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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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Liang CC, Shaw SWS, Chou HH, Huang YH, Lee TH. Amniotic Fluid Stem Cells Improve Rat Bladder Dysfunction After Pelvic Nerve Transection. Cell Transplant 2021; 29:963689720909387. [PMID: 32452747 PMCID: PMC7444231 DOI: 10.1177/0963689720909387] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The effects of human amniotic fluid stem cells (hAFSCs) transplantation on bladder dysfunction after pelvic nerve transection (PNT) remain to be clarified. Five groups of female Sprague-Dawley rats were studied including sham operation, unilateral PNT alone or plus hAFSCs transplantation, and bilateral PNT alone or plus hAFSCs transplantation. hAFSCs were injected at the site of PNT. Cystometries, neurofilament density within bladder nerves, and the expressions of bladder protein gene-product 9.5 (PGP9.5), growth-associated protein 43 (GAP-43), nerve growth factor (NGF), p75 (NGF receptor), CXCL12, CCL7, and enkephalin were studied. Compared to sham-operation group, bladder weight increased and neurofilament density decreased at 10 and 28 days after unilateral and bilateral PNT, but all improved after hAFSCs transplantation. Unilateral PNT could increase bladder capacity, residual volume, and number of nonvoiding contractions but decrease peak voiding pressure and leak point pressure. Bilateral PNT caused overflow incontinence and increased the number of nonvoiding contractions. These cystometric parameters improved after hAFSCs transplantation. After PNT, bladder PGP9.5 mRNA and immunoreactivities decreased at 10 and 28 days, GAP-43 mRNA and immunoreactivities increased at 10 days and decreased at 28 days, both NGF and p75 mRNAs and immunoreactivities increased at 10 and/or 28 days, and enkephalin immunoreactivities decreased at 10 and 28 days, but these were all improved after hAFSCs transplantation. Our results showed that bladder dysfunction induced by PNT could be improved by hAFSCs transplantation, and PGP9.5, GAP-43, and neurotrophins could be involved in the mechanisms of nerve regeneration after hAFSCs transplantation.
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Affiliation(s)
- Ching-Chung Liang
- Female Urology Section, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan.,College of Medicine, Chang Gung University, Taoyuan
| | - Sheng-Wen Steven Shaw
- College of Medicine, Chang Gung University, Taoyuan.,Division of Obstetrics, Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei.,Prenatal Cell and Gene Therapy Group, Institute for Women's Health, University College London, London, UK
| | - Hung-Hsueh Chou
- College of Medicine, Chang Gung University, Taoyuan.,Gynecologic Oncology Section, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan
| | - Yung-Hsin Huang
- Female Urology Section, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan
| | - Tsong-Hai Lee
- College of Medicine, Chang Gung University, Taoyuan.,Stroke Center and Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan
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Abstract
Stem cells are capable of self-renewal and differentiation into a range of cell types and promote the release of chemokines and progenitor cells necessary for tissue regeneration. Mesenchymal stem cells are multipotent progenitor cells with enhanced proliferation and differentiation capabilities and less tumorigenicity than conventional adult stem cells; these cells are also easier to acquire. Bladder dysfunction is often chronic in nature with limited treatment modalities due to its undetermined pathophysiology. Most treatments focus on symptom alleviation rather than pathognomonic changes repair. The potential of stem cell therapy for bladder dysfunction has been reported in preclinical models for stress urinary incontinence, overactive bladder, detrusor underactivity, and interstitial cystitis/bladder pain syndrome. Despite these findings, however, stem cell therapy is not yet available for clinical use. Only one pilot study on detrusor underactivity and a handful of clinical trials on stress urinary incontinence have reported the effects of stem cell treatment. This limitation may be due to stem cell function loss following ex vivo expansion, poor in vivo engraftment or survival after transplantation, or a lack of understanding of the precise mechanisms of action underlying therapeutic outcomes and in vivo behavior of stem cells administered to target organs. Efficacy comparisons with existing treatment modalities are also needed for the successful clinical application of stem cell therapies. This review describes the current status of stem cell research on treating bladder dysfunction and suggests future directions to facilitate clinical applications of this promising treatment modality, particularly for bladder dysfunction.
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Magnetic targeting of super-paramagnetic iron oxide nanoparticle labeled myogenic-induced adipose-derived stem cells in a rat model of stress urinary incontinence. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 30:102281. [PMID: 32763385 DOI: 10.1016/j.nano.2020.102281] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 06/23/2020] [Accepted: 07/26/2020] [Indexed: 12/31/2022]
Abstract
Cell-based injectable therapy utilizing stem cells is a promising approach for the treatment of stress urinary incontinence (SUI). Applying a magnetically controlled cell delivery approach has enormous potential to enhance cell retention capability within the specified site. To assess the therapeutic efficacy of cellular magnetic targeting, we applied an external magnetic force to target an adipose-derived stem cell based therapy in a rat model of SUI. The results revealed that magnetic attraction of transplanted cells under the magnetic field was generated by cell uptake of superparamagnetic iron oxide nanoparticles in vitro. More importantly, magnetic targeting improved the retention rate of transplanted cells and facilitated the restoration of sphincter structure and function in a rat SUI model according to the results of histological examination and urodynamic testing. Therefore, magnetically guided targeting strategy might be a potential therapy method for treatment of SUI.
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Schmid F, Eberli D. [Modern Therapy of Urinary Incontinence Using Muscle Stem Cells]. PRAXIS 2020; 109:447-452. [PMID: 32345177 DOI: 10.1024/1661-8157/a003421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Modern Therapy of Urinary Incontinence Using Muscle Stem Cells Abstract. Urinary incontinence affects a large number of patients, and the cost of treatment continues to rise with the demographic change. There are various conservative and surgical therapies, which are often limited in their effect or limited in time. We are lacking long-term and sustainable solutions, whereas the treatment with a regenerative approach using stem cells forms a promising alternative. Various preclinical and clinical studies have investigated the use of precursor cells to strengthen the urinary sphincter muscle. This review discusses the issue of stress incontinence from the physiological point of view to conventional treatment and novel therapies using muscle stem cells. In addition, the authors inform about an ongoing prospective trial at the University Hospital in Zurich, which makes use of this modern and regenerative therapy form.
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Kang N, Peng D, Wang B, Ruan Y, Zhou J, Reed-Maldonado AB, Banie L, Wang G, Xing N, Tang Y, Lin G, Lue TF. The effects of microenergy acoustic pulses on animal model of obesity-associated stress urinary incontinence. Part 2: In situ activation of pelvic floor and urethral striated muscle progenitor cells. Neurourol Urodyn 2019; 38:2140-2150. [PMID: 31452249 DOI: 10.1002/nau.24152] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 08/05/2019] [Indexed: 12/15/2022]
Abstract
AIM To investigate the possibility and mechanism of microenergy acoustic pulses (MAP) for activating tissue resident stem/progenitor cells within pelvic and urethral muscle and possible mechanism. METHODS The female Zucker Lean and Zucker Fatty rats were randomly divided into four groups: ZL control, ZLMAP, ZF control, and ZFMAP. MAP was applied at 0.033 mJ/mm2 , 3 Hz for 500 pulses, and the urethra and pelvic floor muscles of each rat was then harvested for cell isolation and flow cytometry assay. Freshly isolated cells were analyzed by flow cytometry for Pax-7, Int-7α, H3P, and EdU expression. Meanwhile, pelvic floor muscle-derived stem cells (MDSCs) were harvested through magnetic-activated cell sorting, MAP was then applied to MDSCs to assess the mechanism of stem cell activation. RESULTS Obesity reduced EdU-label-retaining cells and satellite cells in both pelvic floor muscle and urethra, while MAP activated those cells and enhanced cell proliferation, which promoted regeneration of striated muscle cells of the pelvic floor and urethral sphincter. Activation of focal adhesion kinase (FAK)/AMP-activated protein kinase (AMPK) /Wnt/β-catenin signaling pathways by MAP is the potential mechanism. CONCLUSIONS MAP treatment activated tissue resident stem cells within pelvic floor and urethral muscle in situ via activating FAK-AMPK and Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Ning Kang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California.,Department of Urology, Chaoyang Hospital, Beijing Captial Medical University, Beijing, China
| | - Dongyi Peng
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California.,Department of Urology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Bohan Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Yajun Ruan
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Jun Zhou
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Amanda B Reed-Maldonado
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Lia Banie
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Guifang Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Nianzeng Xing
- Department of Urology, Chaoyang Hospital, Beijing Captial Medical University, Beijing, China
| | - Yuxin Tang
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Guiting Lin
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Tom F Lue
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
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Gallo F, Ninotta G, Schenone M, Cortese P, Giberti C. Advances in stem cell therapy for male stress urinary incontinence. Expert Opin Biol Ther 2019; 19:293-300. [PMID: 30709326 DOI: 10.1080/14712598.2019.1578343] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
INTRODUCTION Among the several options that have been proposed in recent years for the management of male stress urinary incontinence (SUI), stem cell therapy represents a new frontier in treatment. The aim of this paper is to update the current status of stem cell therapy in animal and human studies for the management of iatrogenic male SUI. AREAS COVERED A literature review was conducted based on MEDLINE/PubMed searches for English articles using a combination of the following keywords: stem cell therapy, urinary incontinence, prostatectomy, regenerative medicine, mesenchymal stem cells. EXPERT OPINION The few studies reported in the literature have demonstrated short-term safety and promising results of stem cell therapy in treating male SUI. However, many aspects need to be clarified before stem cell therapy can be introduced into daily urologic practice. In fact, important issues such as the limitations of these studies in terms of small sample sizes and short follow-ups, the incomplete knowledge of the mechanism of action of stem cells, the technical details regarding the delivery method and the best sources of stem cells, the safety risks regarding genomic or epigenetic changes and potential immune reactions in the longer term need to be identified in more stringent clinical trials.
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Affiliation(s)
- Fabrizio Gallo
- a Department of Surgery, Division of Urology , San Paolo Hospital , Savona , Italy
| | - Gaetano Ninotta
- a Department of Surgery, Division of Urology , San Paolo Hospital , Savona , Italy
| | - Maurizio Schenone
- a Department of Surgery, Division of Urology , San Paolo Hospital , Savona , Italy
| | - Pierluigi Cortese
- a Department of Surgery, Division of Urology , San Paolo Hospital , Savona , Italy
| | - Claudio Giberti
- a Department of Surgery, Division of Urology , San Paolo Hospital , Savona , Italy
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Colaco M, Osman NI, Karakeçi A, Artibani W, Andersson KE, Badlani GH. Current concepts of the acontractile bladder. BJU Int 2018; 122:195-202. [PMID: 29633516 DOI: 10.1111/bju.14236] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The acontractile bladder (AcB) is a urodynamic-based diagnosis wherein the bladder is unable to demonstrate any contraction during a pressure flow study. Although it is often grouped with underactive bladder, it is a unique phenomenon and should be investigated independently. The purpose of the present review was to examine the current literature on AcB regarding its pathology, diagnosis, current management guidelines, and future developments. We performed a review of the PubMed database, classifying the evidence for AcB pathology, diagnosis, treatment, and potential future treatments. Over the 67 years covered in our review period, 42 studies were identified that met our criteria. Studies were largely poor quality and mainly consisted of retrospective review or animal models. The underlying pathology of AcB is variable with both neurological and myogenic aetiologies. Treatment is largely tailored for renal preservation and reduction of infection. Although future developments may allow more functional restorative treatments, current treatments mainly focus on bladder drainage. AcB is a unique and understudied bladder phenomenon. Treatment is largely based on symptoms and presentation. While cellular therapy and neuromodulation may hold promise, further research is needed into the underlying neuro-urological pathophysiology of this disease so that we may better develop future treatments.
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Affiliation(s)
- Marc Colaco
- Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Nadir I Osman
- Academic Urology Unit, Royal Hallamshire Hospital, Sheffield, UK
| | | | - Walter Artibani
- Urologic Clinic, University Hospital, Ospedale Policlinico, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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Aizawa N, Igawa Y. Pathophysiology of the underactive bladder. Investig Clin Urol 2017; 58:S82-S89. [PMID: 29279880 PMCID: PMC5740034 DOI: 10.4111/icu.2017.58.s2.s82] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 08/22/2017] [Indexed: 01/05/2023] Open
Abstract
Underactive bladder (UAB), which has been described as a symptom complex suggestive of detrusor underactivity, is usually characterized by prolonged urination time with or without a sensation of incomplete bladder emptying, usually with hesitancy, reduced sensation on filling, and slow stream often with storage symptoms. Several causes such as aging, bladder outlet obstruction, diabetes mellitus, neurologic disorders, and nervous injury to the spinal cord, cauda equine, and peripheral pelvic nerve have been assumed to be responsible for the development of UAB. Several contributing factors have been suggested in the pathophysiology of UAB, including myogenic failure, efferent and/or afferent dysfunctions, and central nervous system dysfunction. In this review article, we have described relationships between individual contributing factors and the pathophysiology of UAB based on previous reports. However, many pathophysiological uncertainties still remain, which require more investigations using appropriate animal models.
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Affiliation(s)
- Naoki Aizawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Igawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Vinarov A, Atala A, Yoo J, Slusarenco R, Zhumataev M, Zhito A, Butnaru D. Cell therapy for stress urinary incontinence: Present-day frontiers. J Tissue Eng Regen Med 2017; 12:e1108-e1121. [PMID: 28482121 DOI: 10.1002/term.2444] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 01/28/2017] [Accepted: 05/03/2017] [Indexed: 01/16/2023]
Abstract
Stress urinary incontinence (SUI) significantly diminishes the quality of patients' lives. Currently available surgical and nonsurgical therapies remain far from ideal. At present, advances in cellular technologies have stirred growing interest in the use of autologous cell treatments aimed to regain urinary control. The objective was to conduct a review of the literature and analyse preclinical and clinical studies dedicated to various cell therapies for SUI, assessing their effectiveness, safety, and future prospects. A systematic literature search in PubMed was conducted using the following key terms: "stem," "cell," "stress," "urinary," and "incontinence." A total of 32 preclinical studies and 15 clinical studies published between 1946 and December 2014 were included in the review. Most preclinical trials have used muscle-derived stem cells and adipose-derived stem cells. However, at present, the application of other types of cells, such as human amniotic fluid stem muscle-derived progenitor cells and bone marrow mesenchymal stromal cells, is becoming more extensive. While the evidence shows that these therapies are effective and safe, further work is required to standardize surgical techniques, as well as to identify indications for their use, doses and number of doses. Future research will have to focus on clinical applications of cell therapies; namely, it will have to determine indications for their use, doses of cells, optimal surgical techniques and methods, attractive cell sources, as well as to develop clinically relevant animal models and make inroads into understanding the mechanisms of SUI improvement by cell therapies.
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Affiliation(s)
- Andrey Vinarov
- Research Institute for Uronephrology and Reproductive Health, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Anthony Atala
- Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - James Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Roman Slusarenco
- Research Institute for Uronephrology and Reproductive Health, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Marat Zhumataev
- Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Alexey Zhito
- Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Denis Butnaru
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation
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Giberti C, Gallo F, Schenone M, Cortese P, Ninotta G. Stem Cell Therapy for Male Urinary Incontinence. Urol Int 2016; 90:249-52. [PMID: 23221307 DOI: 10.1159/000342415] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Among the medical and surgical options which have been proposed in the last years for the management of male stress urinary incontinence (SUI), stem cell therapy represents a new frontier treatment. The aim of this paper is to update the current status of stem cell therapy in animal and human studies for the management of iatrogenic male SUI. MATERIAL AND METHODS A PubMed review of the literature on stem cell therapy for the treatment of male SUI was performed. RESULTS Regarding animal studies, bone marrow-, muscle- and adipose-derived stem cells have been widely studied, showing regeneration of the urethral sphincter and recovery of the damaged pelvic nerves. With regard to human studies, only four papers are available in the literature using muscle- and adipose-derived stem cells which reported a significant improvement in sphincteric function and incontinence with no severe side effects. CONCLUSIONS In spite of these promising results, further studies are needed with longer follow-ups and larger numbers of patients in order to clarify the potential role of stem cell therapy for the treatment of male SUI.
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Affiliation(s)
- C Giberti
- Department of Surgery, Division of Urology, San Paolo Hospital, Savona, Italy
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13
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Mesenchymal stromal cells for sphincter regeneration. Adv Drug Deliv Rev 2015; 82-83:123-36. [PMID: 25451135 DOI: 10.1016/j.addr.2014.10.026] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 09/29/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023]
Abstract
Stress urinary incontinence (SUI), defined as the involuntary loss of considerable amounts of urine during increased abdominal pressure (exertion, effort, sneezing, coughing, etc.), is a severe problem to the individuals affected and a significant medical, social and economic challenge. SUI is associated with pelvic floor debility, absence of detrusor contraction, or a loss of control over the sphincter muscle apparatus. The pathology includes an increasing loss of muscle cells, replacement of muscular tissue with fibrous tissue, and general aging associated processes of the sphincter complex. When current therapies fail to cure or improve SUI, application of regeneration-competent cells may be an alternative therapeutic option. Here we discuss different aspects of the biology of mesenchymal stromal cells, which are relevant to their clinical applications and for regenerating the sphincter complex. However, there are reports in favor of and against cell-based therapies. We therefore summarize the potential and the risks of cell-based therapies for the treatment of SUI.
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Amend B, Vaegler M, Fuchs K, Mannheim JG, Will S, Kramer U, Hart ML, Feitz W, Chapple C, Stenzl A, Aicher WK. Regeneration of degenerated urinary sphincter muscles: improved stem cell-based therapies and novel imaging technologies. Cell Transplant 2015; 24:2171-83. [PMID: 25608017 DOI: 10.3727/096368915x686229] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Stress urinary incontinence (SUI) is a largely ousted but significant medical, social, and economic problem. Surveys suggest that nowadays approximately 10% of the male and 15% of the female population suffer from urinary incontinence at some stage in their lifetime. In women, two major etiologies contribute to SUI: degeneration of the urethral sphincter muscle controlling the closing mechanism of the bladder outflow and changes in lower pelvic organ position associated with degeneration of connective tissue or with mechanical stress, including obesity and load and tissue injury during pregnancy and delivery. In males, the reduction of the sphincter muscle function is sometimes due to surgical interventions as a consequence of prostate cancer treatment, benign prostate hyperplasia, or of neuropathical origin. Accordingly, for women and men different therapies were developed. In some cases, SUI can be treated by physical exercise, electrophysiological stimulation, and pharmacological interventions. If this fails to improve the situation, surgical interventions are required. In standard procedures, endoprostheses for mechanical support of the weakened tissue or mechanical valves for a bladder outflow control are implanted. In 20% of cases treated, repeat procedures are required as implants yield all sorts of side effects in time. Based on preclinical studies, the application of an advanced therapy medicinal product (ATMP) such as implantation of autologous cells may be a curative and long-lasting therapy for SUI. Cellular therapy could also be an option for men suffering from incontinence caused by injury of the nerves controlling the muscular sphincter system. Here we briefly report on human progenitor cells, especially on mesenchymal stromal cells (MSCs), their expansion and differentiation to smooth muscle or striated muscle cells in vitro, labeling of cells for in vivo imaging, concepts of improved, precise, yet gentle application of cells in muscle tissue, and monitoring of injected cells in situ.
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Affiliation(s)
- Bastian Amend
- Department of Urology, University of Tuebingen Hospital, Tuebingen, Germany
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Effect of myogenic stem cells on the integrity and histomorphology of repaired transected external anal sphincter. Int Urogynecol J 2014; 26:251-6. [PMID: 25253391 DOI: 10.1007/s00192-014-2496-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 08/24/2014] [Indexed: 01/30/2023]
Abstract
INTRODUCTION AND HYPOTHESIS The objective was to evaluate the effect of myogenic stem cells on histological properties and the volume of striated muscle of the external anal sphincter after transection and repair. METHODS Histological analysis was performed on the external anal sphincters of 40 young female rats euthanized at 7 or 90 days after transection and repair and randomization to injection of either phosphate buffered solution (PBS) or myogenic stem cells (SC) at the transection site. Sphincter complexes, previously evaluated for neurophysiological function, were processed for histology and analyzed for possible disruption, amount of inflammation, and volume of striated muscle. The relationship between the muscular disruption and contractile force of sphincters was evaluated. RESULTS Disruption was seen in 100 % of sphincters 7 days after repair for both SC and control animals. Eighty-nine percent of controls and 78% of SC-administered animals had intact sphincters at 90 days. Significant inflammatory infiltrate was seen in repaired anal sphincters for both the PBS and the SC groups at 7 days, and persisted at 90 days, with no difference between treatment groups. Striated muscle volume increased from 7 to 90 days for both control and SC-administered animals. Although there was no difference in volume between treatments, there was substantial temporal improvement in contractile force generation of the sphincters receiving SC compared with those receiving PBS. CONCLUSION In this animal model, administration of myogenic stem cells to transected/repaired anal sphincters did not alter the amount of inflammation nor the volume of striated muscle, suggesting that stem cells might improve contractile function through other cellular processes.
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Kim JH, Lee HJ, Song YS. Treatment of bladder dysfunction using stem cell or tissue engineering technique. Korean J Urol 2014; 55:228-38. [PMID: 24741410 PMCID: PMC3988432 DOI: 10.4111/kju.2014.55.4.228] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 02/28/2014] [Indexed: 01/22/2023] Open
Abstract
Tissue engineering and stem cell transplantation are two important options that may help overcome limitations in the current treatment strategy for bladder dysfunction. Stem cell therapy holds great promise for treating pathophysiology, as well as for urological tissue engineering and regeneration. To date, stem cell therapy in urology has mainly focused on oncology and erectile dysfunction. The therapeutic potency of stem cells (SCs) was originally thought to derive from their ability to differentiate into various cell types including smooth muscle. The main mechanisms of SCs in reconstituting or restoring bladder function are migration, differentiation, and paracrine effects. Nowadays, paracrine effects of stem cells are thought to be more prominent because of their stimulating effects on stem cells and adjacent cells. Studies of stem cell therapy for bladder dysfunction have been limited to experimental models and have been less focused on tissue engineering for bladder regeneration. Bladder outlet obstruction is a representative model. Adipose-derived stem cells, bone marrow stem cells (BMSCs), and skeletal muscle-derived stem cells or muscle precursor cells are used for transplantation to treat bladder dysfunction. The aim of this study is to review stem cell therapy and updated tissue regeneration as treatments for bladder dysfunction and to provide the current status of stem cell therapy and tissue engineering for bladder dysfunction including its mechanisms and limitations.
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Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Hong Jun Lee
- Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
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Vaegler M, DaSilva L, Benz K, Amend B, Mollenhauer J, Aicher W, Stenzl A, Sievert KD. Zellbasierte Therapie der Belastungsinkontinenz. Urologe A 2014; 53:354-61. [DOI: 10.1007/s00120-013-3353-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Aicher WK, Hart ML, Stallkamp J, Klünder M, Ederer M, Sawodny O, Vaegler M, Amend B, Sievert KD, Stenzl A. Towards a Treatment of Stress Urinary Incontinence: Application of Mesenchymal Stromal Cells for Regeneration of the Sphincter Muscle. J Clin Med 2014; 3:197-215. [PMID: 26237258 PMCID: PMC4449674 DOI: 10.3390/jcm3010197] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 01/16/2014] [Accepted: 01/17/2014] [Indexed: 02/07/2023] Open
Abstract
Stress urinary incontinence is a significant social, medical, and economic problem. It is caused, at least in part, by degeneration of the sphincter muscle controlling the tightness of the urinary bladder. This muscular degeneration is characterized by a loss of muscle cells and a surplus of a fibrous connective tissue. In Western countries approximately 15% of all females and 10% of males are affected. The incidence is significantly higher among senior citizens, and more than 25% of the elderly suffer from incontinence. When other therapies, such as physical exercise, pharmacological intervention, or electrophysiological stimulation of the sphincter fail to improve the patient’s conditions, a cell-based therapy may improve the function of the sphincter muscle. Here, we briefly summarize current knowledge on stem cells suitable for therapy of urinary incontinence: mesenchymal stromal cells, urine-derived stem cells, and muscle-derived satellite cells. In addition, we report on ways to improve techniques for surgical navigation, injection of cells in the sphincter muscle, sensors for evaluation of post-treatment therapeutic outcome, and perspectives derived from recent pre-clinical studies.
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Affiliation(s)
- Wilhelm K Aicher
- KFO273, Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
| | - Melanie L Hart
- KFO273, Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
| | - Jan Stallkamp
- FRAUNHOFER Institute, Klinikum Mannhein, Mannheim 68167, Germany.
| | - Mario Klünder
- Department for Systems Dynamics, University of Stuttgart, Stuttgart 70569, Germany.
| | - Michael Ederer
- Department for Systems Dynamics, University of Stuttgart, Stuttgart 70569, Germany.
| | - Oliver Sawodny
- Department for Systems Dynamics, University of Stuttgart, Stuttgart 70569, Germany.
| | - Martin Vaegler
- KFO273, Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
| | - Bastian Amend
- KFO273, Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
- Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
| | - Karl D Sievert
- KFO273, Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
- Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
| | - Arnulf Stenzl
- KFO273, Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
- Department of Urology, University of Tuebingen Hospital, Tuebingen 72076, Germany.
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Bisson A, Fréret M, Drouot L, Jean L, Le Corre S, Gourcerol G, Doucet C, Michot F, Boyer O, Lamacz M. Restoration of anal sphincter function after myoblast cell therapy in incontinent rats. Cell Transplant 2013; 24:277-86. [PMID: 24143883 DOI: 10.3727/096368913x674053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Fecal incontinence (FI) remains a socially isolating condition with profound impact on quality of life for which autologous myoblast cell therapy represents an attractive treatment option. We developed an animal model of FI and investigated the possibility of improving sphincter function by intrasphincteric injection of syngeneic myoblasts. Several types of anal cryoinjuries were evaluated on anesthetized Fischer rats receiving analgesics. The minimal lesion yielding sustainable anal sphincter deficiency was a 90° cryoinjury of the sphincter, repeated after a 24-h interval. Anal sphincter pressure was evaluated longitudinally by anorectal manometry under local electrostimulation. Myoblasts were prepared using a protocol mimicking a clinical-grade process and further transduced with a GFP-encoding lentiviral vector before intrasphincteric injection. Experimental groups were uninjured controls, cryoinjured + PBS, and cryoinjured + myoblasts (different doses or injection site). Myoblast injection was well tolerated. Transferred myoblasts expressing GFP integrated into the sphincter and differentiated in situ into dystrophin-positive mature myofibers. Posttreatment sphincter pressures increased over time. At day 60, pressures in the treated group were significantly higher than those of PBS-injected controls and not significantly different from those of normal rats. Longitudinal follow-up showed stability of the therapeutic effect on sphincter function over a period of 6 months. Intrasphincteric myoblast injections at the lesion borders were equally as effective as intralesion administration, but an injection opposite to the lesion was not. These results provide proof of principle for myoblast cell therapy to treat FI in a rat model. This strategy is currently being evaluated in humans in a randomized double-blind placebo-controlled clinical trial.
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Kim JH, Lee SR, Song YS, Lee HJ. Stem cell therapy in bladder dysfunction: where are we? And where do we have to go? BIOMED RESEARCH INTERNATIONAL 2013; 2013:930713. [PMID: 24151627 PMCID: PMC3787556 DOI: 10.1155/2013/930713] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 08/07/2013] [Accepted: 08/07/2013] [Indexed: 12/19/2022]
Abstract
To date, stem cell therapy for the bladder has been conducted mainly on an experimental basis in the areas of bladder dysfunction. The therapeutic efficacy of stem cells was originally thought to be derived from their ability to differentiate into various cell types. Studies about stem cell therapy for bladder dysfunction have been limited to an experimental basis and have been less focused than bladder regeneration. Bladder dysfunction was listed in MESH as "urinary bladder neck obstruction", "urinary bladder, overactive", and "urinary bladder, neurogenic". Using those keywords, several articles were searched and studied. The bladder dysfunction model includes bladder outlet obstruction, cryoinjured, diabetes, ischemia, and spinal cord injury. Adipose derived stem cells (ADSCs), bone marrow stem cells (BMSCs), and skeletal muscle derived stem cells (SkMSCs) are used for transplantation to treat bladder dysfunction. The main mechanisms of stem cells to reconstitute or restore bladder dysfunction are migration, differentiation, and paracrine effects. The aim of this study is to review the stem cell therapy for bladder dysfunction and to provide the status of stem cell therapy for bladder dysfunction.
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Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang School of Medicine, Seoul 140-743, Republic of Korea
| | - Sang-Rae Lee
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Republic of Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang School of Medicine, Seoul 140-743, Republic of Korea
| | - Hong Jun Lee
- Medical Research Institute, Chung-Ang School of Medicine, Seoul 156-756, Republic of Korea
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Functional and molecular changes of the bladder in rats with crushing injury of nerve bundles from major pelvic ganglion to the bladder: role of RhoA/Rho kinase pathway. Int J Mol Sci 2013; 14:17511-24. [PMID: 23985824 PMCID: PMC3794738 DOI: 10.3390/ijms140917511] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Revised: 07/20/2013] [Accepted: 08/05/2013] [Indexed: 02/07/2023] Open
Abstract
Voiding dysfunction is a common complication after radical pelvic surgery. To reduce this complication, nerve-sparing radical pelvic surgery was introduced. However, several patients experienced voiding difficulty despite nerve-sparing radical pelvic surgery. Thus, we investigated the functional and molecular changes of the bladder in rats, which demonstrated voiding dysfunction induced by nerve damage during nerve-sparing radical pelvic surgery. Male rats were used and assigned to normal, sham-operated, and bilateral crushing nerve bundles from major pelvic ganglion (MPG) to bladder group. After one, two, and four-week crushing injury, significantly decreased contractile response and increased connective tissue of the detrusor were observed and these results were reliable findings with voiding difficulty following nerve-sparing radical pelvic surgery. After crushing injury, significantly increased M2 muscarinic receptor expression was observed and this might be regarded as the compensatory response. However, M3 muscarinic receptor expression was not significantly changed. The expression of RhoA, ROCK-α, and ROCK-β was significantly increased after one, two, and four-week crushing injury. From these results, the down-regulation of RhoA/Rho kinase pathway might lead to the decreased bladder contractility after crushing injury of nerve bundles from MPG to the bladder despite of the compensated up-regulation of M2 muscarinic receptor.
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Yiou R, Hogrel JY, Loche CM, Authier FJ, Lecorvoisier P, Jouany P, Roudot-Thoraval F, Lefaucheur JP. Periurethral skeletal myofibre implantation in patients with urinary incontinence and intrinsic sphincter deficiency: a phase I clinical trial. BJU Int 2013; 111:1105-16. [PMID: 23470219 DOI: 10.1111/j.1464-410x.2012.11682.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Cell therapy using muscle precursor cell (MPC) injections has shown promise for urinary incontinence due to intrinsic sphincter deficiency (ISD), but the cell-preparation process is complex and costly. Implantation of freshly isolated myofibres carrying MPCs, mainly satellite cells, was very efficient in repairing muscle damage in recent animal experiments. In a phase I clinical trial, we investigated whether periurethral myofibre implantation generated local myogenesis and improved continence in 10 patients (five men and five women) with ISD. We found that myofibre implantation increased intraurethral pressure and periurethral electromyographic activity in patients with ISD. There were no serious side-effects. OBJECTIVES To assess the safety of periurethral myofibre implantation in patients with urinary incontinence due to intrinsic sphincter deficiency (ISD) To assess the resulting myogenic process and effects on urinary continence. PATIENTS AND METHODS An open-label non-randomised phase I clinical trial was conducted in five men and five women with ISD (mean age, 62.5 years). A free muscle strip from the patient's gracilis muscle was implanted around the urethra as a means to deliver locally myofibres and muscle precursor cells (MPCs). Patients were assessed for collection formation and incomplete bladder emptying. The maximum urethral closure pressure (MUCP) and concomitant periurethral electromyographic (EMG) activity were recorded before surgery and 1 and 3 months after surgery. Continence was assessed using the 24-h pad test and self-completed questionnaires, for 12 months. RESULTS There were no serious side-effects. Continence improved significantly during the 12-month follow-up in four of the five women, including two who recovered normal continence. In the women, MUCP increased two-fold and de novo EMG periurethral activity was recorded. In the men, MUCP and EMG recordings showed similar improvements but the effect on continence was moderate. The few patients enrolled could affect these results. CONCLUSIONS This is the first report of a one-step procedure for transferring autologous MPCs via myofibre implantation in patients with ISD. EMG and urodynamic assessments showed improvement of periurethral muscle activity. Further work is needed to confirm and improve the therapeutic efficiency of this procedure.
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Affiliation(s)
- René Yiou
- Service d’Urologie, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre deTassigny, Créteil, France.
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Khodari M, Souktani R, Le Coz O, Bedretdinova D, Figeac F, Acquistapace A, Lesault PF, Cognet J, Rodriguez AM, Yiou R. Monitoring of Erectile and Urethral Sphincter Dysfunctions in a Rat Model Mimicking Radical Prostatectomy Damage. J Sex Med 2012; 9:2827-37. [DOI: 10.1111/j.1743-6109.2012.02905.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Chang HH, Havton LA. Serotonergic 5-HT(1A) receptor agonist (8-OH-DPAT) ameliorates impaired micturition reflexes in a chronic ventral root avulsion model of incomplete cauda equina/conus medullaris injury. Exp Neurol 2012; 239:210-7. [PMID: 23099413 DOI: 10.1016/j.expneurol.2012.10.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Revised: 10/05/2012] [Accepted: 10/16/2012] [Indexed: 12/17/2022]
Abstract
Trauma to the thoracolumbar spine commonly results in injuries to the cauda equina and the lumbosacral portion of the spinal cord. Both complete and partial injury syndromes may follow. Here, we tested the hypothesis that serotonergic modulation may improve voiding function after an incomplete cauda equina/conus medullaris injury. For this purpose, we used a unilateral L5-S2 ventral root avulsion (VRA) injury model in the rat to mimic a partial lesion to the cauda equina and conus medullaris. Compared to a sham-operated series, comprehensive urodynamic studies demonstrated a markedly reduced voiding efficiency at 12 weeks after the VRA injury. Detailed cystometrogram studies showed injury-induced decreased peak bladder pressures indicative of reduced contractile properties. Concurrent external urethral sphincter (EUS) electromyography demonstrated shortened burst and prolonged silent periods associated with the elimination phase. Next, a 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), was administered intravenously at 12 weeks after the unilateral L5-S2 VRA injury. Both voiding efficiency and maximum intravesical pressure were significantly improved by 8-OH-DPAT (0.3-1.0 mg/kg). 8-OH-DPAT also enhanced the amplitude of EUS tonic and bursting activity as well as duration of EUS bursting and silent period during EUS bursting. The results indicate that 8-OH-DPAT improves voiding efficiency and enhances EUS bursting in rats with unilateral VRA injury. We conclude that serotonergic modulation of the 5-HT(1A) receptor may represent a new strategy to improve lower urinary tract function after incomplete cauda equina/conus medullaris injuries in experimental studies.
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Affiliation(s)
- Huiyi H Chang
- Department of Anesthesiology and Perioperative Care, UC Irvine, Irvine, CA 92697, USA
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Gräs S, Lose G. The clinical relevance of cell-based therapy for the treatment of stress urinary incontinence. Acta Obstet Gynecol Scand 2011; 90:815-24. [PMID: 21564032 DOI: 10.1111/j.1600-0412.2011.01184.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Stress urinary incontinence is a common disorder affecting the quality of life for millions of women worldwide. Effective surgical procedures involving synthetic permanent meshes exist, but significant short- and long-term complications occur. Cell-based therapy using autologous stem cells or progenitor cells presents an alternative approach, which aims at repairing the anatomical components of the urethral continence mechanism. In vitro expanded progenitor cells isolated from muscle biopsies have been most intensely investigated, and both preclinical trials and a few clinical trials have provided proof of concept for the idea. An initial enthusiasm caused by positive results from early clinical trials has been dampened by the recognition of scientific irregularities. At the same time, the safety issue for cell-based therapy has been highlighted by the appearance of new and comprehensive regulatory demands. The influence on the cost effectiveness, the clinical relevance and the future perspectives of the present clinical approach are discussed.
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Affiliation(s)
- Søren Gräs
- Department of Obstetrics and Gynecology, Copenhagen University Hospital, Herlev, Denmark.
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Abstract
Stress urinary incontinence (SUI) is highly prevalent. As of now, there is no minimally invasive long-term treatment available. Adult stem cells are nonimmunogenic and have the ability to self-renew and to differentiate into multiple cell types. Over the past decade, in vivo studies have described periurethral injections of adult-derived stem cells for the treatment of SUI. The ultimate goal has been to achieve a permanent cure for SUI by restoration of the intrinsic and extrinsic urethral sphincter and the surrounding connective tissue, including peripheral nerves and blood vessels. For this purpose, future studies need to focus on delivery systems, cell survival, and functional improvement of the urethral closure mechanism, including improvement of innervation and vascularization.
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Affiliation(s)
- Andrea Staack
- UCLA School of Medicine, 200 Medical Plaza, Suite 240, Los Angeles, CA 90095 USA
| | - Larissa V. Rodríguez
- UCLA School of Medicine, 200 Medical Plaza, Suite 240, Los Angeles, CA 90095 USA
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Kim SO, Na HS, Kwon D, Joo SY, Kim HS, Ahn Y. Bone-marrow-derived mesenchymal stem cell transplantation enhances closing pressure and leak point pressure in a female urinary incontinence rat model. Urol Int 2010; 86:110-6. [PMID: 20689260 DOI: 10.1159/000317322] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Accepted: 06/18/2010] [Indexed: 12/15/2022]
Abstract
PURPOSE The purpose of this study was to determine whether periurethral injection of allogenic mesenchymal stem cells (MSCs) could increase the leak point pressure (LPP) in a rat model of stress urinary incontinence. MATERIALS AND METHODS Female Sprague-Dawley rats (230-240 g, n = 30) were divided into 3 groups: sham operation (group C), saline-treated (group S) and MSC-treated (group M). Bilateral pudendal nerve dissection followed by normal saline or MSC injection on both sides of the urethra was done. LPP and closing pressure (CP) testing was performed after the treatment. The specific markers for smooth muscle cells in the transplantation sites of the urethra were determined. RESULTS Both the LPP and CP were significantly lower in group S than controls. However, these were restored to the control values in group M (p < 0.05). The LPPs of groups C, S and M were 29.1 ± 2.1, 22.0 ± 2.2 and 43.1 ± 3.2 cm H(2)O, respectively. The CPs of groups C, S and M were 27.1 ± 3.1, 21.1 ± 3.2, and 32.1 ± 2.1 cm H(2)O, respectively. The injected MSCs stained positive for muscle-specific markers. CONCLUSION This study suggests that MSCs might differentiate into muscle lineage cells and may contribute to the repair of damaged muscle tissue.
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Affiliation(s)
- Sun-Ouck Kim
- Department of Urology, Chonnam National University Medical School, Gwangju, Republic of Korea
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Reconstitution of experimental neurogenic bladder dysfunction using skeletal muscle-derived multipotent stem cells. Transplantation 2010; 89:1043-9. [PMID: 20150836 DOI: 10.1097/tp.0b013e3181d45a7f] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND.: Postoperative neurogenic bladder dysfunction is a major complication of radical hysterectomy for cervical cancer and is mainly caused by unavoidable damage to the bladder branch of the pelvic plexus (BBPP) associated with colateral blood vessels. Thus, we attempted to reconstitute disrupted BBPP and blood vessels using skeletal muscle-derived multipotent stem cells that show synchronized reconstitution capacity of vascular, muscular, and peripheral nervous systems. METHODS.: Under pentobarbital anesthesia, intravesical pressure by electrical stimulation of BBPP was measured as bladder function. The distal portion of BBPP with blood vessels was then cut unilaterally (experimental neurogenic bladder model). Measurements were performed before, immediately after, and at 4 weeks after transplantation as functional recovery. Stem cells were obtained from the right soleus and gastrocnemius muscles after enzymatic digestion and cell sorting as CD34/45 (Sk-34) and CD34/45 (Sk-DN). Suspended cells were autografted around the damaged region, whereas medium alone and CD45 cells were transplanted as control groups. To determine the morphological contribution of the transplanted cells, stem cells obtained from green fluorescent protein transgenic mouse muscles were transplanted into a nude rat model and were examined by immunohistochemistry and immunoelectron microscopy. RESULTS.: At 4 weeks after surgery, the transplantation group showed significantly higher functional recovery ( approximately 80%) than the two controls ( approximately 28% and 24%). The transplanted cells showed an incorporation into the damaged peripheral nerves and blood vessels after differentiation into Schwann cells, perineurial cells, vascular smooth muscle cells, pericytes, and fibroblasts around the bladder. CONCLUSION.: Transplantation of multipotent Sk-34 and Sk-DN cells is potentially useful for the reconstitution of damaged BBPP.
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Effect of myogenic stem cells on contractile properties of the repaired and unrepaired transected external anal sphincter in an animal model. Obstet Gynecol 2010; 115:815-823. [PMID: 20308844 DOI: 10.1097/aog.0b013e3181d56cc5] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To estimate the effect of myogenic stem cells on contractile function of the external anal sphincter after transection with or without repair in an animal model. METHODS One hundred twenty virginal female rats were randomly assigned to repair (n=60) or no repair (n=60) after anal sphincter transection. Animals were further divided into two groups: 40-microliter injection at the transection site with either phosphate-buffered solution (control) or myogenic stem cells (3.2x10 cells). Animals were killed at 7, 21, or 90 days, and the anal sphincter complex dissected and analyzed for contractile function. RESULTS Contractile function of the external anal sphincter was severely impaired 7 days after sphincter transection with or without repair. Twitch tension, maximal tetanic contraction, and maximal contractile force in response to electrical field stimulation improved significantly with time after sphincter repair. Injection of myogenic stem cells in the anal sphincter at the time of repair resulted in superior contractile function at both 7 days and 90 days compared with controls. Interestingly, contractile function of the nonrepaired external anal sphincter did not improve with time with or without myogenic stem cells. Indicators of denervation (fatigue and twitch or tetany ratios) did not change among groups. CONCLUSION In this animal model, injection of myogenic stem cells at the time of external anal sphincter repair resulted in enhanced contractile function at 90 days compared with repair alone. Without repair, function of the external anal sphincter was not improved by stem cell therapy at any time point. These results suggest that addition of myogenic stem cells improves both acute and long-term function of the external anal sphincter after mechanical injury.
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Lorenzi B, Pessina F, Lorenzoni P, Urbani S, Vernillo R, Sgaragli G, Gerli R, Mazzanti B, Bosi A, Saccardi R, Lorenzi M. Treatment of experimental injury of anal sphincters with primary surgical repair and injection of bone marrow-derived mesenchymal stem cells. Dis Colon Rectum 2008; 51:411-20. [PMID: 18224375 DOI: 10.1007/s10350-007-9153-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2007] [Revised: 07/16/2007] [Accepted: 08/25/2007] [Indexed: 12/15/2022]
Abstract
PURPOSE Sphincter injury is a common cause of anal incontinence. Surgical repair remains the operation of choice; however, the outcome often is poor. We investigated the ability of injected bone marrow-derived mesenchymal stem cells to enhance sphincter healing after injury and primary repair in a preclinical model. METHODS Twenty-four inbred Wistar Furth rats were divided into three groups. As a control, Group A underwent sham operation. Group B had sphincterotomy and repair of both anal sphincters plus saline injections. The study group (Group C) underwent sphincterotomy and repair followed by intrasphincteric injections of syngenic bone marrow-derived mesenchymal stem cells. A further group (Group D) of outbred Wistar rats treated with mesenchymal stem cells and immunosuppressive therapy also was evaluated. At 30 days, histologic and morphometric analysis and in vitro contractility testing was performed. RESULTS A significant decrease of muscle tissue was observed at the site of repair after sphincter injury. However, in Groups C and D, histologic examination demonstrated new muscle fibers and morphometric analysis revealed a significantly greater muscle area fraction than in Group B (P < 0.05). Moreover, mesenchymal stem cells injection improved contractility of sphincters strips compared with Group B (P < 0.05). No significant differences were found between Groups C and D. CONCLUSIONS In our experimental model, bone marrow-derived mesenchymal stem cells injection improved muscle regeneration and increased contractile function of anal sphincters after injury and repair. Therefore, mesenchymal stem cells may represent an attractive tool for treating anal sphincter lesions in humans. Investigations into the biologic basis of this phenomenon should increase our knowledge on underlying mechanisms involved in sphincter repair.
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Affiliation(s)
- Bruno Lorenzi
- Department of Surgery, University of Siena, Viale Bracci, 53100 Siena, Italy.
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