|
1
|
Zheng Z, Lin X, Zhao Z, Lin Q, Liu J, Chen M, Wu W, Wu Z, Liu N, Chen H. A vascular endothelial growth factor-loaded chitosan-hyaluronic acid hydrogel scaffold enhances the therapeutic effect of adipose-derived stem cells in the context of stroke. Neural Regen Res 2025; 20:3591-3605. [PMID: 39248177 PMCID: PMC11974663 DOI: 10.4103/nrr.nrr-d-24-00129] [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: 01/31/2024] [Revised: 05/13/2024] [Accepted: 07/05/2024] [Indexed: 09/10/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202512000-00028/figure1/v/2025-01-31T122243Z/r/image-tiff Adipose-derived stem cell, one type of mesenchymal stem cells, is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery. However, its application has been limited by the complexities of the ischemic microenvironment. Hydrogel scaffolds, which are composed of hyaluronic acid and chitosan, exhibit excellent biocompatibility and biodegradability, making them promising candidates as cell carriers. Vascular endothelial growth factor is a crucial regulatory factor for stem cells. Both hyaluronic acid and chitosan have the potential to make the microenvironment more hospitable to transplanted stem cells, thereby enhancing the therapeutic effect of mesenchymal stem cell transplantation in the context of stroke. Here, we found that vascular endothelial growth factor significantly improved the activity and paracrine function of adipose-derived stem cells. Subsequently, we developed a chitosan-hyaluronic acid hydrogel scaffold that incorporated vascular endothelial growth factor and first injected the scaffold into an animal model of cerebral ischemia-reperfusion injury. When loaded with adipose-derived stem cells, this vascular endothelial growth factor-loaded scaffold markedly reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation and substantially restored mitochondrial membrane potential and axon morphology. Further in vivo experiments revealed that this vascular endothelial growth factor-loaded hydrogel scaffold facilitated the transplantation of adipose-derived stem cells, leading to a reduction in infarct volume and neuronal apoptosis in a rat model of stroke induced by transient middle cerebral artery occlusion. It also helped maintain mitochondrial integrity and axonal morphology, greatly improving rat motor function and angiogenesis. Therefore, utilizing a hydrogel scaffold loaded with vascular endothelial growth factor as a stem cell delivery system can mitigate the adverse effects of ischemic microenvironment on transplanted stem cells and enhance the therapeutic effect of stem cells in the context of stroke.
Collapse
Affiliation(s)
- Zhijian Zheng
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xiaohui Lin
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Zijun Zhao
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Qiang Lin
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Ji Liu
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Manli Chen
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Wenwen Wu
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Zhiyun Wu
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Nan Liu
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Hongbin Chen
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
- Institute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| |
Collapse
|
|
2
|
Luo JQ, Wang L, Liao ZQ, Lu BX, Luo CY, He HY, Ou Yang ZH, Duan SB, He SH, Wei AY, Zhang HB. Adipose stem cells ameliorate erectile dysfunction in diabetes mellitus rats by attenuating ferroptosis through NRP1 with SLC7A11 interaction. Free Radic Biol Med 2025; 232:40-55. [PMID: 40020883 DOI: 10.1016/j.freeradbiomed.2025.02.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Adipose stem cells (ADSCs) have garneVred increasing attention for their potential to treat diabetes mellitus erectile dysfunction (DMED), but the underlying molecular mechanisms remain unclear. The aim of this study was to identify and investigate the key cytokines and mechanisms by which ADSCs improve erectile function in DMED rats. METHODS We performed in vivo and in vitro assays, including rat erectile function assessment, cell co-culture, cytokine microarray screening and co-immunoprecipitation to investigate the role of ADSCs in improving erectile function in DMED rats. RESULTS Our analyses confirmed the occurrence of ferroptosis in the corpus cavernosum of DMED rats, while ADSCs treatment significantly restored erectile function and improved relevant indicators of ferroptosis. In vitro assays further indicated that corpus cavernosum smooth muscle cells (CCSMCs) co-cultured with ADSCs exhibited enhanced resistance to ferroptosis, with notably lower levels of cytoplasmic and lipid reactive oxygen species compared to the ferroptosis inducer Erastin-treated group. Mechanistic studies revealed that Neuropilin 1 (NRP1) may be a key molecule in ADSCs to improve erectile function in DMED rats. Furthermore, NRP1 in CCSMCs can interact with solute carrier family 7 member 11 (SLC7A11) to enhance the function of the glutamate-cysteine countertransport (Xc-) system and ferroptosis resistance in CCSMCs. CONCLUSION In conclusion, our findings indicate that NRP1 is a key molecule for ADSCs treatment to alleviate ferroptosis and improve erectile function in DMED rats, providing a promising target for DMED treatment and prognosis.
Collapse
Affiliation(s)
- Jun-Qi Luo
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China
| | - Li Wang
- Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Zi-Qi Liao
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China
| | - Bing-Xin Lu
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China
| | - Cai-Yu Luo
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China
| | - Hai-Yang He
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China
| | - Zhi-Han Ou Yang
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China
| | - Song-Bo Duan
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China
| | - Shu-Hua He
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China.
| | - An-Yang Wei
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China; Department of Urology, Foresea Life Insurance Guangzhou General Hospital, Guangzhou, Guangdong, 511340, China.
| | - Hai-Bo Zhang
- Department of Urology, Nanfang Hospital, Southern Medical University, North of Guangzhou Avenue 1838#, Guangzhou, Guangdong, 510515, China.
| |
Collapse
|
|
3
|
Doghish AS, Elsakka EGE, Moustafa HAM, Ashraf A, Mageed SSA, Mohammed OA, Abdel-Reheim MA, Zaki MB, Elimam H, Rizk NI, Omran SA, Farag SA, Youssef DG, Abulsoud AI. Harnessing the power of miRNAs for precision diagnosis and treatment of male infertility. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3271-3296. [PMID: 39535597 DOI: 10.1007/s00210-024-03594-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Infertility is a multifactorial reproductive system disorder, and most infertility cases occur in men. Semen testing is now thought to be the most important diagnostic test for infertile men; nonetheless, because of its limitations, the cause of infertility remains unknown for 40% of infertile men. Semen assessment's shortcomings indicate the need for improved and innovative diagnostic techniques and biomarkers worldwide. Non-coding RNAs with a length of roughly 18-22 nucleotides are called microRNAs (miRNAs). Most of our protein-coding genes are post-transcriptionally regulated by them. These molecules are unusual in bodily fluids, and aberrant variations in their expression can point to specific conditions like infertility. As a result, fresh potential biomarkers for the diagnosis and prognosis of various forms of male infertility may be represented by miRNAs. This review examined the most recent research revealing the association between different miRNAs' functions in male infertility and their expression patterns. Also, it aims to figure out the most recent strategies that could be applied for using such miRNAs as possible therapeutic targets for infertility treatment.
Collapse
Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City , 11829, Cairo, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Hebatallah Ahmed Mohamed Moustafa
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Alaa Ashraf
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | | | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Menoufia, Egypt
| | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Menoufia, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Nasr City, 11786, Egypt, Cairo
| | - Sarah A Omran
- Pharmacognosy Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Shimaa A Farag
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Donia G Youssef
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, El-Salam City, Cairo, 11785, Egypt
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| |
Collapse
|
|
4
|
Kılıç E, Çolakerol A, Temiz MZ, Yentur S, Başağa Y, Gonen ZB, Tavukcu HH, Ozsoy S, Muslumanoglu AY, Dursun M, Kadıoğlu A, Kandirali IE. Intracavernosal mesenchymal stem cell therapy in ischaemic priapism: an experimental study. Int Urol Nephrol 2025; 57:723-734. [PMID: 39443434 DOI: 10.1007/s11255-024-04248-6] [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: 10/01/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
INTRODUCTION The most common form of priapism is ischaemic and its prevalence in men has increased in recent years as a result of intracavernosal drug use. Currently, there is no approved specific treatment for ischaemic priapism other than cavernosal aspiration, which can only provide detumescence. This study aims to evaluate the efficacy of intracavernosal mesenchymal stem cell (MSC) therapy in an ischaemic priapism model. MATERIAL AND METHODS Thirty male Wistar albino rats were divided into three groups: sham (n = 6), priapism (n = 12) and priapism + MSC treatment (n = 12). The experimental groups were also divided into 1 and 12 h subgroups of ischaemic priapism. The experimental model was created using a vacuum erection device and constrictive tape technique, and intracavernosal MSC were applied immediately after the tape was removed. After 4 weeks, intracavernosal pressures (ICPs) and systemic mean arterial pressure (MAP) were measured. Penectomy was then performed to assess histopathological and molecular changes in the rats' penile tissues. RESULTS In the ischaemic priapism model, MSC therapy showed significant improvements in peak and mean ICPs and mean ICP/MAP ratio. Histopathological analysis showed significant increases in smooth-muscle/collagen ratio and e-NOS and n-NOS expression. Although there was a decrease in fibrosis, it was not significant. At the molecular level, there were significant decreases in TGF-beta and VEGF mRNA expression, whilst NGF and BDNF mRNA-expression levels showed significant increases with MSC therapy. In terms of ICPs, the therapy showed more significant improvements in short-term priapism. However, when looking at histopathological and molecular parameters, the therapy had positive effects on a wider range of parameters in the long-term priapism. CONCLUSION MSC treatment improved cavernosal physiology and had positive effects at the histopathological and molecular level in the ischaemic priapism model.
Collapse
Affiliation(s)
- Enes Kılıç
- Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Aykut Çolakerol
- Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Mustafa Zafer Temiz
- Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Serhat Yentur
- Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Yaşar Başağa
- Department of Urology, Nisantasi University, Istanbul, Turkey
| | - Zeynep Burcin Gonen
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry and Genome- Stem Cell Center, Erciyes University, Kayseri, Turkey
| | | | - Sule Ozsoy
- Department of Pathology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | | | - Murat Dursun
- Department of Urology, Faculty of Medicine, Section of Andrology, Istanbul University, Millet Cad. Istanbul Tıp Fakültesi, Cerrahi Monoblok, Kat:1, 34104, Fatih, Istanbul, Turkey
| | - Ateş Kadıoğlu
- Department of Urology, Faculty of Medicine, Section of Andrology, Istanbul University, Millet Cad. Istanbul Tıp Fakültesi, Cerrahi Monoblok, Kat:1, 34104, Fatih, Istanbul, Turkey.
| | | |
Collapse
|
|
5
|
Patel AA, Shafie A, Mohamed AH, Ali SAJ, Tayeb FJ, Waggiallah HA, Ahmad I, Sheweita SA, Muzammil K, AlShahrani AM, Al Abdulmonem W. The promise of mesenchymal stromal/stem cells in erectile dysfunction treatment: a review of current insights and future directions. Stem Cell Res Ther 2025; 16:98. [PMID: 40012076 PMCID: PMC11866689 DOI: 10.1186/s13287-025-04221-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/11/2025] [Indexed: 02/28/2025] Open
Abstract
Erectile dysfunction is a common and multifactorial condition that significantly impacts men's quality of life. Traditional treatments, such as phosphodiesterase type 5 inhibitors (PDE5i), often fail to provide lasting benefits, particularly in patients with underlying health conditions. In recent years, regenerative medicine, particularly stem cell therapies, has emerged as a promising alternative for managing erectile dysfunction. This review explores the potential of mesenchymal stromal/stem cells (MSCs) and their paracrine effects, including extracellular vesicles (EVs), in the treatment of erectile dysfunction. MSCs have shown remarkable potential in promoting tissue repair, reducing inflammation, and regenerating smooth muscle cells, offering therapeutic benefits in models of erectile dysfunction. Clinical trials have demonstrated positive outcomes in improving erectile function and other clinical parameters. This review highlights the promise of MSC therapy for erectile dysfunction, discusses existing challenges, and emphasizes the need for continued research to refine these therapies and improve long-term patient outcomes.
Collapse
Affiliation(s)
- Ayyub Ali Patel
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia
| | - Alaa Shafie
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Asma'a H Mohamed
- Department of Optometry Techniques, Technical College Al-Mussaib, Al-Furat Al-Awsat Technical University, Najaf, Iraq.
| | | | - Faris J Tayeb
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Hisham Ali Waggiallah
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Alkarj, Saudi Arabia
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Salah Ahmed Sheweita
- Department of Clinical Biochemistry, Faculty of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, 21526, Egypt
| | - Khursheed Muzammil
- Department of Public Health, College of Applied Medical Sciences, Khamis Mushait, King Khalid University, 62561, Abha, Saudi Arabia
| | - Abdullah M AlShahrani
- Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushait, King Khalid University (KKU), 62561, Abha, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Kingdom of Saudi Arabia
| |
Collapse
|
|
6
|
Liu ZH, Xie QQ, Huang JL. Stromal vascular fraction: Mechanisms and application in reproductive disorders. World J Stem Cells 2025; 17:101097. [PMID: 39866896 PMCID: PMC11752457 DOI: 10.4252/wjsc.v17.i1.101097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 12/02/2024] [Accepted: 12/20/2024] [Indexed: 01/20/2025] Open
Abstract
Stromal vascular fraction (SVF) is a complex mixture derived from adipose tissue, consisting of a variety of cells. Due to its potential for tissue repair, immunomodulation, and support of angiogenesis, SVF represents a promising frontier in regenerative medicine and offers potential therapy for a range of disease conditions. In this article, we delve into the mechanisms through which SVF exerts its effects and explore its potential applications in treating both male and female reproductive disorders, including erectile dysfunction, testicular injury, stress urinary incontinence and intrauterine adhesion.
Collapse
Affiliation(s)
- Zhi-Han Liu
- Department of Clinical Medicine, School of Queen Mary, Nanchang University, Nanchang 330000, Jiangxi Province, China
| | - Qi-Qi Xie
- Center for Reproductive Medicine, Jiangxi Key Laboratory of Reproductive Health, Jiangxi Maternal and Child Health Hospital, Jiangxi Branch of National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang 330000, Jiangxi Province, China
| | - Jia-Lyu Huang
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, Jiangxi Branch of National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang 330008, Jiangxi Province, China.
| |
Collapse
|
|
7
|
Shen YJ, Huang YC, Cheng YC. Advancements in Antioxidant-Based Therapeutics for Spinal Cord Injury: A Critical Review of Strategies and Combination Approaches. Antioxidants (Basel) 2024; 14:17. [PMID: 39857350 PMCID: PMC11763222 DOI: 10.3390/antiox14010017] [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: 12/01/2024] [Revised: 12/21/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Spinal cord injury (SCI) initiates a cascade of secondary damage driven by oxidative stress, characterized by the excessive production of reactive oxygen species and other reactive molecules, which exacerbate cellular and tissue damage through the activation of deleterious signaling pathways. This review provides a comprehensive and critical evaluation of recent advancements in antioxidant-based therapeutic strategies for SCI, including natural compounds, RNA-based therapies, stem cell interventions, and biomaterial applications. It emphasizes the limitations of single-regimen approaches, particularly their limited efficacy and suboptimal delivery to injured spinal cord tissue, while highlighting the synergistic potential of combination therapies that integrate multiple modalities to address the multifaceted pathophysiology of SCI. By analyzing emerging trends and current limitations, this review identifies key challenges and proposes future directions, including the refinement of antioxidant delivery systems, the development of multi-targeted approaches, and strategies to overcome the structural complexities of the spinal cord. This work underscores the pressing need for innovative and integrative therapeutic approaches to advance the clinical translation of antioxidant-based interventions and improve outcomes for SCI patients.
Collapse
Affiliation(s)
- Yang-Jin Shen
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yin-Cheng Huang
- Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333423, Taiwan
- Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan 333423, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yi-Chuan Cheng
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333423, Taiwan
| |
Collapse
|
|
8
|
Meng Q, Chen Y, Cui L, Wei Y, Li T, Yuan P. Comprehensive analysis of biological landscape of oxidative stress-related genes in diabetic erectile dysfunction. Int J Impot Res 2024; 36:627-635. [PMID: 38145980 DOI: 10.1038/s41443-023-00814-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 11/27/2023] [Accepted: 12/12/2023] [Indexed: 12/27/2023]
Abstract
Oxidative stress plays a pivotal role in the pathogenesis of diabetic erectile dysfunction, while specific mechanisms have not been illuminated. The study aims to reveal the genetic expression patterns of oxidative stress in diabetic erectile dysfunction. Transcriptome data of diabetic erectile dysfunction and oxidative stress-related genes (OSRGs) in the Gene Expression Omnibus database were downloaded and analyzed based on differential expression. Functional enrichment analyses were conducted to clarify the biological functions. A protein interaction framework was established, and significant gene profiles were validated in the cavernous endothelial cells, clinical patients, and rat models. A miRNA-OSRGs network was predicted and validated. The results were analyzed using Student's t-test. The analysis screened 203 differentially expressed OSRGs (p < 0.05), which had a close association with oxidoreductase activities, glutathione metabolism, and autophagy. A four-gene signature comprised of EPS8L2 (p = 0.044), GSTA3 (p = 0.015), LOX (p < 0.001) and MGST1 (p = 0.002) was well validated and regarded as the hub OSRGs. Compared with the control group, notable increases and decreases were observed in the expressions of GSTA3 (3.683 ± 0.636 vs. 0.416 ± 0.507) and LOX (2.104 ± 1.895 vs. 18.804 ± 2.751) in the validated diabetic erectile dysfunction group. The hub OSRGs-related miRNAs participated in smooth muscle cell proliferation. Besides, miR-125a-3p (p = 0.034) and miR-138-2-3p (p = 0.012) were validated as promising oxidative stress-related miRNA biomarkers. Our findings revealed the genetic alternations of oxidative stress in diabetic erectile dysfunction. These results will be instructive to explore the molecular landscape and the potential treatment for diabetic erectile dysfunction.
Collapse
Affiliation(s)
- Qingjun Meng
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yinwei Chen
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Lingang Cui
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yinsheng Wei
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Teng Li
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Penghui Yuan
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| |
Collapse
|
|
9
|
Luo L, Wang Z, Tong X, Xiong T, Chen M, Liu X, Peng C, Sun X. LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells and ameliorates erectile dysfunction via the miR-206/CDC42/PAK1/paxillin signalling axis. Reprod Biol Endocrinol 2024; 22:74. [PMID: 38918809 PMCID: PMC11197369 DOI: 10.1186/s12958-024-01240-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 06/03/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND Erectile dysfunction (ED) is a common male sexual dysfunction, with an increasing incidence, and the current treatment is often ineffective. METHODS Vascular endothelial growth factor (VEGFA) was used to treat bone marrow-derived mesenchymal stem cells (BM-MSCs), and their cell migration rates were determined by Transwell assays. The expression of the von Willebrand Factor (vWF)VE-cadherin, and endothelial nitric oxide synthase(eNOS) endothelial markers was determined by qRT‒PCR and Western blot analyses. The MALAT1-induced differentiation of BM-MCs to ECs via the CDC42/PAK1/paxillin pathway was explored by transfecting VEGFA-induced BM-MSC with si-MALAT1 and overexpressing CDC42 and PAK1. The binding capacity between CDC42, PAK1, and paxillin in VEGFA-treated and non-VEGFA-treated BM-MSCs was examined by protein immunoprecipitation. MiR-206 was overexpressed in VEGFA-induced BM-MSC, and the binding sites of MALAT1, miR-206, and CDC42 were identified using a luciferase assay. Sixty male Sprague‒Dawley rats were divided into six groups (n = 10/group). DMED modelling was demonstrated by APO experiments and was assessed by measuring blood glucose levels. Erectile function was assessed by measuring the intracavernosa pressure (ICP) and mean arterial pressure (MAP). Penile erectile tissue was analysed by qRT‒PCR, Western blot analysis, and immunohistochemical staining. RESULTS MALAT1 under VEGFA treatment conditions regulates the differentiation of BM-MSCs into ECs by modulating the CDC42/PAK1/paxillin axis. In vitro experiments demonstrated that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs. CDC42 binds to PAK1, and PAK1 binds to paxillin. In addition, CDC42 in the VEGFA group had a greater ability to bind to PAK1, whereas PAK1 in the VEGFA group had a greater ability to bind to paxillin. Overexpression of miR-206 in VEGFA-induced BM-MSCs demonstrated that MALAT1 competes with the CDC42 3'-UTR for binding to miR-206, which in turn is involved in the differentiation of BM-MSCs to ECs. Compared to the DMED model group, the ICP/MAP ratio was significantly greater in the three BM-MSCs treatment groups. CONCLUSIONS MALAT1 facilitates BM-MSC differentiation into ECs by regulating the miR-206/CDC42/PAK1/paxillin axis to improve ED. The present findings revealed the vital role of MALAT1 in the repair of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSC-mediated repair of DMED.
Collapse
Affiliation(s)
- Longhua Luo
- Jiangxi Provincial Key Laboratory of Urinary System Diseases, Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 17, Yongwai Zheng Street, Nanchang, 330006, China
| | - Zixin Wang
- Jiangxi Provincial Key Laboratory of Urinary System Diseases, Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 17, Yongwai Zheng Street, Nanchang, 330006, China
| | - Xuxian Tong
- Nanchang University, No. 999 Xuefu Avenue, Honggutan District, Nanchang City, 330006, Jiangxi Province, China
| | - Tenxian Xiong
- Nanchang University, No. 999 Xuefu Avenue, Honggutan District, Nanchang City, 330006, Jiangxi Province, China
| | - Minggen Chen
- Nanchang University, No. 999 Xuefu Avenue, Honggutan District, Nanchang City, 330006, Jiangxi Province, China
| | - Xiang Liu
- Nanchang University, No. 999 Xuefu Avenue, Honggutan District, Nanchang City, 330006, Jiangxi Province, China
| | - Cong Peng
- Nanchang University, No. 999 Xuefu Avenue, Honggutan District, Nanchang City, 330006, Jiangxi Province, China
| | - Xiang Sun
- Jiangxi Provincial Key Laboratory of Urinary System Diseases, Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 17, Yongwai Zheng Street, Nanchang, 330006, China.
| |
Collapse
|
|
10
|
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.
Collapse
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.
| |
Collapse
|
|
11
|
Sun T, Liu Y, Yuan P, Jia Z, Yang J. Bibliometric and Visualization Analysis of Stem Cell Therapy for Erectile Dysfunction. Drug Des Devel Ther 2024; 18:731-746. [PMID: 38476204 PMCID: PMC10929656 DOI: 10.2147/dddt.s448483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
Purpose As a common male disease, erectile dysfunction (ED) seriously affects the physical and mental health of patients. In recent years, studies have continued to point out the great potential of stem cell therapy (SCT) in the treatment of ED. The purpose of this study is to comprehensively analyze the research of SCT for ED and understand the development trends and research frontiers in this field. Methods Publications regarding SCT and ED were retrieved and collected from the Web of Science Core Collection. CiteSpace and VOSviewer software were then utilized for bibliometric and visualization analysis. Results A total of 524 publications were eventually included in this study. The annual number of publications in this field was increasing year by year. China and the USA were the two most productive countries. Lin GT, Lue TF and Lin CS, and the University of California San Francisco where they worked were the most productive research group and institution, respectively. The journal with the largest number of publications was The Journal of Sexual Medicine, and the following were mostly professional journals of urology and andrology. Diabetes mellitus-induced ED and cavernous nerve injury-related ED were the two most commonly constructed models of ED in studies. Concerning the types of stem cells, mesenchymal stem cells derived from adipose and bone marrow were most frequently used. Moreover, future research would mainly focus on exosomes, tissue engineering technology, extracorporeal shockwave therapy, and clinical translation. Conclusion The research of SCT for ED will receive increasing global attention in the future. Our study provided bibliometric and visualization analysis of published literature, helping researchers understand the global landscape and frontiers in this field. More preclinical and clinical studies should be conducted to more deeply explore the underlying mechanisms of treatment and promote clinical translation.
Collapse
Affiliation(s)
- Taotao Sun
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China
| | - Yipiao Liu
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China
| | - Penghui Yuan
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China
| | - Zhankui Jia
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China
| | - Jinjian Yang
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China
| |
Collapse
|
|
12
|
Wang G, Li R, Feng C, Li K, Liu S, Fu Q. Galectin-3 is involved in inflammation and fibrosis in arteriogenic erectile dysfunction via the TLR4/MyD88/NF-κB pathway. Cell Death Discov 2024; 10:92. [PMID: 38378809 PMCID: PMC10879531 DOI: 10.1038/s41420-024-01859-x] [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: 08/10/2023] [Revised: 02/04/2024] [Accepted: 02/08/2024] [Indexed: 02/22/2024] Open
Abstract
Galectin-3 (Gal-3) is a multifunctional protein that has been linked to fibrosis and inflammation in the cardiovascular system. In this study, we examined the impact of Gal-3 on inflammation and fibrosis in patients with arteriogenic erectile dysfunction (A-ED) and the underlying mechanisms involved. To induce arterial injury, we utilized cuffs on the periaqueductal common iliac arteries of Sprague‒Dawley (SD) rats and administered a high-fat diet to co-induce local atherosclerosis. Our results showed that we successfully developed a novel A-ED model that was validated based on histological evidence. In vivo, the vascular lumen of rats subjected to a high-fat diet and cuff placement exhibited significant narrowing, accompanied by the upregulation of Gal-3, Toll-like receptor 4 (TLR4), and myeloid differentiation primary response protein 88 (MyD88) expression in the penile cavernosa. This led to the activation of nuclear factor kappa B 65 (NF-κB-p65), resulting in reduced intracavernosal pressure, endothelial nitric oxide synthase expression, and smooth muscle content, promoting inflammation and fibrosis. However, treatment with Gal-3 inhibitor-modified citrus pectin (MCP) significantly normalized those effects. In vitro, knocking down Gal-3 led to a significant reduction in TLR4, MyD88, and NF-κB-p65 expression in corpus cavernosum smooth muscle cells (CCSMCs), decreasing inflammation levels. In conclusion, inhibiting Gal-3 may improve A-ED by reducing inflammation, endothelial injury, and fibrosis in the penile corpus cavernosum through the TLR4/MyD88/NF-κB pathway. These findings highlight the potential therapeutic target of Gal-3 in A-ED.
Collapse
Affiliation(s)
- Guanbo Wang
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ruiyu Li
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Chen Feng
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Kefan Li
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Shuai Liu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China.
- Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Qiang Fu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China.
- Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| |
Collapse
|
|
13
|
Zheng H, Haroon K, Liu M, Hu X, Xu Q, Tang Y, Wang Y, Yang GY, Zhang Z. Monomeric CXCL12-Engineered Adipose-Derived Stem Cells Transplantation for the Treatment of Ischemic Stroke. Int J Mol Sci 2024; 25:792. [PMID: 38255866 PMCID: PMC10815250 DOI: 10.3390/ijms25020792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/06/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024] Open
Abstract
Adipose-derived stem cells (ASCs) possess therapeutic potential for ischemic brain injury, and the chemokine CXCL12 has been shown to enhance their functional properties. However, the cumulative effects of ASCs when combined with various structures of CXCL12 on ischemic stroke and its underlying molecular mechanisms remain unclear. In this study, we genetically engineered mouse adipose-derived ASCs with CXCL12 variants and transplanted them to the infarct region in a mice transient middle cerebral artery occlusion (tMCAO) model of stroke. We subsequently compared the post-ischemic stroke efficacy of ASC-mCXCL12 with ASC-dCXCL12, ASC-wtCXCL12, and unmodified ASCs. Neurobehavior recovery was assessed using modified neurological severity scores, the hanging wire test, and the elevated body swing test. Changes at the tissue level were evaluated through cresyl violet and immunofluorescent staining, while molecular level alterations were examined via Western blot and real-time PCR. The results of the modified neurological severity score and cresyl violet staining indicated that both ASC-mCXCL12 and ASC-dCXCL12 treatment enhanced neurobehavioral recovery and mitigated brain atrophy at the third and fifth weeks post-tMCAO. Additionally, we observed that ASC-mCXCL12 and ASC-dCXCL12 promoted angiogenesis and neurogenesis, accompanied by an increased expression of bFGF and VEGF in the peri-infarct area of the brain. Notably, in the third week after tMCAO, the ASC-mCXCL12 exhibited superior outcomes compared to ASC-dCXCL12. However, when treated with the CXCR4 antagonist AMD3100, the beneficial effects of ASC-mCXCL12 were reversed. The AMD3100-treated group demonstrated worsened neurological function, aggravated edema volume, and brain atrophy. This outcome is likely attributed to the interaction of monomeric CXCL12 with CXCR4, which regulates the recruitment of bFGF and VEGF. This study introduces an innovative approach to enhance the therapeutic potential of ASCs in treating ischemic stroke by genetically engineering them with the monomeric structure of CXCL12.
Collapse
Affiliation(s)
- Haoran Zheng
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| | - Khan Haroon
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| | - Mengdi Liu
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| | - Xiaowen Hu
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| | - Qun Xu
- Health Management Center, Department of Neurology, Renji Hospital of Medical School of Shanghai Jiao Tong University, Shanghai 200127, China;
| | - Yaohui Tang
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| | - Yongting Wang
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| | - Guo-Yuan Yang
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| | - Zhijun Zhang
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (H.Z.); (K.H.); (M.L.); (X.H.); (Y.T.); (Y.W.)
| |
Collapse
|
|
14
|
Yang RL, Chen SY, Fu SP, Zhao DZ, Wan WH, Yang K, Lei W, Yang Y, Zhang Q, Zhang T. Antioxidant mechanisms of mesenchymal stem cells and their therapeutic potential in vitiligo. Front Cell Dev Biol 2023; 11:1293101. [PMID: 38178870 PMCID: PMC10764575 DOI: 10.3389/fcell.2023.1293101] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 12/08/2023] [Indexed: 01/06/2024] Open
Abstract
Vitiligo is a skin pigmentation disorder caused by melanocyte damage or abnormal function. Reac-tive oxygen species Reactive oxygen species can cause oxidative stress damage to melanocytes, which in turn induces vitiligo. Traditional treatments such as phototherapy, drugs, and other methods of treatment are long and result in frequent recurrences. Currently, mesenchymal stem cells (MSCs) are widely used in the research of various disease treatments due to their excellent paracrine effects, making them a promising immunoregulatory and tissue repair strategy. Furthermore, an increasing body of evi-dence suggests that utilizing the paracrine functions of MSCs can downregulate oxidative stress in the testes, liver, kidneys, and other affected organs in animal models of certain diseases. Addition-ally, MSCs can help create a microenvironment that promotes tissue repair and regeneration in are-as with oxidative stress damage, improving the disordered state of the injured site. In this article, we review the pathogenesis of oxidative stress in vitiligo and promising strategies for its treatment.
Collapse
Affiliation(s)
- Rui-lin Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Si-yu Chen
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Sheng-ping Fu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - De-zhi Zhao
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wei-hong Wan
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Kang Yang
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wei Lei
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ying Yang
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qian Zhang
- Department of Human Anatomy, Zunyi Medical University, Zunyi, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| |
Collapse
|
|
15
|
Li K, Li R, Zhao Z, Feng C, Liu S, Fu Q. Therapeutic potential of mesenchymal stem cell-derived exosomal miR-296-5p and miR-337-3p in age-related erectile dysfunction via regulating PTEN/PI3K/AKT pathway. Biomed Pharmacother 2023; 167:115449. [PMID: 37688989 DOI: 10.1016/j.biopha.2023.115449] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are viewed as an increasingly promising treatment for age-related erectile dysfunction (AED). Owing to the limitations of injecting living cells, the injection of exosomes appears to be a more plausible option. However, whether MSC-derived exosomes (MSC-Exos) improve AED and their potential mechanism remains unknown. MSC-Exos were prepared and injected intracavernously into aged rats to determine their effects on AED. Masson's trichrome staining was used to ascertain the changes in the histological structure of the corpus cavernosum. Then miRNA sequencing of MSC-Exos and analysis of the critical exosomal miRNAs were performed, as well as their target pathway enrichment analysis. Real-time quantitative PCR (RT-qPCR) and Western blot assay were performed to reveal the functions of MSC-Exos in regulating the PTEN/PI3K/AKT signaling pathway. Moreover, the effects of MSC-Exos on the corpus cavernosum smooth muscle cells (CCSMCs) apoptosis are explored in vitro. The experimental data validate that intracavernous injection of MSC-Exos ameliorated erectile function in AED rats. Masson's trichrome staining shows MSC-Exos therapy restores the histological structure of the corpus cavernosum by improving the ratios of smooth muscle to collagen. The exosomal miR-296-5p and miR-337-3p target and inhibit PTEN, modulating the PI3K/AKT signaling pathway. Furthermore, exosomes inhibit the apoptosis of CCSMCs. Our findings suggest that MSC-Exos improve AED by delivering miR-296-5p and miR-337-3p to regulate the PTEN/PI3K/AKT signaling pathway. These results bode well for the therapeutic potential of MSC-Exos for AED treatment.
Collapse
Affiliation(s)
- Kefan Li
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Ruiyu Li
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Zongyong Zhao
- Department of Urology, Liaocheng Third People's Hospital, Liaocheng, Shandong, China
| | - Chen Feng
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Shuai Liu
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China.
| | - Qiang Fu
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, China; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China.
| |
Collapse
|
|
16
|
Al-Dhalimy AMB, Salim HM, Shather AH, Naser IH, Hizam MM, Alshujery MK. The pathological and therapeutically role of mesenchymal stem cell (MSC)-derived exosome in degenerative diseases; Particular focus on LncRNA and microRNA. Pathol Res Pract 2023; 250:154778. [PMID: 37683391 DOI: 10.1016/j.prp.2023.154778] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/17/2023] [Accepted: 08/20/2023] [Indexed: 09/10/2023]
Abstract
By releasing exosomes, which create the ideal milieu for the resolution of inflammation, mesenchymal stem cells (MSCs) enhance tissue healing and have strong immunomodulatory capabilities. MSCs-derived exosome also can affect tumor progress by a myriad of mechanisms. Exosomes function as a cell-cell communication tool to affect cellular activity in recipient cells and include an array of efficient bioactive chemicals. Understanding the fundamental biology of inflammation ablation, tissue homeostasis, and the creation of therapeutic strategies is particularly interested in the horizontal transfer of exosomal long non-coding RNAs (lncRNA) and microRNAs (miRNAs) to recipient cells, where they affect target gene expression. Herein, we propose an exosomal lncRNA and microRNA profile in neurological, renal, cardiac, lung, and liver diseases as well as skin wounds and arthritis.
Collapse
Affiliation(s)
| | - Haitham Mukhlif Salim
- Ministry of Health, Directorat of the Public Health, Health Promotion Departments, Baghdad, Iraq
| | - A H Shather
- Department of Computer Engineering Technology, Al Kitab University, Altun Kopru, Kirkuk 00964, Iraq
| | - Israa Habeeb Naser
- Medical Laboratories Techniques Department, AL-Mustaqbal University, 51001 Hillah, Babil, Iraq
| | - Manar Mohammed Hizam
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | | |
Collapse
|
|
17
|
Wang T, Li Y, Zhu Y, Liu Z, Huang L, Zhao H, Zhou Z, Wu Q. Anti-aging mechanism of different age donor-matched adipose-derived stem cells. Stem Cell Res Ther 2023; 14:192. [PMID: 37533129 PMCID: PMC10394785 DOI: 10.1186/s13287-023-03415-3] [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: 02/15/2023] [Accepted: 07/18/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Adipose-derived stem cells (ASCs) have anti-aging and anti-obesity effects in aged animals, but the underlying molecular mechanism remains unknown. METHODS In the present study, we evaluated the in vivo transplantation effects of different age donor-matched ASCs on natural aging and leptin knockout mice (ob-/ob- mice). The multi-omics expression profiles of young and aged mouse donor-derived ASCs were also analyzed. RESULTS The results revealed that ASCs from young donors induced weight and abdominal fat loss for older recipients but not for young or ob-/ob-mice. The young and aged mouse donor ASCs displayed significant phenotypic differences, contributing to the distinguished weight loss and anti-aging effects in aged mice. CONCLUSIONS Our data suggest an underlying molecular mechanism by which young-donor ASCs reduce immune cells and inflammation in aged mice via secreted immune factors. These findings point to a general anti-aging mechanism of stem cells, which may provide new insights into age-related disturbances of stem cell plasticity in healthy aging and age-related diseases.
Collapse
Affiliation(s)
- Tao Wang
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Research Center for Biomedical Sciences, School of Life Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Yingyu Li
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Research Center for Biomedical Sciences, School of Life Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Yu Zhu
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Research Center for Biomedical Sciences, School of Life Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Zebiao Liu
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Research Center for Biomedical Sciences, School of Life Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Li Huang
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Research Center for Biomedical Sciences, School of Life Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Hongxia Zhao
- Faculty of Biological and Environmental Sciences, University of Helsinki, 00014, Helsinki, Finland
| | - Zuping Zhou
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Research Center for Biomedical Sciences, School of Life Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Qiong Wu
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Research Center for Biomedical Sciences, School of Life Sciences, Guangxi Normal University, Guilin, 541004, China.
| |
Collapse
|
|
18
|
Chung DY, Ryu JK, Yin GN. Regenerative therapies as a potential treatment of erectile dysfunction. Investig Clin Urol 2023; 64:312-324. [PMID: 37417556 DOI: 10.4111/icu.20230104] [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: 03/20/2023] [Revised: 05/04/2023] [Accepted: 05/22/2023] [Indexed: 07/08/2023] Open
Abstract
Erectile dysfunction (ED) is the most common sexual dysfunction disease in adult males. ED can be caused by many factors, such as vascular disease, neuropathy, metabolic disturbances, psychosocial causes, and side effects of medications. Although current oral phosphodiesterase type 5 inhibitors can achieve a certain effect, they cause temporary dilatation of blood vessels with no curative treatment effects. Emerging targeted technologies, such as stem cell therapy, protein therapy, and low-intensity extracorporeal shock wave therapy (Li-ESWT), are being used to achieve more natural and long-lasting effects in treating ED. However, the development and application of these therapeutic methods are still in their infancy, and their pharmacological pathways and specific mechanisms have not been fully discovered. This article reviews the preclinical basic research progress of stem cells, proteins, and Li-ESWT therapy, as well as the current status of clinical application of Li-ESWT therapy.
Collapse
Affiliation(s)
- Doo Yong Chung
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
| | - Ji-Kan Ryu
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, Korea
| | - Guo Nan Yin
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea.
| |
Collapse
|
|
19
|
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.
Collapse
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.
| |
Collapse
|
|
20
|
Pérez-Aizpurua X, Garranzo-Ibarrola M, Simón-Rodríguez C, García-Cardoso JV, Chávez-Roa C, López-Martín L, Tufet i Jaumot JJ, Alonso-Román J, Maqueda-Arellano J, Gómez-Jordana B, Ruiz de Castroviejo-Blanco J, Osorio-Ospina F, González-Enguita C, García-Arranz M. Stem Cell Therapy for Erectile Dysfunction: A Step towards a Future Treatment. Life (Basel) 2023; 13:life13020502. [PMID: 36836859 PMCID: PMC9963846 DOI: 10.3390/life13020502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/17/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Background: The improvement of absent or partial response in the medical treatment of erectile dysfunction (ED) has led to the development of minimally invasive new treatment modalities in the field of regenerative medicine. Methods: A literature review on stem cell therapy for the treatment of ED was performed. We searched for the terms "erectile dysfunction" and "stem cell therapy" in PubMed and Clinicaltrials.gov. Literature searching was conducted in English and included articles from 2010 to 2022. Results: New treatment modalities for ED involving stem cell therapy are not only conceived with a curative intent but also aim to avoid unnecessary adverse effects. Several sources of stem cells have been described, each with unique characteristics and potential applications, and different delivery methods have been explored. A limited number of interventional studies over the past recent years have provided evidence of a safety profile in their use and promising results for the treatment of ED, although there are not enough studies to generate an appropriate protocol, dose or cell lineage, or to determine a mechanism of action. Conclusions: Stem cell therapy is a novel treatment for ED with potential future applications. However, most urological societies agree that further research is required to conclusively prove its potential benefit.
Collapse
Affiliation(s)
- Xabier Pérez-Aizpurua
- Urology Department, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain
- Correspondence:
| | | | | | | | - César Chávez-Roa
- Urology Department, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain
| | - Leticia López-Martín
- Urology Department, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain
| | | | - Josué Alonso-Román
- Urology Department, Hospital Universitario Virgen de la Macarena, 41009 Sevilla, Spain
| | | | - Blanca Gómez-Jordana
- Urology Department, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain
| | | | - Felipe Osorio-Ospina
- Urology Department, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain
| | | | - Mariano García-Arranz
- Instituto de Investigación Sanitaria (IIS-FJD), Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain
| |
Collapse
|
|
21
|
Oncologic Safety and Efficacy of Cell-Assisted Lipotransfer for Breast Reconstruction in a Murine Model of Residual Breast Cancer. Aesthetic Plast Surg 2023; 47:412-422. [PMID: 35918436 DOI: 10.1007/s00266-022-03021-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/08/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Cell-assisted lipotransfer (CAL) is a novel technique for fat grafting that combines the grafting of autologous fat and adipose-derived stromal cells (ASCs) to enhance fat graft retention; however, its oncologic safety is controversial. METHODS Herein, we investigated the oncologic safety of CAL for breast reconstruction using a murine model of residual breast cancer. Various concentrations of 4T1 cells (murine breast cancer cells) were injected into female mastectomized BALB/c mice to determine the appropriate concentration for injection. One week after injection, mice were divided into control (100 μL fat), low CAL (2.5 × 105 ASCs/100 μL fat), and high CAL (1.0 × 106 ASCs/100 μL fat) groups, and fat grafting was performed. The injection of 5.0 × 103 4T1 cells was appropriate to produce a murine model of residual breast cancer. RESULTS The weight of the fat tumor mass was significantly higher in the high CAL group than in the other groups (p < 0.05). However, the estimated tumor weight was not significantly different between the groups. Additionally, the fat graft survival rate was significantly higher in the high CAL group than in the control and low CAL groups (p < 0.05). No significant difference was noted in the percentage of Ki-67-positive cells, suggesting that tumor proliferation was not significantly different between the groups. CONCLUSION In summary, CAL significantly improved fat graft survival without affecting tumor size and proliferation in a murine model of residual breast cancer. These results highlight the oncologic safety of CAL for breast reconstruction. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Collapse
|
|
22
|
Sun T, Xu W, Tu B, Wang T, Liu J, Liu K, Luan Y. Engineered Adipose-Derived Stem Cells Overexpressing RXFP1 via CRISPR Activation Ameliorate Erectile Dysfunction in Diabetic Rats. Antioxidants (Basel) 2023; 12:antiox12010171. [PMID: 36671033 PMCID: PMC9854730 DOI: 10.3390/antiox12010171] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/05/2023] [Accepted: 01/09/2023] [Indexed: 01/13/2023] Open
Abstract
Due to the high incidence of diabetes mellitus (DM) and poor response to the first-line treatment of DM-induced erectile dysfunction (DMED), new therapeutic strategies for DMED are needed. Adipose-derived stem cell (ADSC) transplantation is considered a promising treatment modality for DMED but is limited by poor survival and efficacy after transplantation. In this study, we aimed to increase the therapeutic effect of DMED by overexpressing the relaxin family peptide receptor 1 (RXFP1) using a clustered regularly interspaced short palindromic repeats activation (CRISPRa) system in ADSCs. Two lentiviruses carrying the CRISPRa system transfected ADSCs to overexpress RXFP1 (RXFP1-ADSCs). The intracavernous injection of ADSCs was performed in DMED rats induced by the intraperitoneal injection of streptozotocin. Four weeks after transplantation, we measured erectile function and collected specimens of the corpus cavernosum for follow-up detection. The results showed that ADSCs improved erectile function in diabetic rats, and the RXFP1-ADSCs were more significant. We detected reduced levels of oxidative stress, apoptosis and fibrosis together with relative normalization of endothelial and smooth muscle cell function in the penis after ADSC transplantation. RXFP1-ADSCs had more potent efficacy in the above alterations compared to negative control ADSCs due to the high levels of survival and paracrine capacity in RXFP1-ADSCs. The results revealed that RXFP1-ADSC transplantation could partially preserve erectile function in DMED rats associated with the regulation of oxidative stress, apoptosis, fibrosis and endothelial and smooth muscle cell dysfunction. RXFP1 may be the new target for the genetic modification of ADSCs, which benefits the management of DMED.
Collapse
Affiliation(s)
- 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
| | - 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
| | - Bocheng Tu
- 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
| | - 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
| | - Kang 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: (K.L.); (Y.L.)
| | - Yang Luan
- 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: (K.L.); (Y.L.)
| |
Collapse
|
|
23
|
Liu M, Chen J, Cao N, Zhao W, Gao G, Wang Y, Fu Q. Therapies Based on Adipose-Derived Stem Cells for Lower Urinary Tract Dysfunction: A Narrative Review. Pharmaceutics 2022; 14:pharmaceutics14102229. [PMID: 36297664 PMCID: PMC9609842 DOI: 10.3390/pharmaceutics14102229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/05/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Lower urinary tract dysfunction often requires tissue repair or replacement to restore physiological functions. Current clinical treatments involving autologous tissues or synthetic materials inevitably bring in situ complications and immune rejection. Advances in therapies using stem cells offer new insights into treating lower urinary tract dysfunction. One of the most frequently used stem cell sources is adipose tissue because of its easy access, abundant source, low risk of severe complications, and lack of ethical issues. The regenerative capabilities of adipose-derived stem cells (ASCs) in vivo are primarily orchestrated by their paracrine activities, strong regenerative potential, multi-differentiation potential, and cell–matrix interactions. Moreover, biomaterial scaffolds conjugated with ASCs result in an extremely effective tissue engineering modality for replacing or repairing diseased or damaged tissues. Thus, ASC-based therapy holds promise as having a tremendous impact on reconstructive urology of the lower urinary tract.
Collapse
Affiliation(s)
- Meng Liu
- Department of Urology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai 200233, China
| | - Jiasheng Chen
- Department of Urology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai 200233, China
| | - Nailong Cao
- Department of Urology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai 200233, China
| | - Weixin Zhao
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27157, USA
| | - Guo Gao
- Key Laboratory for Thin Film and Micro Fabrication of the Ministry of Education, School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ying Wang
- Department of Urology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai 200233, China
- Correspondence: (Y.W.); (Q.F.)
| | - Qiang Fu
- Department of Urology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai 200233, China
- Correspondence: (Y.W.); (Q.F.)
| |
Collapse
|
|
24
|
Ti Y, Yang M, Chen X, Zhang M, Xia J, Lv X, Xiao D, Wang J, Lu M. Comparison of the therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells and adipose-derived stem cells on erectile dysfunction in a rat model of bilateral cavernous nerve injury. Front Bioeng Biotechnol 2022; 10:1019063. [PMID: 36277409 PMCID: PMC9585154 DOI: 10.3389/fbioe.2022.1019063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 09/20/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Cavernous nerve injury (CNI) is the leading cause of erectile dysfunction (ED) after radical prostatectomy and pelvic fracture. Transplantation of human adipose-derived stem cells (ASCs) has been widely used to restore erectile function in CNI-ED rats and patients. Umbilical cord blood-derived MSCs (CBMSCs) are similarly low immunogenic but much primitive compared to ASCs and more promising in large-scale commercial applications due to the extensive establishment of cord blood banks. However, whether CBMSCs and ASCs have differential therapeutic efficacy on CNI-ED and the underlying mechanisms are still not clear. Materials and methods: A bilateral cavernous nerve injury (BCNI) rat model was established by crushing the bilateral cavernous nerves. After crushing, ASCs and CBMSCs were intracavernously injected immediately. Erectile function, Masson staining, and immunofluorescence analyses of penile tissues were assessed at 4 and 12 weeks. PKH-26-labeled ASCs or CBMSCs were intracavernously injected to determine the presence and differentiation of ASCs or CBMSCs in the penis 3 days after injection. In vitro experiments including intracellular ROS detection, mitochondrial membrane potential assay, EdU cell proliferation staining, cell apoptosis assay, and protein chip assay were conducted to explore the underlying mechanism of CBMSC treatment compared with ASC treatment. Results: CBMSC injection significantly restored erectile function, rescued the loss of cavernous corporal smooth muscles, and increased the ratio of smooth muscle to collagen. PKH-26-labeled CBMSCs or ASCs did not colocalize with endothelial cells or smooth muscle cells in the corpus cavernosum. Moreover, the conditioned medium (CM) of CBMSCs could significantly inhibit the oxidative stress and elevate the mitochondria membrane potential and proliferation of Schwann cells. Better therapeutic effects were observed in the CBMSC group than the ASC group both in vivo and in vitro. In addition, the content of neurotrophic factors and matrix metalloproteinases in CBMSC-CM, especially NT4, VEGF, MMP1, and MMP3 was significantly higher than that of ASC-CM. Conclusion: Intracavernous injection of CBMSCs exhibited a better erectile function restoration than that of ASCs in CNI-ED rats owing to richer secretory factors, which can promote nerve regeneration and reduce extracellular matrix deposition. CBMSC transplantation would be a promising therapeutic strategy for CNI-ED regeneration in the future.
Collapse
Affiliation(s)
- Yunrong Ti
- Department of Urology and Andrology, Renji Hospital, Shanghai Institute of Andrology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Mengbo Yang
- Department of Urology and Andrology, Renji Hospital, Shanghai Institute of Andrology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xinda Chen
- Department of Urology and Andrology, Renji Hospital, Shanghai Institute of Andrology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ming Zhang
- Department of Urology and Andrology, Renji Hospital, Shanghai Institute of Andrology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jingjing Xia
- Greater Bay Area Institute of Precision Medicine, School of Life Sciences, Fudan University, Guangzhou, China
| | - Xiangguo Lv
- Department of Urology and Andrology, Renji Hospital, Shanghai Institute of Andrology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Dongdong Xiao
- Department of Urology and Andrology, Renji Hospital, Shanghai Institute of Andrology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Dongdong Xiao, ; Jiucun Wang, ; Mujun Lu,
| | - Jiucun Wang
- Greater Bay Area Institute of Precision Medicine, School of Life Sciences, Fudan University, Guangzhou, China
- Human Phenome Institute, Fudan University, Shanghai, China
- *Correspondence: Dongdong Xiao, ; Jiucun Wang, ; Mujun Lu,
| | - Mujun Lu
- Department of Urology and Andrology, Renji Hospital, Shanghai Institute of Andrology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Dongdong Xiao, ; Jiucun Wang, ; Mujun Lu,
| |
Collapse
|
|
25
|
Fang D, Tan XH, Song WP, Gu YY, Pan JC, Yang XQ, Song WD, Yuan YM, Peng J, Zhang ZC, Xin ZC, Li XS, Guan RL. Single-Cell RNA Sequencing of Human Corpus Cavernosum Reveals Cellular Heterogeneity Landscapes in Erectile Dysfunction. Front Endocrinol (Lausanne) 2022; 13:874915. [PMID: 35518933 PMCID: PMC9066803 DOI: 10.3389/fendo.2022.874915] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/16/2022] [Indexed: 11/26/2022] Open
Abstract
PURPOSE To assess the diverse cell populations of human corpus cavernosum in patients with severe erectile dysfunction (ED) at the single-cell level. METHODS Penile tissues collected from three patients were subjected to single-cell RNA sequencing using the BD Rhapsody™ platform. Common bioinformatics tools were used to analyze cellular heterogeneity and gene expression profiles from generated raw data, including the packages Seurat, Monocle, and CellPhoneDB. RESULTS Disease-related heterogeneity of cell types was determined in the cavernous tissue such as endothelial cells (ECs), smooth muscle cells, fibroblasts, and immune cells. Reclustering analysis of ECs identified an arteriole ECs subcluster and another one with gene signatures of fibroblasts. The proportion of fibroblasts was higher than the other cell populations and had the most significant cellular heterogeneity, in which a distinct subcluster co-expressed endothelial markers. The transition trajectory of differentiation from smooth muscle cells into fibroblasts was depicted using the pseudotime analysis, suggesting that the expansion of corpus cavernosum is possibly compromised as a result of fibrosis. Cell-cell communications among ECs, smooth muscle cells, fibroblasts, and macrophages were robust, which indicated that inflammation may also have a crucial role in the development of ED. CONCLUSIONS Our study has demonstrated a comprehensive single-cell atlas of cellular components in human corpus cavernosum of ED, providing in-depth insights into the pathogenesis. Future research is warranted to explore disease-specific alterations for individualized treatment of ED.
Collapse
Affiliation(s)
- Dong Fang
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Xiao-Hui Tan
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Wen-Peng Song
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Yang-Yang Gu
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
- Department of Radiation Medicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jian-Cheng Pan
- Male Reproductive and Sexual Medicine, Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Institute of Urology, Tianjin Medical University, Tianjin, China
| | - Xiao-Qing Yang
- Male Reproductive and Sexual Medicine, Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Institute of Urology, Tianjin Medical University, Tianjin, China
| | - Wei-Dong Song
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Yi-Ming Yuan
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Jing Peng
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Zhi-Chao Zhang
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Zhong-Cheng Xin
- Male Reproductive and Sexual Medicine, Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Institute of Urology, Tianjin Medical University, Tianjin, China
| | - Xue-Song Li
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Rui-Li Guan
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| |
Collapse
|
|
26
|
Adipose-Derived Stem Cells from Type 2 Diabetic Rats Retain Positive Effects in a Rat Model of Erectile Dysfunction. Int J Mol Sci 2022; 23:ijms23031692. [PMID: 35163613 PMCID: PMC8836282 DOI: 10.3390/ijms23031692] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/24/2022] [Accepted: 01/28/2022] [Indexed: 12/18/2022] Open
Abstract
Erectile dysfunction is a common complication associated with type 2 diabetes mellitus (T2DM) and after prostatectomy in relation to cancer. The regenerative effect of cultured adipose-derived stem cells (ASCs) for ED therapy has been documented in multiple preclinical trials as well as in recent Pase 1 trials in humans. However, some studies indicate that diabetes negatively affects the mesenchymal stem cell pool, implying that ASCs from T2DM patients could have impaired regenerative capacity. Here, we directly compared ASCs from age-matched diabetic Goto–Kakizaki (ASCGK) and non-diabetic wild type rats (ASCWT) with regard to their phenotypes, proteomes and ability to rescue ED in normal rats. Despite ASCGK exhibiting a slightly lower proliferation rate, ASCGK and ASCWT proteomes were more or less identical, and after injections to corpus cavernosum they were equally efficient in restoring erectile function in a rat ED model entailing bilateral nerve crush injury. Moreover, molecular analysis of the corpus cavernosum tissue revealed that both ASCGK and ASCWT treated rats had increased induction of genes involved in recovering endothelial function. Thus, our finding argues that T2DM does not appear to be a limiting factor for autologous adipose stem cell therapy when correcting for ED.
Collapse
|
|
27
|
Zhou J, Yin Y, Yang Y, Peng D, Wei J, Yin G, Tang Y. Knockdown of miR-423-5p simultaneously upgrades the eNOS and VEGFa pathways in ADSCs and improves erectile function in diabetic rats. J Cell Mol Med 2021; 25:9796-9804. [PMID: 34545676 PMCID: PMC8505849 DOI: 10.1111/jcmm.16927] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 08/24/2021] [Accepted: 09/01/2021] [Indexed: 12/11/2022] Open
Abstract
This study aimed to explore the possibility of miR‐423‐5p modified adipose‐derived stem cell (ADSCs) therapy on streptozotocin (STZ)‐induced diabetes mellitus erectile dysfunction (DMED) rats. MiR‐423‐5p was knocked down in ADSCs. ADSCs, NC‐miR‐ADSCs and miR‐ADSCs were co‐cultured with human umbilical vein endothelial cells (HUVECs). Normal and high glucose media were supplemented. The supernatant and HUVECs were collected for assessment of eNOS and VEGFa expression, cell proliferation, and apoptosis. HUVECs co‐cultured with ADSCs or miR‐ADSCs exhibited higher eNOS and VEGFa protein expression levels compared to DM groups. MiR‐ADSCs enhanced HUVEC proliferation compared to the ADSCs and NC‐miR‐ADSCs. Lower apoptotic rates were observed when HUVECs were co‐cultured with miR‐ADSCs, compared to ADSCs and NC‐miR‐ADSCs. Fifteen male Sprague‐Dawley (SD) rats aged 12 weeks were induced to develop diabetes mellitus by intraperitoneal injection with STZ, and five healthy SD rats were used as normal controls. Eight weeks after developing diabetes, the rats received ADSCs and miR‐ADSCs via injection into the corpora cavernosa, whereas normal controls and DM controls were injected with saline. Erectile function and histological assessment of penile tissues were performed 8 weeks after injection. The ICP/MAP indicated that erectile function was impaired in the DM rats compared with the normal group. Injection of ADSCs and miR‐ADSCs improved erectile function significantly and was associated with the overexpression of eNOS and VEGFa. MiR‐423‐5p knockdown in ADSCs ameliorated high glucose‐mediated damage to HUVECs and improved erectile function in DM rats by inducing eNOS and VEGFa overexpression, indicating that miR‐423‐5p may be a potential target in the treatment of DMED.
Collapse
Affiliation(s)
- Jun Zhou
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yinghao Yin
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yuan Yang
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Dongyi Peng
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jingchao Wei
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Guangming Yin
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yuxin Tang
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China.,Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
| |
Collapse
|
|
28
|
Wu Q, He S, Zhu Y, Pu S, Zhou Z. Antiobesity Effects of Adipose-Derived Stromal/Stem Cells in a Naturally Aged Mouse Model. Obesity (Silver Spring) 2021; 29:133-142. [PMID: 33185001 DOI: 10.1002/oby.23036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/14/2020] [Accepted: 08/22/2020] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Adipose-derived stromal/stem cells (ASCs) have multilineage differentiation potential and functional properties, as well as applications for cell-based therapies in tissue repair and regeneration. However, there is a lack of evidence regarding the efficacy of ASCs as an antiobesity agent in aged organisms. This study aimed to clarify the effectiveness of ASCs at treating obesity using a naturally aged mouse model. METHODS Old (22 months) C57BL/6J mice with transplanted young-mice (2 months) donor ASCs were measured for weight change, biochemistry, cytokines, hormone secretion, cell senescence, lipid metabolism, and functional changes of ASCs. RESULTS The results indicated that old mice treated with ASCs showed antiaging and antiobesity effects such as significant loss of body and organ weight, improved stem cell plasticity, increased antioxidant capacity (superoxide dismutase and catalase), improved liver and kidney function, improved lipid metabolism, and increased hormone secretion (sex hormone-binding globulin, thyrotropin, and leptin). Treatment with ASCs decreased cell senescence and suppressed secretion of inflammatory agents (interleukin-6 and tumor necrosis factor alpha). CONCLUSIONS Traditional drugs used in the treatment of obesity have limitations and are unsuitable for the elderly. Based on the results, the future use of ASCs as primary antiaging and antiobesity agents is suggested because of their positive effects on aged animals.
Collapse
Affiliation(s)
- Qiong Wu
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Shuangli He
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Yu Zhu
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Shiming Pu
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Zuping Zhou
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| |
Collapse
|
|
29
|
Kharazi U, Badalzadeh R. A review on the stem cell therapy and an introduction to exosomes as a new tool in reproductive medicine. Reprod Biol 2020; 20:447-459. [DOI: 10.1016/j.repbio.2020.07.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 05/18/2020] [Accepted: 07/03/2020] [Indexed: 12/12/2022]
|
|
30
|
Chen S, He Z, Xu J. Application of adipose-derived stem cells in photoaging: basic science and literature review. Stem Cell Res Ther 2020; 11:491. [PMID: 33225962 PMCID: PMC7682102 DOI: 10.1186/s13287-020-01994-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022] Open
Abstract
Photoaging is mainly induced by continuous exposure to sun light, causing multiple unwanted skin characters and accelerating skin aging. Adipose-derived stem cells(ADSCs) are promising in supporting skin repair because of their significant antioxidant capacity and strong proliferation, differentiation, and migration ability, as well as their enriched secretome containing various growth factors and cytokines. The identification of the mechanisms by which ADSCs perform these functions for photoaging has great potential to explore therapeutic applications and combat skin aging. We also review the basic mechanisms of UV-induced skin aging and recent improvement in pre-clinical applications of ADSCs associated with photoaging. Results showed that ADSCs are potential to address photoaging problem and might treat skin cancer. Compared with ADSCs alone, the secretome-based approaches and different preconditionings of ADSCs are more promising to overcome the current limitations and enhance the anti-photoaging capacity.
Collapse
Affiliation(s)
- Shidie Chen
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Zhigang He
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
| | - Jinghong Xu
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
| |
Collapse
|
|
31
|
Song J, Sun T, Tang Z, Ruan Y, Liu K, Rao K, Lan R, Wang S, Wang T, Liu J. Exosomes derived from smooth muscle cells ameliorate diabetes-induced erectile dysfunction by inhibiting fibrosis and modulating the NO/cGMP pathway. J Cell Mol Med 2020; 24:13289-13302. [PMID: 33009701 PMCID: PMC7701535 DOI: 10.1111/jcmm.15946] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/06/2020] [Accepted: 08/30/2020] [Indexed: 12/12/2022] Open
Abstract
Erectile dysfunction (ED) is a major health issue among men with diabetes, and ED induced by diabetes mellitus (DMED) is particularly difficult to treat. Therefore, novel therapeutic approaches for the treatment of DMED are urgently needed. Exosomes, nanosized particles involved in many physiological and pathological processes, may become a promising tool for DMED treatment. In this study, we investigated the therapeutic effect of exosomes derived from corpus cavernosum smooth muscle cells (CCSMC‐EXOs) on erectile function in a rat model of diabetes and compared their effect with that of exosomes derived from mesenchymal stem cells (MSC‐EXOs). We incubated labelled CCSMC‐EXOs and MSC‐EXOs with CCSMCs and then observed uptake of the exosomes at different time points using laser confocal microscopy. CCSMC‐EXOs were more easily taken up by CCSMCs. The peak concentration and retention time of labelled CCSMC‐EXOs and MSC‐EXOs in the corpus cavernosum of DMED rats after intracavernous injection were compared by in vivo imaging techniques. Intracavernous injection of CCSMC‐EXOs was associated with a relatively high peak concentration and long retention time. Our data showed that CCSMC‐EXOs could improve erectile function in DMED rats. Meanwhile, CCSMC‐EXOs could exert antifibrotic effects by increasing the smooth muscle content and reducing collagen deposition. CCSMC‐EXOs also increased the expression of eNOS and nNOS, followed by increased levels of NO and cGMP. These findings initially identify the possible role of CCSMC‐EXOs in ameliorating DMED through inhibiting corporal fibrosis and modulating the NO/cGMP signalling pathway, providing a theoretical basis for a breakthrough in the treatment of DMED.
Collapse
Affiliation(s)
- Jingyu Song
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Taotao Sun
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Zhe Tang
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Yajun Ruan
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Kang Liu
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Ke Rao
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Ruzhu Lan
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Shaogang Wang
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Tao Wang
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Jihong Liu
- Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| |
Collapse
|
|
32
|
Afferi L, Pannek J, Louis Burnett A, Razaname C, Tzanoulinou S, Bobela W, da Silva RAF, Sturny M, Stergiopulos N, Cornelius J, Moschini M, Iselin C, Salonia A, Mattei A, Mordasini L. Performance and safety of treatment options for erectile dysfunction in patients with spinal cord injury: A review of the literature. Andrology 2020; 8:1660-1673. [PMID: 32741129 DOI: 10.1111/andr.12878] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/15/2020] [Accepted: 07/24/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND For a large proportion of patients with spinal cord injury, sexuality and reproduction are important issues. However, sparse data exist regarding available treatment options for this patient population. OBJECTIVES We sought to review performance and safety rates of all currently available treatment options for erectile dysfunction in spinal cord injury men. MATERIALS AND METHODS A systematic literature review without time restrictions was performed using PubMed/EMBASE database for English-, Italian-, German-, and Spanish-language articles. Articles' selection was performed according to the PRISMA guidelines. Relevant papers on erectile dysfunction in spinal cord injury patients were included in the final analyses. RESULTS AND DISCUSSION Overall, 47 studies were eligible for inclusion in this review. Of these, most evidence dealt with phosphodiesterase 5-inhibitors and intracavernous drug injection. Both treatment options are associated with high levels of performance and with patients/partners' satisfaction; side effects are acceptable. Overall, penile prostheses and vacuum erection devices are in general less approved by spinal cord injury patients and are correlated with increased rates of complications in comparison with phosphodiesterase 5-inhibitors and intracavernous drug injection. Sacral neuromodulation, transcutaneous electrical nerve stimulation, and intraurethral suppositories have been poorly studied, but preliminary studies did not show convincing results. CONCLUSION The best treatment options for erectile dysfunction in spinal cord injury patients emerged to be phosphodiesterase 5-inhibitors and intracavernous drug injection. The choice of erectile dysfunction treatment should be based on several aspects, including residual erectile function, spinal cord injury location, and patients' comorbidities. Future studies assessing the applicability of less well-studied treatments, as well as evaluating innovative options, are needed in this specific population.
Collapse
Affiliation(s)
- Luca Afferi
- Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland
| | - Jürgen Pannek
- Neuro-Urology, Schweizer Paraplegiker Zentrum, Nottwil, Switzerland.,Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Arthur Louis Burnett
- Department of Urology, John Hopkins Hospital, Brady Urological Institute, Baltimore, MA, USA
| | | | | | | | | | - Mikael Sturny
- Comphya SA, EPFL Innovation Park, Lausanne, Switzerland
| | | | - Julian Cornelius
- Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland
| | - Marco Moschini
- Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland.,Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Christophe Iselin
- Division of Urology, Department of Surgery, Geneva University Hospital, Geneva, Switzerland
| | - Andrea Salonia
- Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Agostino Mattei
- Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland
| | - Livio Mordasini
- Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland
| |
Collapse
|
|
33
|
Yuan P, Ma D, Gao X, Wang J, Li R, Liu Z, Wang T, Wang S, Liu J, Liu X. Liraglutide Ameliorates Erectile Dysfunction via Regulating Oxidative Stress, the RhoA/ROCK Pathway and Autophagy in Diabetes Mellitus. Front Pharmacol 2020; 11:1257. [PMID: 32903510 PMCID: PMC7435068 DOI: 10.3389/fphar.2020.01257] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/30/2020] [Indexed: 12/16/2022] Open
Abstract
Background Erectile dysfunction (ED) occurs more frequently and causes a worse response to the first-line therapies in diabetics compared with nondiabetic men. Corpus cavernosum vascular dysfunction plays a pivotal role in the occurrence of diabetes mellitus ED (DMED). The aim of this study was to investigate the protective effects of glucagon-like peptide-1 (GLP-1) analog liraglutide on ED and explore the underlying mechanisms in vivo and in vitro. Methods Type 1 diabetes was induced in rats by streptozotocin, and the apomorphine test was for screening the DMED model in diabetic rats. Then they were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Erectile function was assessed by cavernous nerve electrostimulation. The corpus cavernosum was used for further study. In vitro, effects of liraglutide were evaluated by primary corpus cavernosum smooth muscle cells (CCSMCs) exposed to low or high glucose (HG)-containing medium with or without liraglutide and GLP-1 receptor (GLP-1R) inhibitor. Western blotting, fluorescent probe, immunohistochemistry, and relevant assay kits were performed to measure the levels of target proteins. Results Administration of liraglutide did not significantly affect plasma glucose and body weights in diabetic rats, but improved erectile function, reduced levels of NADPH oxidases and ROS production, downregulated expression of Ras homolog gene family (RhoA) and Rho-associated protein kinase (ROCK) 2 in the DMED group dramatically. The liraglutide treatment promoted autophagy further and restored expression of GLP-1R in the DMED group. Besides, cultured CCSMCs with liraglutide exhibited a lower level of oxidative stress accompanied by inhibition of the RhoA/ROCK pathway and a higher level of autophagy compared with HG treatment. These beneficial effects of liraglutide effectively reversed by GLP-1R inhibitor. Conclusion Liraglutide exerts protective effects on ED associated with the regulation of smooth muscle dysfunction, oxidative stress and autophagy, independently of a glucose- lowering effect. It provides new insight into the extrapancreatic actions of liraglutide and preclinical evidence for a potential treatment for DMED.
Collapse
Affiliation(s)
- Penghui Yuan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Delin Ma
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xintao Gao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaxing Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuo Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
34
|
Gao T, Tian C, Ma Z, Chu Z, Wang Z, Zhang P. Stem Cell Seeded and Silver Nanoparticles Loaded Bilayer PLGA/PVA Dressings for Wound Healing. Macromol Biosci 2020; 20:e2000141. [PMID: 32734706 DOI: 10.1002/mabi.202000141] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/23/2020] [Indexed: 12/12/2022]
Abstract
Antibacterial activity and promoting wound healing are two important characteristics of ideal dressings. The previous work has successfully prepared a stem cell seeded polyvinyl alcohol (PVA) hydrogel dressing, which could promote wound healing by active factors secreted from the dressing. However, a lack of antibacterial activity might limit its better application. In this study, a photo-active gelatin (Az-Gel) modified stem cell seeded bilayer PVA hydrogel dressings with silver nanoparticles loaded poly(lactic-co-glycolic acid) (PLGA) electrospinning films (Ag-PLGA) in it is prepared. The physical properties of the dressings show the dressings are mechanically enhanced by the addition of Ag-PLGA film. The addition of Ag-PLGA film does not alter the moisture content of PVA, but extends the moisture of the dressing. Obviously, antibacterial activity is observed and Ag-PLGA/PVA scaffold is biocompatible and low toxic to murine dermal fibroblasts (NIH-3T3). When seeded with Adipose-derived stem cells (ADSCs), bioactive factors secreted by ADSCs could penetrate the dressing and promote cell growth and wound healing. It is speculated that the stem cells seeded bilayer dressing would be of great potential for skin tissue engineering, because of its antibacterial activity and safe application of stem cells.
Collapse
Affiliation(s)
- Tianlin Gao
- The College of Medical, Qingdao University, Qingdao, 266021, China.,Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Chunyan Tian
- The College of Medical, Qingdao University, Qingdao, 266021, China
| | - Zepeng Ma
- The College of Medical, Qingdao University, Qingdao, 266021, China
| | - Zunyan Chu
- The College of Medical, Qingdao University, Qingdao, 266021, China
| | - Zongliang Wang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Peibiao Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| |
Collapse
|
|
35
|
Xu Y, Deng M, Cai Y, Zheng H, Wang X, Yu Z, Zhang W, Li W. Cell-Free Fat Extract Increases Dermal Thickness by Enhancing Angiogenesis and Extracellular Matrix Production in Nude Mice. Aesthet Surg J 2020; 40:904-913. [PMID: 31679030 DOI: 10.1093/asj/sjz306] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Although adipose-derived stem cells (ADSCs) and nanofat exert antiaging effects on skin, they contain cellular components that have certain limitations in clinical practice. Cell-free fat extract (Ceffe) is a fraction purified from nanofat through removal of cellular components and lipid remnants that contains various growth factors. OBJECTIVES The purpose of this study was to evaluate the effects of Ceffe on cultured human dermal fibroblasts in vitro and on the dermis of nude mice in vivo. METHODS In the in vitro study, human dermal fibroblasts were cultured with Ceffe for 72 hours, followed by flow cytometry measurement of cell proliferation and cell cycle. In the in vivo study, different concentrations of Ceffe were injected into the dorsal skin of nude mice for 4 weeks. The thickness of the dermis; proliferation of cells; density of the capillary; and expressions of type I and III collagen (Col-1 and Col-3), matrix metalloproteinase-1, matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-3 were measured through histologic and Western blot analyses. RESULTS Ceffe significantly increased cell proliferation in cultured dermal fibroblasts. In the mouse skin, Ceffe significantly increased the thickness of the dermis, number of proliferating cells, density of the capillary, and expressions of Col-1 and Col-3. CONCLUSIONS Ceffe increased the dermal thickness of nude mice, possibly by enhancing angiogenesis and extracellular matrix production, and can therefore be used for skin rejuvenation.
Collapse
Affiliation(s)
- Yuda Xu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mingwu Deng
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yizuo Cai
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hongjie Zheng
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangsheng Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ziyou Yu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wenjie Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Li
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
36
|
Stavely R, Nurgali K. The emerging antioxidant paradigm of mesenchymal stem cell therapy. Stem Cells Transl Med 2020; 9:985-1006. [PMID: 32497410 PMCID: PMC7445024 DOI: 10.1002/sctm.19-0446] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/05/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (multipotent stromal cells; MSCs) have been under investigation for the treatment of diverse diseases, with many promising outcomes achieved in animal models and clinical trials. The biological activity of MSC therapies has not been fully resolved which is critical to rationalizing their use and developing strategies to enhance treatment efficacy. Different paradigms have been constructed to explain their mechanism of action, including tissue regeneration, trophic/anti-inflammatory secretion, and immunomodulation. MSCs rarely engraft and differentiate into other cell types after in vivo administration. Furthermore, it is equivocal whether MSCs function via the secretion of many peptide/protein ligands as their therapeutic properties are observed across xenogeneic barriers, which is suggestive of mechanisms involving mediators conserved between species. Oxidative stress is concomitant with cellular injury, inflammation, and dysregulated metabolism which are involved in many pathologies. Growing evidence supports that MSCs exert antioxidant properties in a variety of animal models of disease, which may explain their cytoprotective and anti-inflammatory properties. In this review, evidence of the antioxidant effects of MSCs in in vivo and in vitro models is explored and potential mechanisms of these effects are discussed. These include direct scavenging of free radicals, promoting endogenous antioxidant defenses, immunomodulation via reactive oxygen species suppression, altering mitochondrial bioenergetics, and donating functional mitochondria to damaged cells. Modulation of the redox environment and oxidative stress by MSCs can mediate their anti-inflammatory and cytoprotective properties and may offer an explanation to the diversity in disease models treatable by MSCs and how these mechanisms may be conserved between species.
Collapse
Affiliation(s)
- Rhian Stavely
- Institute for Health and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia.,Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia.,Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, Victoria, Australia
| |
Collapse
|
|
37
|
Wang J, Mi Y, Wu S, You X, Huang Y, Zhu J, Zhu L. Exosomes from adipose-derived stem cells protect against high glucose-induced erectile dysfunction by delivery of corin in a streptozotocin-induced diabetic rat model. Regen Ther 2020; 14:227-233. [PMID: 32435675 PMCID: PMC7229419 DOI: 10.1016/j.reth.2020.03.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022] Open
Abstract
Introduction Increasing study have found that stem cell transplantation have a therapeutical effect to diabetes mellitus (DM)-induced erectile dysfunction (ED). So, the aim of this study was to evaluate the beneficial effect of corin from adipose-derived stem cells (ADSCs) on DM-induced ED. Methods Exosomes were isolated from ADSCs (ADSC-EXOs) or from ADSCs in which corin gene expression was silenced by siRNA (siCorin). For in vivo studies, rats with streptozotocin-induced DM were intravenously injected with ADSC-EXOs or siCorin-ADSC-EXOs. Two weeks later, intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured to assess erectile function, and penile tissues were harvested for further evaluation of levels of inflammatory factors and expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and neuronal nitric oxide synthase (nNOS). We also evaluated the recovery of neurovascular function in penile tissues by immunofluorescence analysis. Results The results showed that ADSC-EXOs restored erectile function in diabetic rats, as determined by the ICP/MAP ratio. Exosomes from ADSCs also promoted neurovascular function and suppressed expression of inflammatory factors. In contrast, the decreased content of corin in exosomes after silencing corin in ADSCs reduced the therapeutic effect of exosomes on ED. Conclusion These findings demonstrated the therapeutic mechanism underlying the use of ADSC-EXOs for treating ED and the beneficial effect of corin.
Collapse
Affiliation(s)
- Jian Wang
- Department of Urology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214041, China
| | - Yuanyuan Mi
- Department of Urology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214041, China
| | - Sheng Wu
- Department of Urology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214041, China
| | - Xiaoming You
- Department of Urology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214041, China
| | - Yi Huang
- Department of Urology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214041, China
| | - Jin Zhu
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Lijie Zhu
- Department of Urology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214041, China
| |
Collapse
|
|
38
|
Jeon SH, Bae WJ, Zhu GQ, Tian W, Kwon EB, Kim GE, Hwang SY, Lee KW, Cho HJ, Ha US, Hong SH, Lee JY, Kim SW. Combined treatment with extracorporeal shockwaves therapy and an herbal formulation for activation of penile progenitor cells and antioxidant activity in diabetic erectile dysfunction. Transl Androl Urol 2020; 9:416-427. [PMID: 32420147 PMCID: PMC7214964 DOI: 10.21037/tau.2020.01.23] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background A Korean herbal formulation named KH-204 was reported to have an antioxidant effect in our previous study. We hypothesized that Low-intensity extracorporeal shockwave therapy (Li-ESWT) combined with KH-204 would accelerate the treatment of erectile dysfunction (ED) by enhancing antioxidant. We investigated the synergistic effect of Li-ESWT and KH-204 for ED and explored the mechanism. Methods Human umbilical vein endothelial cells (HUVEC) were treated with KH-204 and LI-ESWT in vitro. Fifty 5-week-old male Sprague Dawley rats received an intraperitoneal injection of 5-ethynyl-20-deoxyuridine (EdU) which can label live cells, and were randomly divided into five groups: (I) normal; (II) diabetes mellitus-associated erectile dysfunction (DMED); (III) DMED + KH-204; (IV) DMED + Li-ESWT; and (V) DMED + KH-204/Li-ESWT. Li-ESWT treatment was repeated three times a week every other day for four weeks in group 4 and 5. Meanwhile, rats in group 3 and 5 were orally fed 400 mg/kg of KH-204 daily for 1 month. Following a 1-week washout period, penile tissues were evaluated by immunostaining and Western blotting. Results KH-204 combined with Li-ESWT improved intracavernosal pressure (ICP) in DMED rats. Li-ESWT/KH-204 stimulated HUVEC tube formation and promoted proliferation. Li-ESWT drove progenitor cells to migrate to penile tissue and KH-204 protected penile progenitor cells in the corpus cavernosum. Oxidative stress was relieved by KH-204/Li-ESWT. Treatment with KH-204/Li-ESWT protected penile progenitor cells, which were recruited to the corpus cavernosum by Li-ESWT, from apoptosis via its antioxidant activity. KH-204/Li-ESWT protected penile tissue from oxidative stress by improving the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), increasing superoxide dismutase (SOD), decreasing 8-hydroxy-20-deoxyguanosine (8-OHdG), and reducing apoptosis. KH-204/Li-ESWT promoted stromal derived factor-1 (SDF-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1) in DMED rats. Conclusions KH-204 protected penile progenitor cells, which were recruited to the corpus cavernosum by Li-ESWT, from apoptosis via its antioxidant activity. The combination of Li-ESWT and KH-204 as a synergy therapy could be a potential and effective treatment for DMED.
Collapse
Affiliation(s)
- Seung Hwan Jeon
- 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
| | - 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
| | - Wenjie Tian
- 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
| | - Eun Bi Kwon
- 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
| | - Ga Eun 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
| | | | - Kyu Won Lee
- 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
| | - Hyuk Jin Cho
- Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - U-Syn Ha
- Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung-Hoo Hong
- Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Youl Lee
- Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - 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
| |
Collapse
|
|
39
|
Lin Y, Li X, Fan C, Yang F, Hao D, Ge W, Gao Y. Cardioprotective effects of rat adipose‑derived stem cells differ under normoxic/physioxic conditions and are associated with paracrine factor secretion. Int J Mol Med 2020; 45:1591-1600. [PMID: 32323745 DOI: 10.3892/ijmm.2020.4524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/13/2020] [Indexed: 11/06/2022] Open
Abstract
Adipose tissue‑derived stem cells (ASCs) are beneficial for myocardial regeneration. The physiological oxygen content of human organs is estimated to range between 1 and 11%. However, in the majority of previous in vitro studies with cultured ASCs, the O2 concentration was artificially set to 21%. The present study aimed to compare the protective effects of rat ASCs on neonatal rat ventricular myocytes (NRVMs) under normoxic (21% O2) and physioxic (5% O2) conditions. Rat NRVMs cultured under normoxia or physioxia were treated with H2O2 or left untreated, and further co‑cultured with ASCs in 21% or 5% O2. The apoptosis of NRVMs was evaluated by Annexin V staining and quantitating the protein levels of Bcl‑2 and Bax by western blotting. The oxidative stress of NRVMs was determined by a glutathione/oxidized glutathione assay kit. The concentrations of secreted vascular endothelium growth factor (VEGF), insulin like growth factor‑1 (IGF‑1) and basic fibroblast growth factor (bFGF) in the culture medium were quantified by enzyme‑linked immunosorbent assay. Under both normoxia and physioxia, co‑culture with ASCs protected H2O2‑exposed NRVMs from apoptosis and significantly alleviated the oxidative stress in NRVMs. The protective effects of ASCs were associated with increased secretion of VEGF, IGF‑1 and bFGF. ASCs cultured in 5% O2 exhibited certain cardioprotective effects against H2O2 stress. The results of the present study suggested that O2 concentrations influenced the cardioprotective effects of ASCs. VEGF, IGF‑1 and bFGF may serve a role in the myocardial regeneration mediated by transplanted ASCs.
Collapse
Affiliation(s)
- Yuanyuan Lin
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Xuewen Li
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Chunhui Fan
- Department of Information, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Fan Yang
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Dajie Hao
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Wenjia Ge
- Department of Science Research and Education, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Yuping Gao
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| |
Collapse
|
|
40
|
Icariside II facilitates the differentiation of ADSCs to schwann cells and restores erectile dysfunction through regulation of miR-33/GDNF axis. Biomed Pharmacother 2020; 125:109888. [PMID: 32066039 DOI: 10.1016/j.biopha.2020.109888] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/11/2020] [Accepted: 01/14/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Adipose derived stem cells (ADSCs) have the property to differentiate into neuron-like cells, which may provide a novel insight for the restoration of erectile dysfunction (ED) mainly induced by cavernous nerve injury. Icariside II (ICA II) has been reported to play a key role in the regulation of erectile function via stimulating the differentiation of ADSCs to Schwann Cells (SCs). However, the function and molecular mechanisms of ICA II in ED remains to be further clarified. METHODS The expression of S100, P75, GDNF and miR-33 was detected by qRT-PCR. And the relative proteins expression was determined by western blot. Cell viability was measured by Cell Counting Kit-8 (CCK-8) assay. Bioinformatics, luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to verify the interaction between miR-33 and GDNF. Intracavernosal pressure (ICP), the ratio of ICP and mean arterial pressure (MAP), as well as nNOS expression were examined to evaluate the erectile function of SD rats with bilateral cavernous nerve injury (BCNI). RESULTS ICA II and miR-33 respectively promoted and inhibited the differentiation of ADSCs to SCs. MiR-33 could negatively regulate P75 and GDNF expression. ICA II exerted promotion effects on differentiation of ADSCs to SCs via regulating miR-33. GDNF was identified to be a target of miR-33. MiR-33 overexpression abrogated the stimulatory effect of ICA II on ADSCs' differentiation, which was blocked by GDNF overexpression. treated with ICA II recovered the erectile function of BCNI model rats through regulation of miR-33. CONCLUSION ICA II contributed to the differentiation of ADSCs to SCs viamiR-33/GDNF axis, contributing to the recovery of erectile function in BCNI rats.
Collapse
|
|
41
|
Ding F, Shan C, Li H, Zhang Y, Guo C, Zhou Z, Zheng J, Shen W, Dai Q, Ouyang Q, Wu X. Simvastatin alleviated diabetes mellitus-induced erectile dysfunction in rats by enhancing AMPK pathway-induced autophagy. Andrology 2020; 8:780-792. [PMID: 31955524 DOI: 10.1111/andr.12758] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 01/09/2020] [Accepted: 01/14/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Diabetes mellitus-induced erectile dysfunction is a common diabetic complication, and new therapeutics and the pathogenesis of diabetes mellitus-induced erectile dysfunction need to be investigated. OBJECTIVES The aim was to investigate the pathogenesis of diabetes mellitus-induced erectile dysfunction and the pharmacological mechanism of simvastatin treatment in diabetes mellitus-induced erectile dysfunction model rats. MATERIALS AND METHODS A total of 86 male Sprague Dawley rats aged 8 weeks old were used in this study. The rats were divided into three groups: control (normal), diabetes mellitus-induced erectile dysfunction (streptozotocin-injected), and diabetes mellitus-induced erectile dysfunction + simvastatin (sim). Each group was subdivided into two subgroups for in vitro and in vivo analyses. A bioinformatics method was used to detect differences in gene expression in the corpus cavernosum between normal and diabetes mellitus-induced erectile dysfunction rats. Erectile function was measured by a cavernous nerve electrostimulation test. Corpus cavernosum fibrosis was assessed by Masson staining and Western blotting. Immunofluorescence and Western blotting were performed to explore the differential expression of autophagy-related genes and the AMPK-SKP2-CARM1 pathway genes in rat cavernous smooth muscle cells and the corpus cavernosum. The autophagosomes of the corpus cavernosum tissue were observed by transmission electron microscopy. RESULTS Autophagy-related genes and pathways (the AMPK and FoxO pathway) were identified by bioinformatics analysis and confirmed at the protein level. Simvastatin, an AMPK agonist, was used to treat diabetes mellitus-induced erectile dysfunction rats for 8 weeks, demonstrating that erectile function was improved for 80.5% (P < .05) of rats. Corpus cavernosum fibrosis was alleviated (P < .05), and autophagy was further enhanced (P < .05); these results might be partially caused by AMPK-SKP2-CARM1 pathway activation (P < .05). DISCUSSION AND CONCLUSION Simvastatin could enhance protective autophagy by activating the AMPK-SKP2-CARM1 pathway to improve erectile function in diabetes mellitus-induced erectile dysfunction rats.
Collapse
Affiliation(s)
- Fan Ding
- Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Changyu Shan
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, China
| | - Hongwei Li
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, China
| | - Yuping Zhang
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, China
| | - Chunling Guo
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, China
| | - Zhansong Zhou
- Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ji Zheng
- Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Wenhao Shen
- Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qiang Dai
- Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qin Ouyang
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, China
| | - Xiaojun Wu
- Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| |
Collapse
|
|
42
|
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.
Collapse
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.
| |
Collapse
|
|
43
|
Song J, Tang Z, Li H, Jiang H, Sun T, Lan R, Wang T, Wang S, Ye Z, Liu J. Role of JAK2 in the Pathogenesis of Diabetic Erectile Dysfunction and an Intervention With Berberine. J Sex Med 2019; 16:1708-1720. [DOI: 10.1016/j.jsxm.2019.08.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 08/18/2019] [Accepted: 08/19/2019] [Indexed: 10/25/2022]
|
|
44
|
Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model. J Sex Med 2019; 16:1506-1517. [PMID: 31439521 DOI: 10.1016/j.jsxm.2019.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/18/2019] [Accepted: 07/01/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hyperhomocysteinemia (HHcy) has been reported to be strongly correlated with the occurrence of erectile dysfunction (ED), but the mechanisms are not fully understood. Moreover, whether melatonin could be a potential treatment of HHcy-induced ED needs to be elucidated. AIM The aim of this study was to investigate the effects of melatonin on HHcy-induced ED and the potential mechanisms via modulating oxidative stress and apoptosis. METHODS The Sprague-Dawley (SD) rat model of HHcy was induced by 7% methionine (Met)-rich diets. 36 male SD rats were randomly distributed into 3 groups (n = 12 per group): control group, 7% Met group, and 7% Met + melatonin (Mel; 10 mg/kg, intraperitoneal injection) treatment group. After 4 weeks, the erectile function of all rats was evaluated by electrical stimulation of the cavernous nerve. Histologic and molecular alterations of the corpus cavernosum were also analyzed by immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, Western blotting, and polymerase chain reaction. OUTCOMES HHcy-induced ED rat models were successfully established, and Mel could preserve erectile function mainly through inhibiting oxidative stress via the Erk1/2/Nrf2/HO-1 signaling pathway and suppression of apoptosis. RESULTS Erectile function was significantly reduced in the rats with HHcy compared with that in the control group and was ameliorated in the HHcy rats treated with Mel. Compared with the control group, the rats in the HHcy group showed the following: (1) higher levels of total plasma homocysteine; (2) fewer neuronal nitric oxide synthase-positive cells in the corpus cavernous; (3) higher levels of reactive oxygen species and malondialdehyde, higher expression levels of nicotinamide adenine dinucleotide phosphate oxidase, and lower activities of superoxide dismutase, indicating an overactivated oxidative stress; (4) lower expression levels of Erk1/2/Nrf2/HO-1 signaling pathway components; and (5) higher levels of apoptosis, as determined by the expression levels of Bax, Bcl-2, and caspase 3. Mel treatment improved the erectile response, as well as histologic and molecular alterations. CLINICAL TRANSLATION Our study on a rodent model of HHcy provided evidence that Mel could be a potential therapeutic method for HHcy-related ED. CONCLUSIONS Mel treatment improves erectile function in rats with HHcy probably by potential antioxidative stress activity. This finding provides evidence for a potential new therapy for HHcy-induced ED. Tang Z, Song J, Yu, Z, et al. Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model. J Sex Med 2019;16:1506-1517.
Collapse
|
|
45
|
Protective Effect of Fat Extract on UVB-Induced Photoaging In Vitro and In Vivo. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6146942. [PMID: 31531185 PMCID: PMC6720842 DOI: 10.1155/2019/6146942] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 07/20/2019] [Indexed: 12/19/2022]
Abstract
Background Nanofat can protect against ultraviolet B- (UVB-) induced damage in nude mice. Fat extract (FE) is a cell-free fraction isolated from nanofat that is enriched with a variety of growth factors. Objective To determine whether FE can protect against UVB-induced photoaging in cultured dermal fibroblasts and in nude mice. Method For the in vitro study, human dermal skin fibroblasts were pretreated with FE 24 h prior to UVB irradiation. Generation of reactive oxygen species (ROS) was analyzed immediately following irradiation, while cell cycle analysis was performed 24 h after UVB irradiation. Senescence-associated β-galactosidase (SA-β-gal) expression, cell proliferation, and expression of glutathione peroxidase 1 (GPX-1), catalase, superoxide dismutase-1 (SOD-1), SOD-2, and collagen type 1 (COL-1) were investigated 72 h after UVB irradiation. For the in vivo study, the dorsal skin of nude mice was irradiated with UVB and mice were then treated with FE for 8 weeks. The thickness of the dermis, capillary density, and apoptotic cells in skin tissue sections were investigated after treatment. The expression of GPX-1, catalase, SOD-2, SOD-1, and COL-1 in the tissue was also measured. Result FE significantly increased cell proliferation and protected cells against UVB-induced cell death and cell cycle arrest. FE reduced ROS and the number of aged cells induced by UVB irradiation. FE promoted the expression of COL-1 and GPX-1 in cultured dermal fibroblasts. FE treatment of UVB-irradiated skin increased dermal thickness and capillary density, decreased the number of apoptotic cells, and promoted the expression of COL-1 and GPX-1. Conclusion FE protects human dermal fibroblasts and the skin of nude mice from UVB-induced photoaging through its antioxidant, antiapoptotic, and proangiogenic activities.
Collapse
|
|
46
|
Yu Z, Zhang Y, Tang Z, Song J, Gao X, Sun T, Liu Y, Yang J, Wang T, Liu J. Intracavernosal Adeno-Associated Virus-Mediated S100A1 Gene Transfer Enhances Erectile Function in Diabetic Rats by Promoting Cavernous Angiogenesis via VEGF-A/VEGFR2 Signaling. J Sex Med 2019; 16:1344-1354. [PMID: 31378707 DOI: 10.1016/j.jsxm.2019.06.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/26/2019] [Accepted: 06/17/2019] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Novel therapeutic targets for diabetes-induced erectile dysfunction (DED) are urgently needed. Previous studies have proved that S100A1, a small Ca2+-binding protein, is a pluripotent regulator of cardiovascular pathophysiology. Its absence is associated with endothelial dysfunction, the central event linking cardiovascular changes in diabetes. However, the role of S100A1 in DED remains unknown. AIM To explore the effect and underlying mechanisms of S100A1 in restoring erectile function in type I diabetic rat model. METHODS Diabetes was induced by intraperitoneal injection of streptozotocin and then screened by apomorphine (APO) to confirm erectile dysfunction. Rats that met the criteria of penile erection were marked as APO-positive; otherwise, the result was APO-negative. In experiment 1, S100A1 gene expression alterations in the corpus cavernosum in moderate and established stages of DED were analyzed. In experiment 2, S100A1 and control GFP gene were delivered into the corpus cavernosum in APO-negative rats by adeno-associated virus (AAV) serotype 9. Erectile function was assessed at 4 weeks after gene therapy. MAIN OUTCOME MEASURES Erectile response, histologic and molecular alterations. RESULTS S100A1 protein was localized to the area surrounding the cavernosal sinusoids in the penis, and it was gradually downregulated synchronized with the progression of DED. Compared with an injection of AAV-GFP, a single injection of AAV-S100A1 significantly restored erectile function in diabetic rats. S100A1 overexpression significantly upregulated the expression of endogenous VEGF-A, promoted VEGFR2 internalization, and subsequently triggered the protein kinase B-endothelial nitric oxide synthase pathway in diabetic erectile tissues. Marked increases in nitric oxide and endothelial content were noted in AAV-S100A1-treated diabetic rats. CLINICAL IMPLICATIONS Local S100A1 overexpression may be an alternative therapy for DED and should be further investigated by future clinical studies. STRENGTH & LIMITATIONS This is the first study demonstrating the angiogenic role of S100A1 in DED, but does not preclude the contribution of the effects of S100A1 in other tissues such as the neuronal tissue on the functional effects observed in erectile responses. CONCLUSION The decreased expression of S100A1 during hyperglycemia might be important in the development of erectile dysfunction. S100A1 may play a potential role in restoring erectile function in rats with DED through modulating cavernous angiogenesis. Yu Z, Zhang Y, Tang Z, et al. Intracavernosal Adeno-Associated Virus-Mediated S100A1 Gene Transfer Enhances Erectile Function in Diabetic Rats by Promoting Cavernous Angiogenesis via VEGF-A/VEGFR2 Signaling. J Sex Med 2019;16:1344-1354.
Collapse
Affiliation(s)
- Zhe Yu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yan Zhang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhe Tang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jingyu Song
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xintao Gao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Taotao Sun
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jun Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
47
|
In vivo tracking on longer retention of transplanted myocardin gene-modified adipose-derived stem cells to improve erectile dysfunction in diabetic rats. Stem Cell Res Ther 2019; 10:208. [PMID: 31311594 PMCID: PMC6636019 DOI: 10.1186/s13287-019-1325-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/11/2019] [Accepted: 07/03/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Stem cell therapy has revealed a promising future for treating erectile dysfunction (ED), but the fate and curative mechanism of intracavernosal transplanted stem cells are under further exploration. This study aimed to demonstrate the effects of myocardin gene modification on improving erectile function and prolonging the retention of implanted adipose-derived stem cells (ASCs) using in vivo small animal imaging. METHODS ASCs were isolated, cultured, and identified by flow cytometry and osteogenic and adipogenic induction. The effects of gene modification on cell proliferation, apoptosis, and contraction were determined by CCK-8, EdU, flow cytometry, and collagen gel lattice contraction assays as well as confocal microscopy. A total of 20 normal and 60 diabetes mellitus ED to (DMED) Sprague-Dawley rats were recruited to the 7 day and 21 day groups. Each group contained subgroups of 10 rats each: the negative control (NC), DMED + ASCs plus Ad-Luc-Myocardin, DMED + ASCs plus Ad-Luc, and DMED + phosphate buffer solution (PBS) groups. Erectile function was evaluated with the intracavernosal pressure/mean arterial pressure (△ICP/MAP) ratio. In vivo small animal imaging and an EdU cell tracking strategy were introduced to detect the transplanted ASCs, and IHC and WB were performed to assess smooth muscle cell protein levels. RESULTS The ASCs expressed high CD29 and CD90 and scant CD45, while the multi-induction potential was verified by oil red O and alizarin red staining. Gene transfection of myocardin had no significant influence on ASC apoptosis but inhibited cell proliferation and promoted cell contraction. Myocardin combined with ASCs enhanced the therapeutic potential of ASCs for improving the △ICP/MAP ratio as well as α-SMA and calponin expression. In vivo imaging confirmed that ASCs resided within the cavernous body in 21 days, while only a few red EdU dots were detected. CONCLUSIONS Myocardin induced ASC differentiation towards smooth muscle-like cells and enhanced the therapeutic potential of ASCs for ameliorating ED in STZ-induced diabetic rats. Notably, in vivo small animal tracking was an effective strategy for monitoring the implanted stem cells, and this strategy might have advantages over traditional EdU assays.
Collapse
|
|
48
|
Mesenchymal stem cell therapy improves erectile dysfunction in experimental spinal cord injury. Int J Impot Res 2019; 32:308-316. [DOI: 10.1038/s41443-019-0168-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 03/13/2019] [Accepted: 04/20/2019] [Indexed: 02/08/2023]
|
|
49
|
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
| |
Collapse
|
|
50
|
Abstract
PURPOSE OF REVIEW Tissue engineering and regenerative medicine has emerged as a new scientific interdisciplinary field focusing on developing new strategies to repair or recreate tissues and organs. This review gathers findings on erectile dysfunction and, Peyronie's disease from recent preclinical and clinical studies under heading of stem-cell regenerative medicine. RECENT FINDINGS Over the last 2 years, preclinical studies on rat models demonstrated the tangible beneficial role of stem cells and stromal vascular fraction in the context of preventing fibrosis and restoring erectile function in different animal models of Erectile dysfunction and Peyronie's disease. There are not solid evidences in the clinical settings. SUMMARY Large randomized, double blind clinical trials are needed to prove the efficacy of stem-cell therapy on human patients. Owing to the lack of solid evidences, the stem-cell therapy should be only administrated in a clinical research setting.
Collapse
|