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1
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Holvoet P. Aging and Metabolic Reprogramming of Adipose-Derived Stem Cells Affect Molecular Mechanisms Related to Cardiovascular Diseases. Cells 2023; 12:2785. [PMID: 38132104 PMCID: PMC10741778 DOI: 10.3390/cells12242785] [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: 10/06/2023] [Revised: 11/29/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
We performed a systematic search of the PubMed database for English-language articles related to the function of adipose-derived stem cells in the pathogenesis of cardiovascular diseases. In preclinical models, adipose-derived stem cells protected arteries and the heart from oxidative stress and inflammation and preserved angiogenesis. However, clinical trials did not reiterate successful treatments with these cells in preclinical models. The low success in patients may be due to aging and metabolic reprogramming associated with the loss of proliferation capacity and increased senescence of stem cells, loss of mitochondrial function, increased oxidative stress and inflammation, and adipogenesis with increased lipid deposition associated with the low potential to induce endothelial cell function and angiogenesis, cardiomyocyte survival, and restore heart function. Then, we identify noncoding RNAs that may be mechanistically related to these dysfunctions of human adipose-derived stem cells. In particular, a decrease in let-7, miR-17-92, miR-21, miR-145, and miR-221 led to the loss of their function with obesity, type 2 diabetes, oxidative stress, and inflammation. An increase in miR-34a, miR-486-5p, and mir-24-3p contributed to the loss of function, with a noteworthy increase in miR-34a with age. In contrast, miR-146a and miR-210 may protect stem cells. However, a systematic analysis of other noncoding RNAs in human adipose-derived stem cells is warranted. Overall, this review gives insight into modes to improve the functionality of human adipose-derived stem cells.
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Affiliation(s)
- Paul Holvoet
- Division of Experimental Cardiology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
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Jin Y, Zhao W, Yang M, Fang W, Gao G, Wang Y, Fu Q. Cell-Based Therapy for Urethral Regeneration: A Narrative Review and Future Perspectives. Biomedicines 2023; 11:2366. [PMID: 37760808 PMCID: PMC10525510 DOI: 10.3390/biomedicines11092366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/29/2023] [Accepted: 08/16/2023] [Indexed: 09/29/2023] Open
Abstract
Urethral stricture is a common urological disease that seriously affects quality of life. Urethroplasty with grafts is the primary treatment, but the autografts used in clinical practice have unavoidable disadvantages, which have contributed to the development of urethral tissue engineering. Using various types of seed cells in combination with biomaterials to construct a tissue-engineered urethra provides a new treatment method to repair long-segment urethral strictures. To date, various cell types have been explored and applied in the field of urethral regeneration. However, no optimal strategy for the source, selection, and application conditions of the cells is available. This review systematically summarizes the use of various cell types in urethral regeneration and their characteristics in recent years and discusses possible future directions of cell-based therapies.
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Affiliation(s)
- Yangwang Jin
- 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; (Y.J.)
| | - Weixin Zhao
- Wake Forest Institute for Regenerative Medicine, Winston Salem, NC 27157, USA
| | - Ming Yang
- 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; (Y.J.)
| | - Wenzhuo Fang
- 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; (Y.J.)
| | - 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; (Y.J.)
| | - 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; (Y.J.)
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3
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Lv J, Zhang R, Li D, Liu Y. Resveratrol plays an anti-fibrotic and anti-autophagy role by stimulating miR-192-5p expression in urethral fibrosis. Funct Integr Genomics 2023; 23:241. [PMID: 37450096 DOI: 10.1007/s10142-023-01173-2] [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: 03/14/2023] [Revised: 06/25/2023] [Accepted: 07/09/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Resveratrol (RSV) exerts anti-fibrotic effects on various fibrotic diseases. Whereas the biological role of RSV on urethral fibrosis remains to be elucidated. This study aimed to determine the mechanisms by which RSV affects urethral fibrosis and autophagy. METHODS Sprague‒Dawley rats and primary fibroblasts were treated with transforming growth factor-β1 (TGFβ1) to generate in vivo and in vitro fibrosis models. Then, those were treated with RSV, and autophagy and fibrosis-related indicators were tested. RESULTS Firstly, we found that RSV reversed the upregulation of indicators related to TGFβ1-induced fibrosis (TGFβ1, α-smooth muscle actin, collagen type I, and collagen type III), autophagy (TFEB and LC3), and TGFβR1/Smad4 pathway, as well as the downregulation of p62 and miR-192-5p expression both in vivo and in vitro. Overexpression of miR-192-5p suppressed the upregulation of fibrosis-related markers expression, as well as TFEB and LC3 expression, induced by TGFβ1, while the expression trend of p62 was the opposite. Inhibiting miR-192-5p reversed the effects of RSV on the model group cells. It was also shown that RSV combined with sh-Smad4 inhibited autophagy more effectively than RSV alone. CONCLUSION These results suggest that RSV inhibits urinary fibrosis and autophagy via the miR-192-5p/TGFβR1/Smad4 pathway. RAV may be a potential drug for alleviating urethral fibrosis.
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Affiliation(s)
- Jin Lv
- Hunan Traditional Chinese Medical College, Zhuzhou, China
| | - Rui Zhang
- Hunan Traditional Chinese Medical College, Zhuzhou, China
| | - DaoYuan Li
- Department of Urology, Hainan Afliated Hospital of Hainan Medical University, Haikou, China
- Department of Urology, Hainan General Hospital, Haikou, China
| | - Yan Liu
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, China.
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Doghish AS, Elballal MS, Elazazy O, Elesawy AE, Shahin RK, Midan HM, Sallam AAM, Elbadry AM, Mohamed AK, Ishak NW, Hassan KA, Ayoub AM, Shalaby RE, Elrebehy MA. miRNAs as potential game-changers in bone diseases: Future medicinal and clinical uses. Pathol Res Pract 2023; 245:154440. [PMID: 37031531 DOI: 10.1016/j.prp.2023.154440] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 03/30/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023]
Abstract
MicroRNAs (miRNAs), short, highly conserved non-coding RNA, influence gene expression by sequential mechanisms such as mRNA breakdown or translational repression. Many biological processes depend on these regulating substances, thus changes in their expression have an impact on the maintenance of cellular homeostasis and result in the emergence of a variety of diseases. Relevant studies have shown in recent years that miRNAs are involved in many stages of bone development and growth. Additionally, abnormal production of miRNA in bone tissues has been closely associated with the development of numerous bone disorders, such as osteonecrosis, bone cancer, and bone metastases. Many pathological processes, including bone loss, metastasis, the proliferation of osteosarcoma cells, and differentiation of osteoblasts and osteoclasts, are under the control of miRNAs. By bringing together the most up-to-date information on the clinical relevance of miRNAs in such diseases, this study hopes to further the study of the biological features of miRNAs in bone disorders and explore their potential as a therapeutic target.
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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.
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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.)
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6
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Cao M, Zhao Y, Chen T, Zhao Z, Zhang B, Yuan C, Wang X, Chen L, Wang N, Li C, Zhou X. Adipose mesenchymal stem cell-derived exosomal microRNAs ameliorate polycystic ovary syndrome by protecting against metabolic disturbances. Biomaterials 2022; 288:121739. [PMID: 35987860 DOI: 10.1016/j.biomaterials.2022.121739] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 08/03/2022] [Accepted: 08/07/2022] [Indexed: 11/09/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of childbearing age. Adipose mesenchymal stem cells (AMSCs) secrete cytokines involved in the regulation of metabolism and immunity. However, it remains unclear whether exosomes secreted by AMSCs (AMSC-EXOs) can rescue the polycystic phenotype and metabolic dysfunction in PCOS ovaries. Here, we show that AMSC-EXOs can protect against metabolic disturbances, ameliorate ovarian polycystic, and improve fertility in a rat model of PCOS. AMSC-EXOs inhibited the expression of B-cell translocation gene 2 by transferring miR-21-5p to the livers of rats with PCOS, thus activating the IRS1/AKT pathway and increasing hepatic metabolism. The role of AMSC-EXOs in transferring miRNAs to the liver to improve metabolic dysfunction in PCOS and reproduction by rescuing a non-coding RNA pathway was also discovered. This study provides a theoretical basis for the use of rat adipose stem cells and their secreted exosomes to treat PCOS.
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Affiliation(s)
- Maosheng Cao
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Yun Zhao
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Tong Chen
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Zijiao Zhao
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Boqi Zhang
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Chenfeng Yuan
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Xin Wang
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Lu Chen
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Nan Wang
- College of Animal Sciences, Jilin University, Changchun, 130062, China
| | - Chunjin Li
- College of Animal Sciences, Jilin University, Changchun, 130062, China.
| | - Xu Zhou
- College of Animal Sciences, Jilin University, Changchun, 130062, China.
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7
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Lu Z, Hou J, Li X, Zhou J, Luo B, Liang S, Lo RK, Wong TM, Kuang GM. Exosome-Derived miRNAs as Potential Biomarkers for Prostate Bone Metastasis. Int J Gen Med 2022; 15:5369-5383. [PMID: 35673634 PMCID: PMC9167626 DOI: 10.2147/ijgm.s361981] [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: 02/10/2022] [Accepted: 05/16/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose The purpose of this study was to identify the potential exosome-derived microRNAs (miRNAs) related to prostate cancer (Pca) bone metastasis. Methods Two datasets were collected. One dataset was from the authors’ institute, for which two groups of 10 patients each were designed: in the first one, the patients had early-stage localised Pca without bone metastasis, and in the other, the patients presented with Pca with bone metastasis. Then, the miRNA expression profiles of the blood exosomes were obtained and analysed. The other dataset was a public dataset of the miRNA expression transcriptome (GSE26964), which was downloaded from Gene Expression Omnibus (GEO). The results of both datasets were jointly analysed and the most bone-metastatic-related differentially expressed miRNAs (diff-miRNAs) were identified and further validated. Finally, a series of bioinformatics analyses were performed and the relationship between target genes of the diff-miRNAs and the pathogenesis and progression of bone metastasis of Pca were studied. Results From the authors’ dataset, in all, 313 diff-miRNAs were identified, of which 205 were up-regulated while 108 were down-regulated. From the GSE26964 dataset, 107 diff-miRNAs were found, of which 44 were up-regulated and 63 were down-regulated. Taking the intersection of the results of both datasets, four diff-miRNAs were identified: hsa-miR-125a-3p, hsa-miR-330-3p, hsa-miR-339-5p and hsa-miR-613. In all, 94 target genes of the four diff-miRNAs were predicted. After considering the intersection of the results from the GSE32269 dataset, we obtained 25 target genes. Although either positive or negative correlations were found among the diff-miRNAs with some of the target genes, there is a lack of evidence on how such correlations regulate the development and promotion of Pca bone metastasis. Conclusion Hsa-miR-125a-3p, hsa-miR-330-3p, hsa-miR-339-5p and hsa-miR-613 are potential biomarkers for Pca bone metastasis.
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Affiliation(s)
- Zhenquan Lu
- Department of Urology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Jian Hou
- Department of Urology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Xiao Li
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Jun Zhou
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Bingfeng Luo
- Department of Urology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Songwu Liang
- Department of Urology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Richard K Lo
- Department of Urology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Tak Man Wong
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Guan-Ming Kuang
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People’s Republic of China
- Correspondence: Guan-Ming Kuang, Email
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8
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Caneparo C, Sorroza-Martinez L, Chabaud S, Fradette J, Bolduc S. Considerations for the clinical use of stem cells in genitourinary regenerative medicine. World J Stem Cells 2021; 13:1480-1512. [PMID: 34786154 PMCID: PMC8567446 DOI: 10.4252/wjsc.v13.i10.1480] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/12/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
The genitourinary tract can be affected by several pathologies which require repair or replacement to recover biological functions. Current therapeutic strategies are challenged by a growing shortage of adequate tissues. Therefore, new options must be considered for the treatment of patients, with the use of stem cells (SCs) being attractive. Two different strategies can be derived from stem cell use: Cell therapy and tissue therapy, mainly through tissue engineering. The recent advances using these approaches are described in this review, with a focus on stromal/mesenchymal cells found in adipose tissue. Indeed, the accessibility, high yield at harvest as well as anti-fibrotic, immunomodulatory and proangiogenic properties make adipose-derived stromal/SCs promising alternatives to the therapies currently offered to patients. Finally, an innovative technique allowing tissue reconstruction without exogenous material, the self-assembly approach, will be presented. Despite advances, more studies are needed to translate such approaches from the bench to clinics in urology. For the 21st century, cell and tissue therapies based on SCs are certainly the future of genitourinary regenerative medicine.
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Affiliation(s)
- Christophe Caneparo
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
| | - Luis Sorroza-Martinez
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
| | - Stéphane Chabaud
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
| | - Julie Fradette
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec G1V0A6, Canada
| | - Stéphane Bolduc
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec G1V0A6, Canada
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Hughes M, Blakely S, Nikolavsky D. Advancements in transurethral management of urethral stricture disease. Curr Opin Urol 2021; 31:504-510. [PMID: 34175872 DOI: 10.1097/mou.0000000000000913] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To explore and report the recent evolution of transurethral management of urethral stricture disease. RECENT FINDINGS In recent years, new promising techniques in the transurethral management of urethral stricture disease have emerged including adjuvant therapies to direct vision internal urethrotomy, regenerative therapy with buccal mucosa cells and minimally invasive transurethral urethroplasty procedures that avoid skin incisions. SUMMARY Although further work is needed, the expanding field of transurethral therapies for urethral stricture disease demonstrates early promising results through a variety of modalities.
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Affiliation(s)
- Michael Hughes
- SUNY Upstate Medical University, Department of Urology, Syracuse, New York, USA
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10
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Xu Y, Huang X, Luo Q, Zhang X. MicroRNAs Involved in Oxidative Stress Processes Regulating Physiological and Pathological Responses. Microrna 2021; 10:164-180. [PMID: 34279211 DOI: 10.2174/2211536610666210716153929] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 05/16/2021] [Accepted: 05/18/2021] [Indexed: 11/22/2022]
Abstract
Oxidative stress influences several physiological and pathological cellular events, including cell differentiation, excessive growth, proliferation, apoptosis, and the inflammatory response. Therefore, oxidative stress is involved in the pathogenesis of various diseases, including pulmonary fibrosis, epilepsy, hypertension, atherosclerosis, Parkinson's disease, cardiovascular disease, and Alzheimer's disease. Recent studies have shown that several microRNAs (miRNAs) are involved in developing various diseases caused by oxidative stress and that miRNAs may be helpful to determine the inflammatory characteristics of immune responses during infection and disease. This review describes the known effects of miRNAs on reactive oxygen species to induce oxidative stress and the miRNA regulatory mechanisms involved in the uncoupling of Keap1-Nrf2 complexes. Finally, we summarized the functions of miRNAs in several antioxidant genes. Understanding the crosstalk between miRNAs and oxidative stress-inducing factors during physiological and pathological cellular events may have implications for designing more effective treatments for immune diseases.
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Affiliation(s)
- Yongjie Xu
- Guangdong Provincial Key Laboratory of Conservation and Precision Utilization of Characteristic Agricultural Resources in Mountainous Areas, School of Life Science of Jiaying University, Guangdong Innovation Centre for Science and Technology of Wuhua Yellow Chicken, Meizhou 514015, China
| | - Xunhe Huang
- Guangdong Provincial Key Laboratory of Conservation and Precision Utilization of Characteristic Agricultural Resources in Mountainous Areas, School of Life Science of Jiaying University, Guangdong Innovation Centre for Science and Technology of Wuhua Yellow Chicken, Meizhou 514015, China
| | - Qingbin Luo
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science/ Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, China
| | - Xiquan Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science/ Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, China
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11
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Shi Z, Wang Q, Jiang D. The preventative effect of bone marrow-derived mesenchymal stem cell exosomes on urethral stricture in rats. Transl Androl Urol 2020; 9:2071-2081. [PMID: 33209670 PMCID: PMC7658129 DOI: 10.21037/tau-20-833] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Urethral stricture (US) is a major challenge in urology and there is an urgent need for effective therapies for its treatment. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs-Exos) have been shown to be effective in preventing scar and fibrosis formation after tissue injury. However, the potential utility of BMSCs-Exos in the prevention of US remains unknown. We hypothesized that local administration of BMSCs-Exos may influence urethral healing and scar formation in a rat model of US. Methods A previously established model of rat US was used in this study. Sprague Dawley rats were randomly assigned into sham, US, and US + BMSCs-Exos groups. Micro-ultrasound assessment, histopathology, immunohistochemistry, and gene expression analysis were performed at four weeks post-surgery. Results US rats exhibited thick urethral walls with a narrowed lumen, when compared with sham rats. However, these changes were suppressed in the US + BMSCs-Exos group. The preventative effects of BMSCs-Exos on US formation were also apparent histologically. US + BMSCs-Exos rats demonstrated decreased expression of several fibrosis-related genes in urethral tissues, including Col I, fibronectin, and elastin, when compared with US rats. BMSCs-Exos treatment also led to an increase in the expression of angiogenesis-related genes in these tissues, including VEGF, eNOS, and bFGF. Conclusions Our findings therefore demonstrate that the local administration of BMSCs-Exos prevents urethral stricture formation by regulating fibrosis and angiogenesis. These findings provide a basis for an innovative strategy involving the clinical application of exosomes to counteract US formation.
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Affiliation(s)
- Zhengzhou Shi
- Department of Urology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Wang
- Department of Urology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dapeng Jiang
- Department of Urology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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12
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Lv Q, Deng J, Chen Y, Wang Y, Liu B, Liu J. Engineered Human Adipose Stem-Cell-Derived Exosomes Loaded with miR-21-5p to Promote Diabetic Cutaneous Wound Healing. Mol Pharm 2020; 17:1723-1733. [PMID: 32233440 DOI: 10.1021/acs.molpharmaceut.0c00177] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Diabetic wounds are a worldwide health problem causing extremely heavy public health burden and require effective treatment. Optimal strategies for treating nonhealing diabetic wounds include stem-cell-based therapy and delivery of novel drug substances, such as functional microRNAs (miRNAs); however, miRNA easily degrades in the wound microenvironment. Herein, we developed a human adipose stem-cell-derived exosome (hASC-exos)-based miRNA delivery strategy to enhance its therapeutic efficacy. The miR-21-5p mimics, as novel therapeutic candidates for diabetic wounds, were loaded into hASC-exos by electroporation, taking advantage of natural availability and biocompatibility of exosomes as extracellular miRNA transporting particles. The engineered exosomes (E-exos) exhibited excellent effects on promoting proliferation and migration of keratinocytes via Wnt/β-catenin signaling in vitro and accelerating diabetic wound healing by increasing re-epithelialization, collagen remodeling, angiogenesis, and vessel maturation in vivo. Results from this study would set the fundamentals of applying hASC-exos to deliver future drug substances and to develop cell-free therapy for wound-healing treatments.
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Affiliation(s)
- Qijun Lv
- Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Junfeng Deng
- Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - You Chen
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Yizhen Wang
- Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Bo Liu
- Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Jie Liu
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
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13
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Jiang D, Singh K, Muschhammer J, Schatz S, Sindrilaru A, Makrantonaki E, Qi Y, Wlaschek M, Scharffetter-Kochanek K. MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF-β1 levels. EMBO Rep 2020; 21:e49115. [PMID: 32080965 PMCID: PMC7132342 DOI: 10.15252/embr.201949115] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 12/09/2019] [Accepted: 01/31/2020] [Indexed: 12/13/2022] Open
Abstract
Mutations in the CD18 gene encoding the common β-chain of β2 integrins result in impaired wound healing in humans and mice suffering from leukocyte adhesion deficiency syndrome type 1 (LAD1). Transplantation of adipose tissue-derived mesenchymal stem cells (MSCs) restores normal healing of CD18-/- wounds by restoring the decreased TGF-β1 concentrations. TGF-β1 released from MSCs leads to enhanced myofibroblast differentiation, wound contraction, and vessel formation. We uncover that MSCs are equipped with a sensing mechanism for TGF-β1 concentrations at wound sites. Low TGF-β1 concentrations as occurring in CD18-/- wounds induce TGF-β1 release from MSCs, whereas high TGF-β1 concentrations suppress TGF-β1 production. This regulation depends on TGF-β receptor sensing and is relayed to microRNA-21 (miR-21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF-β1 signaling. Inactivation of TGF-β receptor, or overexpression or silencing of miR-21 or Smad7, abrogates TGF-β1 sensing, and thus prevents the adaptive MSC responses required for tissue repair.
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Affiliation(s)
- Dongsheng Jiang
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
| | - Karmveer Singh
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
| | - Jana Muschhammer
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
| | - Susanne Schatz
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
| | - Anca Sindrilaru
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
| | - Evgenia Makrantonaki
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
| | - Yu Qi
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
| | - Meinhard Wlaschek
- Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
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14
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Chen L, Simões A, Chen Z, Zhao Y, Wu X, Dai Y, DiPietro LA, Zhou X. Overexpression of the Oral Mucosa-Specific microRNA-31 Promotes Skin Wound Closure. Int J Mol Sci 2019; 20:ijms20153679. [PMID: 31357577 PMCID: PMC6696114 DOI: 10.3390/ijms20153679] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/25/2019] [Accepted: 07/26/2019] [Indexed: 02/06/2023] Open
Abstract
Wounds within the oral mucosa are known to heal more rapidly than skin wounds. Recent studies suggest that differences in the microRNAome profiles may underlie the exceptional healing that occurs in oral mucosa. Here, we test whether skin wound-healing can be accelerating by increasing the levels of oral mucosa-specific microRNAs. A panel of 57 differentially expressed high expresser microRNAs were identified based on our previously published miR-seq dataset of paired skin and oral mucosal wound-healing [Sci. Rep. (2019) 9:7160]. These microRNAs were further grouped into 5 clusters based on their expression patterns, and their differential expression was confirmed by TaqMan-based quantification of LCM-captured epithelial cells from the wound edges. Of these 5 clusters, Cluster IV (consisting of 8 microRNAs, including miR-31) is most intriguing due to its tissue-specific expression pattern and temporal changes during wound-healing. The in vitro functional assays show that ectopic transfection of miR-31 consistently enhanced keratinocyte proliferation and migration. In vivo, miR-31 mimic treatment led to a statistically significant acceleration of wound closure. Our results demonstrate that wound-healing can be enhanced in skin through the overexpression of microRNAs that are highly expressed in the privileged healing response of the oral mucosa.
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Affiliation(s)
- Lin Chen
- Center for Wound Healing & Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Alyne Simões
- Center for Wound Healing & Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
- Oral Biology Laboratory, Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo, 05508-000 São Paulo, SP, Brazil
| | - Zujian Chen
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Yan Zhao
- Center for Wound Healing & Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Xinming Wu
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Yang Dai
- Department of Bioengineering, College of Engineering, University of Illinois at Chicago, Chicago, IL 60607, USA
- Graduate College, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Luisa A DiPietro
- Center for Wound Healing & Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
- Graduate College, University of Illinois at Chicago, Chicago, IL 60607, USA.
| | - Xiaofeng Zhou
- Center for Wound Healing & Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
- Graduate College, University of Illinois at Chicago, Chicago, IL 60607, USA.
- UIC Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
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15
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Simões A, Chen L, Chen Z, Zhao Y, Gao S, Marucha PT, Dai Y, DiPietro LA, Zhou X. Differential microRNA profile underlies the divergent healing responses in skin and oral mucosal wounds. Sci Rep 2019; 9:7160. [PMID: 31073224 PMCID: PMC6509259 DOI: 10.1038/s41598-019-43682-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 04/27/2019] [Indexed: 12/31/2022] Open
Abstract
Oral mucosal wounds heal faster than skin wounds, yet the role of microRNAs in this differential healing has never been examined. To delineate the role of microRNAs in this site-specific injury response, we first compared the microRNAome of uninjured skin and oral mucosa in mice. A total of 53 tissue-specific microRNAs for skin and oral mucosa epithelium were identified. The most striking difference was the high abundance of miR-10a/b in skin (accounting for 21.10% of the skin microRNAome) as compared to their low expression in oral mucosa (2.87%). We further examined the dynamic changes of microRNAome throughout the time course of skin and oral mucosal wound healing. More differentially expressed microRNAs were identified in skin wounds than oral wounds (200 and 33, respectively). More specifically, miR-10a/b was significantly down-regulated in skin but not oral wounds. In contrast, up-regulation of miR-21 was observed in both skin and oral wounds. The therapeutic potential of miR-10b and miR-21 in accelerating wound closure was demonstrated in in vitro assays and in a murine skin wound model. Thus, we provided the first site-specific microRNA profile of skin and oral mucosal wound healing, and demonstrate the feasibility of a microRNA-based therapy for promoting wound closure.
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Affiliation(s)
- Alyne Simões
- Center for Wound Healing & Tissue Regeneration, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.,Oral Biology Laboratory, Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil
| | - Lin Chen
- Center for Wound Healing & Tissue Regeneration, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA
| | - Zujian Chen
- Center for Molecular Biology of Oral Diseases, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA
| | - Yan Zhao
- Center for Wound Healing & Tissue Regeneration, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA
| | - Shang Gao
- Department of Bioengineering, College of Engineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Phillip T Marucha
- Center for Wound Healing & Tissue Regeneration, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.,College of Dentistry, Oregon Health and Sciences University, Portland, OR, USA
| | - Yang Dai
- Department of Bioengineering, College of Engineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Luisa A DiPietro
- Center for Wound Healing & Tissue Regeneration, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA. .,Graduate College, University of Illinois at Chicago, Chicago, IL, USA.
| | - Xiaofeng Zhou
- Center for Wound Healing & Tissue Regeneration, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA. .,Center for Molecular Biology of Oral Diseases, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA. .,Graduate College, University of Illinois at Chicago, Chicago, IL, USA. .,UIC Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.
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16
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Feng Z, Chen H, Fu T, Zhang L, Liu Y. miR-21 modification enhances the performance of adipose tissue-derived mesenchymal stem cells for counteracting urethral stricture formation. J Cell Mol Med 2018; 22:5607-5616. [PMID: 30179296 PMCID: PMC6201219 DOI: 10.1111/jcmm.13834] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 04/15/2018] [Accepted: 07/09/2018] [Indexed: 12/28/2022] Open
Abstract
The treatment of complicated long segment strictures remains to a challenge, and the substitution urethroplasty treatment is often accompanied by subsequent tissue fibrosis and secondary stricture formation. In situ injection of human adipose tissue-derived stem cells (hADSC) could potential be applied for prevention of urethral fibrosis, but the cells transplantation alone may be insufficient because of the complicated histopathological micro-environmental changes in the injury site. This study investigated whether miR-21 modification can improve the therapeutic efficacy of ADSCs against urethral fibrosis to limit urethral stricture recurrence. MiR-21-modified ADSCs (miR-21) were constructed via lentivirus-mediated transfer of pre-miR-21 and GFP reporter gene. In vitro results suggested that miR-21 modification can increase the angiogenesis genes expression of ADSCs and enhance its anti-oxidative effects against reactive oxygen species (ROS) damage. In vivo results showed that miR-21 modification contributes to increased urodynamic parameters and better formation of the epithelium and the muscle layer as compared to ADSCs transplantation alone groups. The results demonstrated that miR-21 modification in ADSCs could improve urethral wound healing microenvironment, enhance stem cell survival through ROS scavenging and promote the neovascularization via regulating angiogenic genes expression, which eventually increase the ADSCs' therapeutic potential for urethral wound healing.
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Affiliation(s)
- Zongcheng Feng
- Department of Urology, No. 731 Hospital of China Aerospace Science and Industry Corporation, Beijing, China
| | - Hongrun Chen
- Department of Urology, No. 731 Hospital of China Aerospace Science and Industry Corporation, Beijing, China
| | - Taozhu Fu
- Department of Urology, No. 731 Hospital of China Aerospace Science and Industry Corporation, Beijing, China
| | - Lianfeng Zhang
- Department of Urology, No. 731 Hospital of China Aerospace Science and Industry Corporation, Beijing, China
| | - Yushan Liu
- Department of Urology, No. 731 Hospital of China Aerospace Science and Industry Corporation, Beijing, China
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