Abstract
We aimed to compare intracavernosal injection (ICI), tail vein injection (IV), and periprostatic injection (PPI) of adipose-derived stem cells (ADSCs) for their ability to improve erectile function in cavernous nerve injury-induced erectile dysfunction (CNIED) rats and to explore the possible mechanism. Eighty-four male SD rats were divided into the sham group (n = 6), BCNI group (bilateral CN crush injury, n = 6), PBS-ICI group (n = 6), PBS-IV group (n = 6), PBS-PPI group (n = 6), ADSC-ICI group (n = 18), ADSC-IV group (n = 18) and ADSC-PPI group (n = 18). ADSCs were labelled with 5-ethynyl-2'-deoxyuridine (EdU), and six rats each in the ADSC-ICI group, ADSC-IV group, and ADSC-PPI group were sacrificed 2, 7, and 28 days after injection. EdU-labelled ADSCs were tracked by immunofluorescence staining. The intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio, neuronal nitric oxide synthase (nNOS)-positive nerve fibres in the dorsal penile nerve and the smooth muscle/collagen ratio in the cavernosum between groups were also evaluated. ADSCs can significantly improve erectile function through ICI or IV. The two are similar in efficacy and superior to PPI. The mechanism may be that after CN injury, ADSCs are recruited to around the MPG and secrete a variety of neurotrophic factors that promote the repair of the CN, thereby improving erectile function.
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Affiliation(s)
- Xin Chen
- Department of Andrology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Qiyun Yang
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yun Xie
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chunhua Deng
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guihua Liu
- Reproductive Medicine Research Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiangsheng Zhang
- Department of Andrology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
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23
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Hiremath DS, Priviero FB, Webb RC, Ko C, Narayan P. Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation. Reproduction 2021; 161:31-41. [PMID: 33112284 PMCID: PMC7686140 DOI: 10.1530/rep-20-0447] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/12/2020] [Indexed: 12/16/2022]
Abstract
Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study, we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)-mediated signaling. Cyclic GMP (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.
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Affiliation(s)
- Deepak S. Hiremath
- Department of Physiology, Southern Illinois School of Medicine, Carbondale, IL, USA
| | - Fernanda B.M. Priviero
- Cardiovascular Translational Research Center and Department of Cell Biology and Anatomy University of South Carolina, Columbia, SC, USA
| | - R. Clinton Webb
- Cardiovascular Translational Research Center and Department of Cell Biology and Anatomy University of South Carolina, Columbia, SC, USA
| | - CheMyong Ko
- Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Prema Narayan
- Department of Physiology, Southern Illinois School of Medicine, Carbondale, IL, USA
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24
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Kazemi E, Zargooshi J, Kaboudi M, Heidari P, Kahrizi D, Mahaki B, Mohammadian Y, Khazaei H, Ahmed K. A genome-wide association study to identify candidate genes for erectile dysfunction. Brief Bioinform 2020; 22:6034052. [PMID: 33316063 DOI: 10.1093/bib/bbaa338] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/22/2022] Open
Abstract
Erectile dysfunction (ED) can be caused by different diseases and controlled by several genetic networks. In this study, to identify the genes related to ED, the expression profiles of normal and ED samples were investigated by the Gene Expression Omnibus (GEO) database. Seventeen genes were identified as associated genes with ED. The protein and nucleic acid sequences of selected genes were retrieved from the UCSC database. Selected genes were diverse according to their physicochemical properties and functions. Category function revealed that selected genes are involved in pathways related to humans some diseases. Furthermore, based on protein interactions, genes associated with the insulin pathway had the greatest interaction with the studied genes. To identify the common cis-regulatory elements, the promoter site of the selected genes was retrieved from the UCSC database. The Gapped Local Alignment of Motifs tool was used for finding common conserved motifs into the promoter site of selected genes. Besides, INSR protein as an insulin receptor precursor showed a high potential site for posttranslation modifications, including phosphorylation and N-glycosylation. Also, in this study, two Guanine-Cytosine (GC)-rich regions were identified as conserved motifs in the upstream of studied genes which can be involved in regulating the expression of genes associated with ED. Also, the conserved binding site of miR-29-3p that is involved in various cancers was observed in the 3' untranslated region of genes associated with ED. Our study introduced new genes associated with ED, which can be good candidates for further analyzing related to human ED.
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Affiliation(s)
- Elham Kazemi
- Family Sexual Health at Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Javaad Zargooshi
- Department of Sexual Medicine at the Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marzieh Kaboudi
- Reproductive Health Department of the Kermanshah University of Medical Sciences
| | | | | | - Behzad Mahaki
- Department of Bio-Statistics and Epidemiology, School of Health, Kermanshah University of Medical Sciences
| | | | | | - Kawsar Ahmed
- Department of Information and Communication Technology (ICT) at the Mawlana Bhashani Science and Technology University, Tangail, Bangladesh
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25
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Combined Transplantation of Adipose Tissue-Derived Stem Cells and Endothelial Progenitor Cells Improve Diabetic Erectile Dysfunction in a Rat Model. Stem Cells Int 2020; 2020:2154053. [PMID: 32714394 PMCID: PMC7354671 DOI: 10.1155/2020/2154053] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 01/31/2020] [Accepted: 02/25/2020] [Indexed: 12/24/2022] Open
Abstract
Erectile dysfunction (ED) is a common complication in men suffered with diabetic mellitus. Stem cell transplantation is a promising strategy for the treatment of diabetic ED (DED). In this study, we evaluated whether combined transplantation of adipose tissue-derived stem cells (ADSCs) and endothelial progenitor cells (EPCs) could improve the erectile function of the DED rat model. DED rats were induced via intraperitoneal injection of streptozotocin (50 mg/kg), and ED was screened by apomorphine (100 mg/kg). DED rats were divided into 4 groups (n = 14 each): DED, ADSC, EPC, and ADSC/EPC group. Another 14 age-matched male SD rats with normal erectile function were served as the normal group. The normal group and the DED group were received intracavernous injection with phosphate-buffered saline (PBS). And the other groups were received intracavernous injection with ADSCs (1 × 106), EPCs (1 × 106), and ADSCs/EPCs (0.5 × 106/0.5 × 106), respectively. The total intracavernous pressure (ICP) and mean arterial pressure (MAP) were recorded at day 28 after injection. The endothelium, smooth muscle, and penile dorsal nerves were assessed within cavernoursal tissue. On day 28 after injection, the ADSC/EPC group displayed more significantly enhanced ICP and ICP/MAP than the DED or ADSC or EPC group (p < 0.05). Immunofluorescent analysis and western blot demonstrated that the improvement of erectile function in the ADSC/EPC5 group was associated with increased expression of endothelial marker (CD31) and the correction of eNOS-cGMP-NO signaling. More 5-ethynyl-2′-deoxyuridine- (EdU-) positive EPCs could be found lining in the cavernous endothelial layer in the ADSC/EPC group than the EPC group, which was attributed to the paracrine of vascular endothelial growth factor (VEGF) and stromal-derived factor-1 (SDF-1) by ADSCs. Combined transplantation of ADSCs and EPCs has a synergic effect in repairing the endothelial function of DED rats, and the underlying mechanism might be the paracrine of VEGF and SDF-1 by ADSCs, which improves the recruitment and proliferation of EPCs in the cavernosum.
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26
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Yan H, Ding Y, Lu M. Current Status and Prospects in the Treatment of Erectile Dysfunction by Adipose-Derived Stem Cells in the Diabetic Animal Model. Sex Med Rev 2020; 8:486-491. [DOI: 10.1016/j.sxmr.2019.09.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/08/2019] [Accepted: 09/21/2019] [Indexed: 12/19/2022]
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27
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Gur S, Hellstrom WJ. Harnessing Stem Cell Potential for the Treatment of Erectile Function in Men with Diabetes Mellitus: From Preclinical/Clinical Perspectives to Penile Tissue Engineering. Curr Stem Cell Res Ther 2020; 15:308-320. [DOI: 10.2174/1574888x14666190828142045] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 07/10/2019] [Accepted: 08/06/2019] [Indexed: 12/20/2022]
Abstract
Background::
According to the World Health Organization, more than 150 million people
are diabetic, and this number will increase twofold by the year 2025. Diabetes-related complications
affect all body organ systems, including the penis. Diabetes-induced Erectile Dysfunction (ED) is
caused by neuropathy of the penile nerves and vasculopathy involving the smooth muscle and endothelium
of the corpus cavernosum.
Objective::
This study aims to present an overview of Stem Cell (SC) research in diabetic animal models
of ED, focusing on the function, signaling, and niches that have a prominent role in the regeneration
of cavernosal cells and penile tissues. We highlight common erectile pathologies caused by diabetes
and review relevant preclinical trials. We also discuss paracrine mechanisms of various SC therapies
involved in the repair of endothelial cells and cavernous nerves in these diabetic models.
Method::
A PubMed search was performed, with dates ranging from inception until Mar 31, 2019.
Results::
This review provides a comprehensive evaluation of the various strategies that have been
investigated for improving SC delivery methods, through preclinical literature and published clinical
trials regarding ED in men with diabetes. Various cell-type applications have benefited erectile function
in diabetic models of ED.
Conclusion::
This review examines the progress and remaining challenges in diabetes-related SC research
regarding ED. Moving forward, it is only with a combined effort of basic biology and translational
work that the potential of SC-based therapies in diabetes in ED can be realized.
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Affiliation(s)
- Serap Gur
- Department of Urology, Tulane University Health Sciences Center, New Orleans, LA, United States
| | - Wayne J.G. Hellstrom
- Department of Urology, Tulane University Health Sciences Center, New Orleans, LA, United States
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28
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Liu MC, Chang ML, Wang YC, Chen WH, Wu CC, Yeh SD. Revisiting the Regenerative Therapeutic Advances Towards Erectile Dysfunction. Cells 2020; 9:E1250. [PMID: 32438565 PMCID: PMC7290763 DOI: 10.3390/cells9051250] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 12/12/2022] Open
Abstract
Erectile dysfunction (ED) is an inability to attain or maintain adequate penile erection for successful vaginal intercourse, leading to sexual and relationship dissatisfaction. To combat ED, various surgical and non-surgical approaches have been developed in the past to restore erectile functions. These therapeutic interventions exhibit significant impact in providing relief to patients; however, due to their associated adverse effects and lack of long-term efficacy, newer modalities such as regenerative therapeutics have gained attention due to their safe and prolonged efficacy. Stem cells and platelet-derived biomaterials contained in platelet-rich plasma (PRP) are thriving as some of the major therapeutic regenerative agents. In recent years, various preclinical and clinical studies have evaluated the individual, as well as combined of stem cells and PRP to restore erectile function. Being rich in growth factors, chemokines, and angiogenic factors, both stem cells and PRP play a crucial role in regenerating nerve cells, myelination of axons, homing and migration of progenitor cells, and anti-fibrosis and anti-apoptosis of damaged cavernous nerve in corporal tissues. Further, platelet-derived biomaterials have been proven to be a biological supplement for enhancing the proliferative and differentiation potential of stem cells towards neurogenic fate. Therefore, this article comprehensively analyzes the progresses of these regenerative therapies for ED.
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Affiliation(s)
- Ming-Che Liu
- Department of Urology, Taipei Medical University Hospital, Taipei 11031, Taiwan; (M.-C.L.); (C.-C.W.)
- Clinical Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Graduate Institute of Clinical Medicine, school of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Meng-Lin Chang
- Department of Urology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 242, Taiwan;
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Graduate Institute of Applied Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Ya-Chun Wang
- TCM Biotech International Corp., New Taipei City 22175, Taiwan; (Y.-C.W.); (W.-H.C.)
| | - Wei-Hung Chen
- TCM Biotech International Corp., New Taipei City 22175, Taiwan; (Y.-C.W.); (W.-H.C.)
| | - Chien-Chih Wu
- Department of Urology, Taipei Medical University Hospital, Taipei 11031, Taiwan; (M.-C.L.); (C.-C.W.)
- Department of Education and Humanities in Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Shauh-Der Yeh
- Department of Urology and Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Liu G, Wu R, Yang B, Shi Y, Deng C, Atala A, Mou S, Criswell T, Zhang Y. A cocktail of growth factors released from a heparin hyaluronic-acid hydrogel promotes the myogenic potential of human urine-derived stem cells in vivo. Acta Biomater 2020; 107:50-64. [PMID: 32044457 DOI: 10.1016/j.actbio.2020.02.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 01/22/2020] [Accepted: 02/04/2020] [Indexed: 01/19/2023]
Abstract
Traditional cell therapy technology relies on the maximum expansion of primary stem cells in vitro, through multiple passages and potential differentiation protocols, in order to generate the abundance of cells needed prior to transplantation in vivo. Implantation of in vitro over-expanded and pre-differentiated cells typically results in poor cell survival and reduced regeneration capacity for tissue repair in vivo. We hypothesized that implantation of primary stem cells, after a short time culture in vitro (passage number ≤p3), in combination with controlled release of relevant growth factors would improve in vivo cell viability, engraftment and tissue regeneration. The goal of this study was to determine whether the release of myogenic growth factors from a heparin-hyaluronic acid gel (hp-HA gel) could enhance in vivo cell survival, in-growth and myogenic differentiation of human urine-derived stem cells (USC) with a corresponding enhancement in graft vascularization, innervation and regenerative properties. Human USC were obtained from healthy adult donors (n = 6), expanded and then mixed with a hp-HA gel containing sets of growth factors known to enhance myogenesis (IGF1, HGF, PDGF-BB), neurogenesis (NGF, FGF) and angiogenesis (VEGF), or a cocktail with a combination of growth factors. Primary cultured USC (p3) mixed with the hp-HA gel and the various combinations of growth factors, were subcutaneously injected into athymic mice. In vivo cell survival, engraftment and functional differentiation within the host tissue were assessed. The implanted grafts containing USC and the growth factor cocktail showed the greatest number of surviving cells as well as increased numbers of cells that expressed myogenic and endothelial cell markers as compared to other groups 4 weeks after implantation. Moreover, the graft with USC and the growth factor cocktail showed increased numbers of blood vessels and infiltrating neurons. Thus, growth factors released in a controlled manner from an hp-HA gel containing USC efficiently improved in vivo cell survival and supported vascularization and myogenic differentiation within the grafts. This study provides evidence for the use of primary USC and growth factors in a hydrogel as a novel mode of cell therapy for the promotion of myogenic differentiation for the treatment of injured muscle tissue. STATEMENT OF SIGNIFICANCE: Cell therapies are a promising treatment option for neuromuscular dysfunction disorders. However, major limitations in cell retention and engraftment after implantation remain a hindrance to the use of stem cell therapy for the treatment of muscle injuries or diseased tissues. Implanted long-term in vitro cultured cells tend to demonstrate low rates of survival and tissue engraftment, lessened paracrine effects, and poor homing and differentiation. Human USC are an easily obtainable stem cell source that possess stem cell characteristics such as a robust proliferative potential, paracrine effects on neighboring cells, and multi-potential differentiation. In this study, we demonstrated that a combination of primary human USC with a cocktail of growth factors combined in a hyaluronic gel was optimal for cell survival and engraftment, including myogenic differentiation potential of USC, angiogenesis and host nerve fiber recruitment in vivo. The present study also demonstrated that the use of primary urine derived stem cells at early passages, without in vitro pre-differentiation, implanted in a hyaluronic-heparin hydrogel containing a cocktail of growth factors, provided an alternative safe site-specific delivery method for cell therapy.
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Affiliation(s)
- Guihua Liu
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Reproductive Medicine Research Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Rongpei Wu
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bin Yang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Yingai Shi
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Chunhua Deng
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Steven Mou
- Anesthesiology-Pediatric ICU Anesthesia at WakeForest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Tracy Criswell
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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Gu X, Thakker PU, Matz EL, Terlecki RP, Marini FC, Allickson JG, Lue TF, Lin G, Atala A, Yoo JJ, Zhang Y, Jackson JD. Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model. J Sex Med 2020; 17:400-411. [PMID: 32001204 DOI: 10.1016/j.jsxm.2019.12.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 11/06/2019] [Accepted: 12/07/2019] [Indexed: 10/25/2022]
Abstract
INTRODUCTION The human placenta provides a bountiful and noncontroversial source of stem cells which have the potential for regeneration of injured tissue. These cells may restore erectile function after neurovascular tissue injury such as that seen in radical pelvic surgeries and pelvic trauma. AIM To determine the effect of human placenta-derived stem cells on erectile function recovery and histological changes at various time points in a cavernous nerve injury rat model and to study the fate of injected stem cells throughout the regenerative process. METHODS Human placental stem cells (PSCs) were dual labeled with monomeric Katushka far red fluorescent protein (mKATE)-renLUC using a lentivirus vector. A pelvic neurovascular injury-induced erectile dysfunction model was established in male, athymic rats by crushing the cavernous nerves and ligating the internal pudendal neurovascular bundles, bilaterally. At the time of defect creation, nonlabeled PSCs were injected into the corpus cavernosum at a concentration of 2.5 × 106 cells/0.2 mL. The phosphate-buffered saline-treated group served as the negative control group, and age-matched rats (age-matched controls) were used as the control group. Erectile function, histomorphological analyses, and Western blot were assessed at 1, 6, and 12 weeks after model creation. The distribution of implanted, dual-labeled PSCs was monitored using an in vivo imaging system (IVIS). Implanted cells were further tracked by detection of mKATE fluorescence in histological sections. MAIN OUTCOME MEASURE The main outcome measure includes intracavernous pressure/mean arterial pressure ratio, neural, endothelial, smooth muscle cell regeneration, mKATE fluorescence, and IVIS imaging. RESULTS The ratio of intracavernous pressure to mean arterial pressure significantly increased in PSC-injected rats compared with phosphate-buffered saline controls (P < 0.05) at the 6- and 12-week time points, reaching 72% and 68% of the age-matched control group, respectively. Immunofluorescence staining and Western blot analysis showed significant increases in markers of neurons (84.3%), endothelial cells (70.2%), and smooth muscle cells (70.3%) by 6 weeks in treatment groups compared with negative controls. These results were maintained through 12 weeks. IVIS analysis showed luminescence of implanted PSCs in the injected corpora immediately after injection and migration of cells to the sites of injury, including the incision site and periprostatic vasculature by day 1. mKATE fluorescence data revealed the presence of PSCs in the penile corpora and major pelvic ganglion at 1 and 3 days postoperatively. At 7 days, immunofluorescence of penile PSCs had disappeared and was diminished in the major pelvic ganglion. CLINICAL IMPLICATIONS Placenta-derived stem cells may represent a future "off-the-shelf" treatment to mitigate against development of erectile dysfunction after radical prostatectomy or other forms of pelvic injury. STRENGTH & LIMITATIONS Single dose injection of PSCs after injury resulted in maximal functional recovery and tissue regeneration at 6 weeks, and the results were maintained through 12 weeks. Strategies to optimize adult stem cell therapy might achieve more effective outcomes for human clinical trials. CONCLUSION Human PSC therapy effectively restores the erectile tissue and function in this animal model. Thus, PSC therapy may provide an attractive modality to lessen the incidence of erectile dysfunction after pelvic neurovascular injury. Further improvement in tissue regeneration and functional recovery may be possible using multiple injections or systemic introduction of stem cells. Gu X, Thakker PU, Matz EL, et al. Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model. J Sex Med 2020;17:400-411.
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Affiliation(s)
- Xin Gu
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Parth U Thakker
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Urology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Ethan L Matz
- Department of Urology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Ryan P Terlecki
- Department of Urology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Frank C Marini
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Julie G Allickson
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Tom F Lue
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
| | - Guiting Lin
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Urology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - John D Jackson
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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Liu Q, Cui Y, Lin H, Hu D, Qi T, Wang B, Huang Z, Chen J, Li K, Xiao H. MicroRNA-145 engineered bone marrow-derived mesenchymal stem cells alleviated erectile dysfunction in aged rats. Stem Cell Res Ther 2019; 10:398. [PMID: 31852516 PMCID: PMC6921450 DOI: 10.1186/s13287-019-1509-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/12/2019] [Accepted: 11/22/2019] [Indexed: 01/25/2023] Open
Abstract
Background Aging is one of the dominant factors contributing to erectile dysfunction (ED), and effective treatments for age-associated ED are urgently demanded. In this study, the therapeutic efficiency of bone marrow-derived mesenchymal stem cells (BMSCs) overexpressing microRNA-145 (miR-145) was evaluated in ED. Methods Sixty male Sprague-Dawley rats (24 months old) were randomly divided into 4 treatment groups (n = 15/group): PBS (control), BMSCs, BMSCs transfected with a blank vector (vector-BMSCs), and BMSCs transfected with a lentivirus overexpressing miR-145 (OE-miR-145-BMSCs). Fourteen days after transplantation of BMSCs, erectile function was evaluated by measuring intra-cavernous pressure (ICP) and mean arterial pressure (MAP). Subsequently, penile erectile tissues were harvested and subjected to Masson staining, qRT-PCR, immunofluorescence staining, dual luciferase assay, and Western blot analysis. Results Fourteen days after transplantation, the ICP/MAP was 0.79 ± 0.05 in the OE-miR-145-BMSC group, 0.61 ± 0.06 in the BMSC group, 0.57 ± 0.06 in the vector-BMSC group, and 0.3 ± 0.01 in the PBS group. Treatment with OE-miR-145-BMSCs significantly improved ED (P < 0.05), and the treatment increased the smooth muscle content in the penis tissues of ED rats (P < 0.05). In the OE-miR-145-BMSC group, the expression levels of α-SMA, desmin, and SM-MHC were higher than they were in the other ED groups (P < 0.05). In addition, the levels of collagen 1, MMP2, and p-Smad2 in the BMSC-treated group, especially in the OE-miR-145-BMSC group, were lower than those in the control group (P < 0.05). Conclusions MicroRNA-145 engineered BMSCs effectively attenuate age-related ED. Transplantation of miR-145-overexpressing BMSCs may provide a promising novel avenue for age-associated ED therapy.
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Affiliation(s)
- Qiwei Liu
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Yubin Cui
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Haojian Lin
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Daoyuan Hu
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Tao Qi
- Department of Infertility and Sexual Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Bo Wang
- Department of Infertility and Sexual Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Zhansen Huang
- Department of Infertility and Sexual Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Jun Chen
- Department of Infertility and Sexual Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China
| | - Ke Li
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China.
| | - Hengjun Xiao
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600#, Guangzhou, 510630, China.
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Kim SW, Zhu GQ, Bae WJ. Mesenchymal Stem Cells Treatment for Erectile Dysfunction in Diabetic Rats. Sex Med Rev 2019; 8:114-121. [PMID: 31653438 DOI: 10.1016/j.sxmr.2019.09.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 09/03/2019] [Accepted: 09/15/2019] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Aging men with diabetes mellitus are more easily suffering from erectile dysfunction (ED), which was poor to respond to drugs. Mesenchymal stem cell treatment (MSCT) offers us an alternative approach that might reverse diabetes mellitus erectile dysfunction (DMED). AIM The aim of this study was to review the current studies investigating mesenchymal stem cell approach in diabetic rat models of ED for future research. METHODS A medical literature search was performed in PubMed by using the keywords including erectile dysfunction, mesenchymal stem cells, diabetes mellitus, and rat model. MAIN OUTCOME MEASURE Representative studies on DMED rats treated by MSCT were reviewed. RESULTS Streptozocin-induced type 1 diabetes mellitus rats were used in most studies because of cost and convenience. With the development of stem cell treatment for DMED research, many kinds of stem cells were used in animal experiment, such as bone marrow-derived mesenchymal stem cells, adipose-derived stem cells, human umbilical cord blood mononuclear cells, muscle-derived stem cells, urine-derived stem cells, neural crest stem cells, and endothelial progenitor cells. Although diverse stem cells were applied for DMED treatment, the mechanism behind these approaches was identical, including improving vascular injury, recovering smooth muscle, restoring neuronal cells, inhibiting the generation of inflammatory cytokines, homing mesenchymal stem cells, and decreasing apoptosis in corpus cavernosum. Meanwhile, combination therapies, including MSCT with drug, herb, and low-energy extracorporeal shockwave treatment showed satisfactory results for ED. CONCLUSION It has been proved that MSCT is an effective and safe treatment for the DMED rats. What's more, MSCT might be a potential and promising approach for patients with DMED as a minimally invasive treatment. Combination of MSCT with various methods was proved to be a more efficient treatment and dependable option to make up for deficiencies of MSCT. Kim SW, Zhu GQ, Bae WJ. Mesenchymal Stem Cells Treatment for Erectile Dysfunction in Diabetic Rats. Sex Med Rev 2020;8:114-121.
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Affiliation(s)
- Sae Woong Kim
- Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Integrative Medicine Research Institute, The Catholic University of Korea, Seoul, Republic of Korea
| | - Guan Qun Zhu
- Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Integrative Medicine Research Institute, The Catholic University of Korea, Seoul, Republic of Korea
| | - Woong Jin Bae
- Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Integrative Medicine Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.
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Transplantation of Human Urine-Derived Stem Cells Ameliorates Erectile Function and Cavernosal Endothelial Function by Promoting Autophagy of Corpus Cavernosal Endothelial Cells in Diabetic Erectile Dysfunction Rats. Stem Cells Int 2019; 2019:2168709. [PMID: 31582984 PMCID: PMC6754951 DOI: 10.1155/2019/2168709] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 07/03/2019] [Accepted: 08/08/2019] [Indexed: 02/07/2023] Open
Abstract
Aims Cavernosal endothelial dysfunction is one of the factors in developing diabetic erectile dysfunction (DED), but the mechanism of cavernosal endothelial dysfunction is unclear. The present study is aimed at determining the contribution of autophagy in cavernosal endothelial dysfunction of DED rats and explaining the therapeutic effect of urine-derived stem cells (USCs). Methods After rat corpus cavernosal vascular endothelial cells (CCECs) were isolated and cultured in vitro, CCECs were treated with advanced glycation end products (AGEs) to mimic the diabetic situation. Autophagy flux, proliferation, and apoptosis of CCECs were determined by mRFP-GFP-LC3 adenovirus infection combined with fluorescence observation and western blot analysis. USCs were isolated from the urine of six healthy male donors, and coculture systems of USCs and CCECs were developed to assess the protective effect of USCs for CCECs in vitro. The contribution of autophagy to the cellular damage in CCECs was evaluated by the autophagic inhibitor, 3-methyladenine (3-MA). Then, DED rats were induced by streptozotocin (50 mg/kg) and screened by apomorphine test (100 μg/kg). In DED rats, USCs or PBS as vehicle was administrated by intracavernous injection (n = 15 per group), and another 15 normal rats served as normal controls. Four weeks after injection, erectile function was evaluated by measuring the intracavernosal pressure (ICP) and mean arterial pressure (MAP). Cavernosal endothelial function and autophagic activity were examined by western blot, immunofluorescence, and transmission electron microscopy. Results In vitro, AGE-treated CCECs displayed fewer LC3 puncta formation and expressed less LC3-II, Beclin1, and PCNA but expressed more p62 and cleaved-caspase3 than controls (p < 0.05). Coculture of USCs with CCECs demonstrated that USCs were able to protect CCECs from AGE-induced autophagic dysfunction and cellular damage, which could be abolished by 3-MA (p < 0.05). DED rats showed lower ratio of ICP/MAP, reduced expression of endothelial markers, and fewer autophagic vacuoles in the cavernosal endothelium when compared with normal rats (p < 0.05). Intracavernous injection of USCs improved erectile function and cavernosal endothelial function of DED rats (p < 0.05). Most importantly, our data showed that the repaired erectile function and cavernosal endothelial function were the result of restored autophagic activity of the cavernosal endothelium in DED rats (p < 0.05). Conclusions Impaired autophagy is involved in the cavernosal endothelial dysfunction and erectile dysfunction of DED rats. Intracavernous injection of USCs upregulates autophagic activity in the cavernosal endothelium, contributing to ameliorating cavernosal endothelial dysfunction and finally improving the erectile dysfunction induced by diabetes.
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Chen S, Zhu J, Wang M, Huang Y, Qiu Z, Li J, Chen X, Chen H, Xu M, Liu J, She M, Li H, Yang X, Wang Y, Cai X. Comparison of the therapeutic effects of adipose‑derived and bone marrow mesenchymal stem cells on erectile dysfunction in diabetic rats. Int J Mol Med 2019; 44:1006-1014. [PMID: 31257465 PMCID: PMC6658012 DOI: 10.3892/ijmm.2019.4254] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Accepted: 06/13/2019] [Indexed: 12/15/2022] Open
Abstract
The aim of the present study was to compare the effects of adipose‑derived mesenchymal stem cell (ADSC) and bone marrow mesenchymal stem cell (BMSC) transplantation into the corpora cavernosa of diabetic rats with erectile function. ADSCs and BMSCs were isolated and identified by flow cytometry. Rats with streptozocin‑induced diabetes were screened using apomorphine to obtain a rat model of diabetic erectile dysfunction, followed by transplantation of ADSCs and BMSCs into the corpora cavernosa. Two weeks later, the rats were again injected with apomorphine, the intracavernous pressure (ICP) and mean arterial pressure (MAP) of the penile tissue were measured, and the corpus cavernosum tissues were harvested. Angiogenic endothelial nitric oxide synthase (eNOS) expression was detected by western blotting and immunofluorescence analysis. The blood vessels in the corpus cavernosum were observed following hematoxylin and eosin (H&E) staining, and the expression of collagen was detected by Sirius Red staining. The cellular ultrastructure was examined by transmission electron microscopy. Intracavernous injection of ADSCs significantly increased ICP and ICP/MAP. Western blotting and immunofluorescence results revealed that ADSC treatment improved the expression of eNOS in the penile tissue of diabetic rats. The H&E staining results demonstrated that ADSC treatment promoted revascularization of the corpus cavernosum, and the results of Sirius Red staining revealed that ADSC treatment reduced penile collagen in diabetic rats. Transmission electron microscopy examination revealed that the ultrastructure of the tissues in the ADSC‑treated group was more complete compared with that in the untreated diabetic model group. In conclusion, ADSCs were found to be more effective compared with BMSCs in treating diabetes‑related erectile dysfunction.
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Affiliation(s)
- Sansan Chen
- Department of Urology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080
- Institute of Biotherapy, Southern Medical University, Guangzhou, Guangdong 510515
| | - Jianbin Zhu
- Technology Center, Guangdong Vitalife Bio-Tech Co., Ltd., Foshan, Guangdong 528200
| | - Mingzhu Wang
- Reproductive Center of Obstetrics and Gynecology, Southern Medical University, Guangzhou, Guangdong 510515
| | - Yanting Huang
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080
| | - Zhuolin Qiu
- Reproductive Center of Obstetrics and Gynecology, Southern Medical University, Guangzhou, Guangdong 510515
| | - Jingjing Li
- Technology Center, Guangdong Vitalife Bio-Tech Co., Ltd., Foshan, Guangdong 528200
| | - Xinglu Chen
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080
| | - Huiying Chen
- Institute of Biotherapy, Southern Medical University, Guangzhou, Guangdong 510515
| | - Mingyu Xu
- Institute of Biotherapy, Southern Medical University, Guangzhou, Guangdong 510515
| | - Jun Liu
- Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong 510091
| | - Miaoqin She
- Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510660
| | - Hongwei Li
- Institute of Biotherapy, Southern Medical University, Guangzhou, Guangdong 510515
| | - Xiaorong Yang
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080
- Correspondence to: Dr Xiangsheng Cai or Dr Xiaorong Yang, Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, 39 Nonglin Xia Road, Guangzhou, Guangdong 510080, P.R. China, E-mail: , E-mail:
| | - Yi Wang
- Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiangsheng Cai
- Institute of Biotherapy, Southern Medical University, Guangzhou, Guangdong 510515
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080
- Correspondence to: Dr Xiangsheng Cai or Dr Xiaorong Yang, Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, 39 Nonglin Xia Road, Guangzhou, Guangdong 510080, P.R. China, E-mail: , E-mail:
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Yang J, Yu Z, Zhang Y, Zang G, Zhuan L, Tang Z, Liu Y, Wang T, Wang S, Liu J. Preconditioning of adipose‐derived stem cells by phosphodiesterase‐5 inhibition enhances therapeutic efficacy against diabetes‐induced erectile dysfunction. Andrology 2019; 8:231-240. [DOI: 10.1111/andr.12661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 04/08/2019] [Accepted: 05/06/2019] [Indexed: 12/17/2022]
Affiliation(s)
- J. Yang
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - Z. Yu
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - Y. Zhang
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - G.‐H. Zang
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - L. Zhuan
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - Z. Tang
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - Y. Liu
- Department of Neurology, Tongji Medical College Huazhong University of Science and Technology Hubei China
| | - T. Wang
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - S.‐G. Wang
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
| | - J.‐H. Liu
- Department of Urology, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
- Institute of Urology of Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and Technology HubeiChina
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Ouyang B, Xie Y, Zhang C, Deng C, Lv L, Yao J, Zhang Y, Liu G, Deng J, Deng C. Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA. Sex Med 2019; 7:241-250. [PMID: 30910509 PMCID: PMC6522949 DOI: 10.1016/j.esxm.2019.02.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/18/2019] [Accepted: 02/11/2019] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Stem cell therapies represent a promising new frontier for the treatment of refractory diabetic erectile dysfunction (DED). The use of stem cell-derived extracellular vesicles (EVs) is a novel strategy for cell-free stem cell therapy. We have reported that urine-derived stem cells (USCs) can improve DED; however, the therapeutic effects of EVs secreted by USCs (USC-EVs) remain unknown. AIM To determine the therapeutic effects of USC-EVs on DED in a rat model. METHODS USC-EVs were isolated from conditioned medium by ultracentrifugation. DED was induced in male Sprague-Dawley rats via an intraperitoneal injection of streptozotocin. Sixteen DED rats were divided into phosphate-buffered saline (PBS) and USC-EV groups. Eight normal rats served as the normal control group. PBS or USC-EVs were transplanted into the corpora cavernosa in the corresponding groups. MAIN OUTCOME MEASURE Intracavernosal pressure (ICP), mean arterial pressure (MAP), expression of endothelial markers (CD31), endothelial nitric oxide synthase (eNOS), phospho-eNOS, and neural nitric oxide synthase (nNOS) were assessed in each group. Masson's trichrome staining was used to determine the collagen deposition and ratio of smooth muscle cells to collagen. The microRNA (miRNA) cargo of USC-EVs was characterized by high-throughput RNA sequencing. RESULTS Recovery of erectile function was observed in the USC-EV group, as represented by improved ICP and ICP/MAP ratio. CD31, eNOS, phospho-eNOS, and nNOS expression in the penis was significantly improved in the USC-EV group. In addition, the ratio of smooth muscle to collagen was significantly increased in the USC-EV group. RNA sequencing revealed that USC-EVs were enriched for distinct classes of miRNA (miR-21-5p, let-7 family, miR-10 family, miR-30 family, and miR-148a-3p) that promote angiogenesis. CONCLUSION USC-EV transplantation can ameliorate DED in rats. Its mechanism may involve the delivery of proangiogenic miRNA. Ouyang B, Xie Y, Zhang C, et al. Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA. Sex Med 2019;7:241-250.
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Affiliation(s)
- Bin Ouyang
- Department of Andrology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China; Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yun Xie
- Department of Andrology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chi Zhang
- Department of Andrology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cuncan Deng
- Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Linyan Lv
- Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiahui Yao
- Department of Andrology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuanyuan Zhang
- Department of Andrology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China; Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China; Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Guihua Liu
- Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Junhong Deng
- Department of Andrology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China; Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Chunhua Deng
- Department of Andrology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Gu X, Shi H, Matz E, Zhong L, Long T, Clouse C, Li W, Chen D, Chung H, Murphy S, Yoo J, Lin G, Lue T, Atala A, Jackson J, Zhang Y. Long‐term therapeutic effect of cell therapy on improvement in erectile function in a rat model with pelvic neurovascular injury. BJU Int 2019; 124:145-154. [DOI: 10.1111/bju.14631] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Xin Gu
- Department of Urology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai China
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Hua Shi
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Ethan Matz
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Liren Zhong
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Ting Long
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Cara Clouse
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Wei Li
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Dong Chen
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - HyunChul Chung
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Sean Murphy
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - James Yoo
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Guiting Lin
- Department of Urology University of California San Francisco San Francisco CA USA
| | - Tom Lue
- Department of Urology University of California San Francisco San Francisco CA USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - John Jackson
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston‐Salem NCUSA
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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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Gur S, Abdel-Mageed AB, Sikka SC, Hellstrom WJG. Advances in stem cell therapy for erectile dysfunction. Expert Opin Biol Ther 2018; 18:1137-1150. [PMID: 30301368 DOI: 10.1080/14712598.2018.1534955] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Stem cell (SC) application is a promising area of research in regenerative medicine, with the potential to treat, prevent, and cure disease. In recent years, the number of studies focusing on SCs for the treatment of erectile dysfunction (ED) and other sexual dysfunctions has increased significantly. AREAS COVERED This review includes critical ED targets and preclinical studies, including the use of SCs and animal models in diabetes, aging, cavernous nerve injury, and Peyronie's disease. A literature search was performed on PubMed for English articles. EXPERT OPINION Combination treatment offers better results than monotherapy to improve pathological changes in diabetic ED. Regenerative medicine is a promising approach for the maintenance of sexual health and erectile function later in life. Cavernous nerve regeneration and vascular recovery employing SC treatment may be focused on radical prostatectomy-induced ED. Notwithstanding, there are a number of hurdles to overcome before SC-based therapies for ED are considered in clinical settings. Paracrine action, not cellular differentiation, appears to be the principal mechanism of action underlying SC treatment of ED. Intracavernosal injection of a single SC type should be the choice protocol for future clinical trials.
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Affiliation(s)
- Serap Gur
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA.,b Department of Pharmacology, Faculty of Pharmacy , Ankara University , Ankara , Turkey
| | - Asim B Abdel-Mageed
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA
| | - Suresh C Sikka
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA
| | - Wayne J G Hellstrom
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA
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40
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Zhu LL, Zhang Z, Jiang HS, Chen H, Chen Y, Dai YT. Superparamagnetic iron oxide nanoparticle targeting of adipose tissue-derived stem cells in diabetes-associated erectile dysfunction. Asian J Androl 2018; 19:425-432. [PMID: 27157506 PMCID: PMC5507087 DOI: 10.4103/1008-682x.179532] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Erectile dysfunction (ED) is a major complication of diabetes, and many diabetic men with ED are refractory to common ED therapies. Adipose tissue-derived stem cells (ADSCs) have been shown to improve erectile function in diabetic animal models. However, inadequate cell homing to damaged sites has limited their efficacy. Therefore, we explored the effect of ADSCs labeled with superparamagnetic iron oxide nanoparticles (SPIONs) on improving the erectile function of streptozotocin-induced diabetic rats with an external magnetic field. We found that SPIONs effectively incorporated into ADSCs and did not exert any negative effects on stem cell properties. Magnetic targeting of ADSCs contributed to long-term cell retention in the corpus cavernosum and improved the erectile function of diabetic rats compared with ADSC injection alone. In addition, the paracrine effect of ADSCs appeared to play the major role in functional and structural recovery. Accordingly, magnetic field-guided ADSC therapy is an effective approach for diabetes-associated ED therapy.
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Affiliation(s)
- Lei-Lei Zhu
- Department of Andrology, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008, China
| | - Zheng Zhang
- Department of Andrology, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008, China
| | - He-Song Jiang
- Department of Andrology, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008, China
| | - Hai Chen
- Department of Andrology, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008, China
| | - Yun Chen
- Department of Andrology, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008, China
| | - Yu-Tian Dai
- Department of Andrology, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008, China
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Yang Q, Chen X, Zheng T, Han D, Zhang H, Shi Y, Bian J, Sun X, Xia K, Liang X, Liu G, Zhang Y, Deng C. Transplantation of Human Urine-Derived Stem Cells Transfected with Pigment Epithelium-Derived Factor to Protect Erectile Function in a Rat Model of Cavernous Nerve Injury. Cell Transplant 2018; 25:1987-2001. [PMID: 27075964 DOI: 10.3727/096368916x691448] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The aim of this study was to investigate whether intracavernous injection of urine-derived stem cells (USCs) or USCs genetically modified with pigment epithelium-derived factor (PEDF) could protect the erectile function and cavernous structure in a bilateral cavernous nerve injury-induced erectile dysfunction (CNIED) rat model. USCs were cultured from the urine of six healthy male donors. Seventy-five rats were randomly divided into five groups ( n = 15 per group): sham, bilateral cavernous nerve (CN) crush injury (BCNI), USC, USCGFP+, and USCGFP/PEDF+ groups. The sham group received only laparotomy without CN crush injury and intracavernous injection with phosphate-buffered saline (PBS). All of the other groups were subjected to BCNI and intracavernous injection with PBS, USCs, USCsGFP+, or USCsGFP/PEDF+, respectively. The total intracavernous pressure (ICP) and the ratio of ICP to mean arterial pressure (ICP/MAP) were recorded. The penile dorsal nerves, the endothelium, and the smooth muscle were assessed within the penile tissue. The USC and USCGFP/PEDF+ groups displayed more significantly enhanced ICP and ICP/MAP ratio ( p < 0.05) 28 days after cell transplantation. Immunohistochemistry (IHC) and Western blot analysis demonstrated that the protection of erectile function and the cavernous structure by USCsGFP/PEDF+ was associated with an increased number of nNOS-positive fibers within the penile dorsal nerves, improved expression of endothelial markers (CD31 and eNOS) and a smooth muscle marker (smoothelin), an enhanced smooth muscle to collagen ratio, decreased expression of transforming growth factor-β1 (TGF-β1), and decreased cell apoptosis in the cavernous tissue. The paracrine effect of USCs and USCsGFP/PEDF+ prevented the destruction of erectile function and the cavernous structure in the CNIED rat model by nerve protection, thereby improving endothelial cell function, increasing the smooth muscle content, and decreasing fibrosis and cell apoptosis in the cavernous tissue.
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Affiliation(s)
- Qiyun Yang
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Xin Chen
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Tao Zheng
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Dayu Han
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Heng Zhang
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Yanan Shi
- Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Jun Bian
- Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, P.R. China
| | - Xiangzhou Sun
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Kai Xia
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Xiaoyan Liang
- Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Guihua Liu
- Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Yuanyuan Zhang
- Wake Forest Institute of Regenerative Medicine, Wake Forest University, Winston Salem, NC, USA
| | - Chunhua Deng
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
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Zhang Y, Chen Z, Wang T, Yang J, Li R, Wang S, Liu J, Ye Z. Treatment of diabetes mellitus-induced erectile dysfunction using endothelial progenitor cells genetically modified with human telomerase reverse transcriptase. Oncotarget 2018; 7:39302-39315. [PMID: 27283992 PMCID: PMC5129934 DOI: 10.18632/oncotarget.9909] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 04/28/2016] [Indexed: 01/02/2023] Open
Abstract
The efficacy of treatments for diabetes mellitus-induced erectile dysfunction (DMED) is quite poor, and stem cell therapy is emerging as a useful method. In this study, we used endothelial progenitor cells (EPCs) overexpressing human telomerase reverse transcriptase (hTERT) for the treatment of DMED. Rat EPCs were transfected with hTERT (EPCs-hTERT). EPCs-hTERT secreted more growth factors and demonstrated enhanced proliferation and resistance to oxidative stress. Twenty-four male DMED rats were subjected to four treatments: DMED (DMED group), EPCs (EPCs group), EPCs transduced with control lentivirus (EPC-control group) and EPCs-hTERT (EPCs-hTERT group). A group of healthy rats were used as the normal control group. The erectile function in the EPCs-hTERT group was markedly increased compared with the EPCs and EPCs-control groups. The EPCs-hTERT group exhibited more growth factors, smooth muscle content and retained stem cells in penile tissues. The degree of apoptosis and collagen/smooth muscle ratio in penile tissues of the EPCs-hTERT group was considerably reduced. Endothelial nitric oxide synthase (eNOS) expression increased significantly in the EPCs-hTERT group. Taken together, these data showed that the enhanced paracrine effect, resistance to oxidative stress and proliferation of EPCs-hTERT may contribute to the improvements of erectile function in DMED rats.
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Affiliation(s)
- Yan Zhang
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi Chen
- Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Yang
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Li
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangqun Ye
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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El Osta R, Decot V, Bensoussan D, Stoltz JF, Eschwege P, Hubert J. [Treatment by stem cell therapy of erectile dysfunction of diabetic origin: State of the art]. Prog Urol 2017; 28:74-84. [PMID: 29170014 DOI: 10.1016/j.purol.2017.10.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 10/11/2017] [Accepted: 10/20/2017] [Indexed: 01/15/2023]
Abstract
PURPOSE Review of various publications on stem cell therapy to treat erectile dysfunction of diabetic origin. MATERIAL AND METHODS Bibliographic search in PUBMED performed using the keywords cell therapy strain/erectile dysfunction associated with diabetes. Among the 51 articles obtained from the PUBMED research, we selected 16 articles for their specificity of studying erectile dysfunction (DE) related to diabetes. RESULTS Different types of stem cells have been studied: adipose derived mesenchymal stem cells/bone marrow derived mesenchymal stem cells as well as progenitor endothelial cells. The experimental protocols are quite similar from one study to the next with nevertheless some specifications concerning the studied cells and the monitoring of the latter. Intracavernous pressure (ICP) measured after the injection of stem cells into the corpus cavernosum was always significantly higher than the control populations. The addition of certain growth factors to stem cells by gene transfection improve the efficacy of the cells. No ideal tracking markers of the cells have been identified. CONCLUSION The positive effect of the injection of stem cells on the ICP belongs to the cellular trans-differentiation effect but especially to the paracrine effects which have not yet been completely elucidated.
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Affiliation(s)
- R El Osta
- Service d'urologie, hôpitaux de Brabois, CHRU de Nancy, 54500 Vandœuvre-lès-Nancy, France; IADI-UL-Inserm (U947), faculté de médecine, 54500 Vandœuvre-lès-Nancy, France.
| | - V Decot
- CNRS UMR 7563, Bio pôle, faculté de médecine, 54500 Vandœuvre-lès-Nancy, France; CNRS FR3208, UTCT, CHRU de Nancy, 54500 Vandœuvre-lès-Nancy, France
| | - D Bensoussan
- CNRS UMR 7563, Bio pôle, faculté de médecine, 54500 Vandœuvre-lès-Nancy, France; CNRS FR3208, UTCT, CHRU de Nancy, 54500 Vandœuvre-lès-Nancy, France
| | - J F Stoltz
- CNRS UMR 7563, Bio pôle, faculté de médecine, 54500 Vandœuvre-lès-Nancy, France; CNRS FR3208, UTCT, CHRU de Nancy, 54500 Vandœuvre-lès-Nancy, France
| | - P Eschwege
- Service d'urologie, hôpitaux de Brabois, CHRU de Nancy, 54500 Vandœuvre-lès-Nancy, France; CNRS, UMR 7039 CRAN, université de Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - J Hubert
- Service d'urologie, hôpitaux de Brabois, CHRU de Nancy, 54500 Vandœuvre-lès-Nancy, France; IADI-UL-Inserm (U947), faculté de médecine, 54500 Vandœuvre-lès-Nancy, France
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Li J, Wu C, Fu F, You X, Gao L, Wazir R, Qin F, Han P, Yuan J. Isoflurane inhalation anesthesia should be a new requirement in intracavernosal pressure detection-the gold standard of erectile function assessment. Sci Rep 2017; 7:14949. [PMID: 29097758 PMCID: PMC5668264 DOI: 10.1038/s41598-017-15020-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 10/19/2017] [Indexed: 02/05/2023] Open
Abstract
Intracavernosal pressure (ICP) is gold standard for the detection of erectile function in animals, but no consensus has yet been achieved on what kind of anesthetic protocol should be applied. A total of 16 adult male Sprague-Dawley rats were randomized into two groups. In group A, chloral hydrate was injected intraperitoneally. Rats in group B were induced in 5% isoflurane for 3 min and then maintained in 1.0–1.5% isoflurane. Mean arterial pressure (MAP), respiratory rate (RR) and heart rate were monitored during all experiments. After ICP detection, tail vein and carotid artery blood were collected. The maximum ICP value, MAP and ICP/MAP ratio in group B was significantly higher than in that of group A. The RR in group A was lower than in that of group B, but the heart rate in group A was higher than in group B. There were no significant differences in both pO2 and pCO2 between groups. While the data showed that animals in group A were relatively hypoxemic. Isoflurane inhalation anesthesia in detection of erectile function could offer a relatively more stable physical state than in that under the effect of chloral hydrate intraperitoneal anesthesia. Isoflurane inhalation anesthesia is more suitable for ICP test.
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Affiliation(s)
- Jinhong Li
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, 610000, China.,Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Changjing Wu
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Fudong Fu
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Xuanhe You
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Liang Gao
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, 610000, China.,Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Romel Wazir
- Field Hospital, Zarghun Field, Mari Petroleum Company Limited, Daharki, District Ghotki, Sindh, Pakistan
| | - Feng Qin
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Ping Han
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiuhong Yuan
- Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, 610000, China. .,Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Wu XJ, Shen WH, He P, Zhou XZ, Zhi Y, Dai Q, Chen ZW, Zhou ZS. Telomerase reverse transcriptase genetically modified adipose tissue derived stem cells improves erectile dysfunction by inhibiting oxidative stress and enhancing proliferation in rat model. Biomed Pharmacother 2017; 92:595-605. [DOI: 10.1016/j.biopha.2017.04.088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 04/17/2017] [Accepted: 04/19/2017] [Indexed: 12/21/2022] Open
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Hou QL, Ge MY, Zhang CD, Tian DD, Wang LK, Tian HZ, Wang WH, Zhang WD. Adipose tissue-derived stem cell therapy for erectile dysfunction in rats: a systematic review and meta-analysis. Int Urol Nephrol 2017; 49:1127-1137. [PMID: 28417342 DOI: 10.1007/s11255-017-1590-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 04/09/2017] [Indexed: 01/10/2023]
Abstract
OBJECTIVE We aimed to systematically assess the effect of adipose tissue-derived stem cell (ADSC) therapy and its influential factors on the treatment of erectile dysfunction (ED) in rats. METHODS Two authors independently searched for published studies through PubMed and EMBASE from study inception until August 31, 2016. A meta-analysis was used to combine the effect estimate from the published studies. A subgroup analysis was performed to identify the effect of some influential factors. The pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model analysis. RESULTS Twenty studies with a total of 248 rats were included in this meta-analysis. The pooled analysis showed that ADSC therapy significantly increased the ratio of intracavernous pressure and mean arterial pressure (ICP/MAP; SMD 3.46, 95% CI 2.85-4.06; P < 0.001) compared to control therapy. The levels of neuronal nitric oxide synthase (nNOS; SMD 6.37, 95% CI 4.35-8.39; P < 0.001), the cavernous smooth muscle content (CSMC; SMD 3.65, 95% CI 2.65-4.65; P < 0.001), the ratio of cavernous smooth muscle and collagen (CSM/collagen; SMD 4.16, 95% CI 2.59-5.72; P < 0.001), and the cyclic guanosine monophosphate (cGMP; SMD 7.12, 95% CI 2.76-11.48; P = 0.001) were higher following ADSC therapy than following control therapy. Subgroup analysis showed that ADSCs modified by growth or neurotrophic factors significantly recovered erectile function (P < 0.001) compared with ADSC therapy. CONCLUSION The adequate data indicated that ADSC therapy recovered erectile function and regenerated cavernous structures in ED rats, and ADSCs modified by some growth and neurotrophic factors accelerated the recovery of erectile function and cavernous structures in ED rats.
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Affiliation(s)
- Quan-Liang Hou
- Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Meng-Ying Ge
- Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Cheng-da Zhang
- School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA
| | - Dan-Dan Tian
- Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Lian-Ke Wang
- Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Hui-Zi Tian
- Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Wen-Hua Wang
- Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Wei-Dong Zhang
- Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China.
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Soebadi MA, Milenkovic U, Weyne E, Castiglione F, Albersen M. Stem Cells in Male Sexual Dysfunction: Are We Getting Somewhere? Sex Med Rev 2017; 5:222-235. [PMID: 28041853 DOI: 10.1016/j.sxmr.2016.11.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/02/2016] [Accepted: 11/22/2016] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Stem cells for sexual disorders are steadily being introduced into clinical trials. Two conditions of importance are the main target for this line of treatment, especially when regarding the wide array of translational and basic science highlighting the potential advantages of regenerative therapy: erectile dysfunction (ED) and more recently Peyronie disease (PD). Cellular therapy offers a treatment modality that might reverse disease progression. It would be used in a curative setting, in contrast to other pharmaceutical agents that are currently available. AIM To review basic preclinical studies and recent clinical trials of stem cells on ED and PD. METHODS A search of the medical literature for the following terms was performed using PubMed: stem cells, cellular therapy, erectile dysfunction, Peyronie's disease, and clinical trial. MAIN OUTCOME MEASURES A non-systematic narrative review and critical reflection on preclinical and clinical studies administering stem cells for ED and PD in animal models and human subjects. RESULTS Numerous studies have confirmed the beneficial functional effects of stem cell injection in established animal models on ED and PD. Various stem cell types have been adopted, from embryonic to adult mesenchymal cell types. Each cell type offers distinctive advantages and disadvantages. Diverse administrations of stem cells were investigated, with insignificant variability in the ultimate results. Stem cells appear to have a pronounced paracrine effect, rather than the classic engraftment and differentiation hypothesis. Phase 1 clinical trials using stem cells have not reported any severe adverse events in animals. However, these results cannot be extrapolated to draw any conclusions about efficacy in human patients. CONCLUSION Stem cells have an established efficacy in preclinical studies and early clinical trials. Studies are currently being published demonstrating the safety of intrapenile injection of autologous bone marrow- and adipose tissue-derived stem cells. Soebadi MA, Milenkovic U, Weyne E, et al. Stem Cells in Male Sexual Dysfunction: Are We Getting Somewhere? Sex Med Rev 2017;5:222-235.
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Affiliation(s)
- Mohammad Ayodhia Soebadi
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Urology, Airlangga University School of Medicine, Dr Soetomo General Hospital, Surabaya, Indonesia
| | - Uros Milenkovic
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Emmanuel Weyne
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Fabio Castiglione
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Maarten Albersen
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
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Wang X, Liu C, Xu Y, Chen P, Shen Y, Xu Y, Zhao Y, Chen W, Zhang X, Ouyang Y, Wang Y, Xie C, Zhou M, Liu C. Combination of mesenchymal stem cell injection with icariin for the treatment of diabetes-associated erectile dysfunction. PLoS One 2017; 12:e0174145. [PMID: 28350842 PMCID: PMC5369760 DOI: 10.1371/journal.pone.0174145] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 02/16/2017] [Indexed: 12/18/2022] Open
Abstract
The present study was aimed to examine whether icariin, a traditional Chinese medicine, could improve therapeutic effects of adipose derived mesenchymal stem cells (ADSCs) for diabetes-associated erectile dysfunction (DMED). DMED were induced in rats by intraperitoneal injection of streptozotocin and confirmed by erectile function measurement. Then, rats of diabetic ED were randomly divided to receive the treatment of saline, ADSCs, icariin or ADSCs combined with icariin respectively. Compared with the treatment by ADSCs or icariin alone, intracavernosum injection of ADSCs combined with the following daily gastric gavage of icariin significantly augmented the value of ICP and ICP/MAP (p<0.01). Meanwhile, the survival of transplanted ADSCs was much improved due to the application of icariin. Similarly, immunofluorescent staining analysis demonstrated that the improved erectile tissue structure by combination of ADSCs and icariin was significantly associated with the increased expression of endothelial markers (vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Furthermore, the structure changes in corpus cavernosum were further confirmed by the Masson’s trichrome staining. To explore the possible mechanism underlying icariin-enhanced therapeutic efficacy of MSCs, we employed an in vitro testing system by introducing H2O2 to imitate oxidative stress condition considering the oxidative environment faced by engrafted ADSCs and anti-oxidative capacity of icariin.In vitro, we found that the addition of icariin considerably reduced the apoptosis of ADSCs, and attenuated the intracellular reactive oxygen species (ROS), the superoxidase dismutase (SOD) activity and the lactate dehydrogenase (LDH). Subsequently, we examined the expression of apoptosis-related proteins and explored the potential signaling pathway through which icariin promoted the survival of ADSCs against oxidative stress. It was demonstrated that icariin significantly inhibited the upregulation of apoptosis-related proteins under oxidative condition, including Bax and cleaved caspase-3, while promoted the expression of anti-apoptotic factor BCL2. These effects were accompanied with the activation of signal molecules, PI3K/Akt and STAT3. The further signal protein inhibition assays exhibited that the suppression of STAT3 abrogated the icariin-mediated anti-apoptotic effects observed above, while did not influence the expression of PI3K/Akt. However, PI3K inhibition could abrogate icariin–mediated STAT3 activation and achieved a similar effect as STAT3 inhibition. Our results suggested that icariin was an effective adjuvant for enhancing ADSC-based therapy of DMEM, which may be ascribed to their protection of ADSCs against oxidative stress via the regulation of PI3K/Akt-STAT3 signal pathway.
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Affiliation(s)
- Xiyou Wang
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Chuanhai Liu
- Department of Urology, The Second Artillery General Hospital of Chinese People’s Liberation Army, Xicheng District, Beijing, People's Republic of China
| | - Yong Xu
- Department of Urology, PLA General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Ping Chen
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Yue Shen
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Yansheng Xu
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Yubo Zhao
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Weihao Chen
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Xinyu Zhang
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Yun Ouyang
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Yi Wang
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Changliang Xie
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Maojun Zhou
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
| | - Cuilong Liu
- Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China
- * E-mail:
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Abstract
INTRODUCTION Like other fibrotic diseases, the cause of Peyronie's disease (PD) is still obscure. Since there is now increasing evidence for the role of Mesenchymal Stem Cells (MSCs) as potential treatment to fibrosis, it is crucial to determine their possible efficacy in the treatment of PD. Areas covered: In this review, the authors summarize the emerging data and published studies regarding the use of SCs for the treatment of PD. The authors provide particular focus on the three-first experimental studies for the use of SCs in rat models as well as the sole two studies undertaken in humans. Expert opinion: It seems evident in experimental settings that SCs in general (Adipose Derived SCs in particular) provide a feasible, safe and effective therapy for PD. The potential limits of the rat models used initially have been somewhat overcome with the inception of studies in men. However, further prospective studies are needed in humans to further elucidate the therapeutic potential of stem cell therapy in PD.
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Affiliation(s)
- Athanasios Dellis
- a University Department of Urology , Sismanoglio General Hospital , Athens , Greece
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Shan HT, Zhang HB, Chen WT, Chen FZ, Wang T, Luo JT, Yue M, Lin JH, Wei AY. Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats. Asian J Androl 2017; 19:26-33. [PMID: 27427555 PMCID: PMC5227668 DOI: 10.4103/1008-682x.184271] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Stem cell transplantation and low-energy shock-wave therapy (LESWT) have emerged as potential and effective treatment protocols for diabetic erectile dysfunction. During the tracking of transplanted stem cells in diabetic erectile dysfunction models, the number of visible stem cells was rather low and decreased quickly. LESWT could recruit endogenous stem cells to the cavernous body and improve the microenvironment in diabetic cavernous tissue. Thus, we deduced that LESWT might benefit transplanted stem cell survival and improve the effects of stem cell transplantation. In this research, 42 streptozotocin-induced diabetic rats were randomized into four groups: the diabetic group (n = 6), the LESWT group (n = 6), the bone marrow-derived mesenchymal stem cell (BMSC) transplantation group (n = 15), and the combination of LESWT and BMSC transplantation group (n = 15). One and three days after BMSC transplantation, three rats were randomly chosen to observe the survival numbers of BMSCs in the cavernous body. Four weeks after BMSC transplantation, the following parameters were assessed: the surviving number of transplanted BMSCs in the cavernous tissue, erectile function, real-time polymerase chain reaction, and penile immunohistochemical assessment. Our research found that LESWT favored the survival of transplanted BMSCs in the cavernous body, which might be related to increased stromal cell-derived factor-1 expression and the enhancement of angiogenesis in the diabetic cavernous tissue. The combination of LESWT and BMSC transplantation could improve the erectile function of diabetic erectile function rats more effectively than LESWT or BMSC transplantation performed alone.
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Affiliation(s)
- Hai-Tao Shan
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Urology, Shawan People's Hospital, Panyu District, Guangzhou, China
| | - Hai-Bo Zhang
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wen-Tao Chen
- Shenzhen Hyde Medical Equipment Co., Ltd., Shenzhen, China
| | - Feng-Zhi Chen
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tao Wang
- Department of Urology, Longjiang Hospital, Shunde District, Foshan, China
| | - Jin-Tai Luo
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Min Yue
- Laboratory Animals Center, Southern Medical University, Guangzhou, China
| | - Ji-Hong Lin
- Laboratory Animals Center, Southern Medical University, Guangzhou, China
| | - An-Yang Wei
- Department of Urology, Medical Center for Overseas Patients, Nanfang Hospital, Southern Medical University, Guangzhou, China
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