Stemcell Research & Evidence - Urologic Conditions
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Roles of mesenchymal stem cells and exosomes in interstitial cystitis/bladder pain syndrome
J Cell Mol Med. 2022 Feb;26(3):624-635.
Source
Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by several symptoms of higher sensitivity of the lower urinary tract, such as bladder pain/discomfort, urgency, urinary frequency, pelvic pain and nocturia. Although the pathophysiology of IC/BPS is not fully understood, the hypothesis suggests that mast cell activation, glycosaminoglycan (GAG) layer defects, urothelium permeability disruption, inflammation, autoimmune disorder and infection are potential mechanisms. Mesenchymal stem cells (MSCs) have been proven to protect against tissue injury in IC/BPS by migrating into bladders, differentiating into key bladder cells, inhibiting mast cell accumulation and cellular apoptosis, inhibiting inflammation and oxidative stress, alleviating collagen fibre accumulation and enhancing tissue regeneration in bladder tissues. In addition, MSCs can protect against tissue injury in IC/BPS by secreting various soluble factors, including exosomes and other soluble factors, with antiapoptotic, anti-inflammatory, angiogenic and immunomodulatory properties in a cell-to-cell independent manner. In this review, we comprehensively summarized the current potential pathophysiological mechanisms and standard treatments of IC/BPS, and we discussed the potential mechanisms and therapeutic effects of MSCs and MSC-derived exosomes in alleviating tissue injury in IC/BPS models.
Extracellular vesicles derived from mesenchymal stem cells alleviate neuroinflammation and mechanical allodynia in interstitial cystitis rats
J Neuroinflammation. 2022 Apr 6;19(1):80.
Chi Zhang, Yong Huang, Fubing Ouyang, Minzhi Su, Wenbiao Li, Jialiang Chen, Hengjun Xiao, Xiangfu Zhou, Bolong Liu
Source
Department of Urology, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China.
Abstract
Background: Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation.
Methods: Female IC rat model was established by intraperitoneal injection of cyclophosphamide (50 mg/kg, every 3 days for 3 doses). Inhibition of NLRP3 inflammasome was performed by intraperitoneal injection of MCC950 (10 mg/kg). MSC-EVs were isolated from the culture supernatants of human umbilical cord derived MSCs using ultracentrifugation, and then injected intrathecally into IC rats (20 μg in 10 μl PBS, every other day for 3 doses). Suprapubic mechanical allodynia was assessed using up-down method with von Frey filaments, and micturition frequency was examined by urodynamics. The expression of NLRP3 inflammasome components (NLRP3 and Caspase-1), glial cell markers (IBA-1 and GFAP), proinflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-18) and TLR4/NF-κB signal pathway (TLR4, p65 NK-κB and phospho-p65 NK-κB) in L6-S1 SDH was measured by Western blot analysis. The cellular localization of NLRP3 in SDH was detected using immunofluorescence co-staining.
Results: NLRP3 inflammasome was activated in neurons in SDH of IC rats. NLRP3 inflammasome activation contributed to activation of glial cells and process of spinal neuroinflammation in IC rats, and was related to suprapubic mechanical allodynia and frequent micturition. Intrathecal injection of MSC-EVs alleviated suprapubic mechanical allodynia and frequent micturition in IC rats, restrained activation of glial cells and attenuated neuroinflammation in SDH. In addition, MSC-EV treatment significantly inhibited activation of both NLRP3 inflammasomes and TLR4/NF-κB signal pathway.
Conclusions: NLRP3 inflammasome activation is involved in the neuroinflammation of IC. Intrathecal injection of MSC-EVs alleviates neuroinflammation and mechanical allodynia in IC by inhibiting the activation of NLRP3 inflammasome, and TLR4/NF-κB signal pathway may be the potential regulatory target.
Application of Adult and Pluripotent Stem Cells in Interstitial Cystitis/Bladder Pain Syndrome Therapy
J Clin Med. 2020 Mar 12;9(3):766.
Source
Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a multifactorial, chronic disease without definite etiology characterized by bladder-related pelvic pain. IC/BPS is associated with pain that negatively affects the quality of life. There are various therapeutic approaches against IC/BPS. However, no efficient therapeutic agent against IC/BPS has been discovered yet. Urothelium dysfunction is one of the key factors of IC/BPS-related pathogenicity. Stem cells, including adult stem cells (ASCs) and pluripotent stem cells (PSCs), such as embryonic stem cells (ESCs) and induced PSCs (iPSCs), possess the abilities of self-renewal, proliferation, and differentiation into various cell types, including urothelial and other bladder cells. Therefore, stem cells are considered robust candidates for bladder regeneration. This review provides a brief overview of the etiology, pathophysiology, diagnosis, and treatment of IC/BPS as well as a summary of ASCs and PSCs. The potential of ASCs and PSCs in bladder regeneration via differentiation into bladder cells or direct transplantation into the bladder and the possible applications in IC/BPS therapy are described in detail. A better understanding of current studies on stem cells and bladder regeneration will allow further improvement in the approaches of stem cell applications for highly efficient IC/BPS therapy.
Intravital imaging and single cell transcriptomic analysis for engraftment of mesenchymal stem cells in an animal model of interstitial cystitis/bladder pain syndrome
Biomaterials. 2022 Jan;280:121277.
Hwan Yeul Yu, Seungun Lee, Hyein Ju, Youngkyu Kim, Jung-Hyun Shin, HongDuck Yun, Chae-Min Ryu, Jinbeom Heo, Jisun Lim, Sujin Song, Sanghwa Lee, Ki-Sung Hong, Hyung-Min Chung, Jun Ki Kim, Myung-Soo Choo, Dong-Myung Shin
Source
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; ToolGen Inc., Seoul, South Korea.
Abstract
Mesenchymal stem cell (MSC) therapy is a promising treatment for various intractable disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). However, an analysis of fundamental characteristics driving in vivo behaviors of transplanted cells has not been performed, causing debates about rational use and efficacy of MSC therapy. Here, we implemented two-photon intravital imaging and single cell transcriptome analysis to evaluate the in vivo behaviors of engrafted multipotent MSCs (M-MSCs) derived from human embryonic stem cells (hESCs) in an acute IC/BPS animal model. Two-photon imaging analysis was performed to visualize the dynamic association between engrafted M-MSCs and bladder vasculature within live animals until 28 days after transplantation, demonstrating the progressive integration of transplanted M-MSCs into a perivascular-like structure. Single cell transcriptome analysis was performed in highly purified engrafted cells after a dual MACS-FACS sorting procedure and revealed expression changes in various pathways relating to pericyte cell adhesion and cellular stress. Particularly, FOS and cyclin dependent kinase-1 (CDK1) played a key role in modulating the migration, engraftment, and anti-inflammatory functions of M-MSCs, which determined their in vivo therapeutic potency. Collectively, this approach provides an overview of engrafted M-MSC behavior in vivo, which will advance our understanding of MSC therapeutic applications, efficacy, and safety.
Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis
BMB Rep. 2022 May;55(5):205-212.
Source
Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disorder characterized by suprapubic pain and urinary symptoms such as urgency, nocturia, and frequency. The prevalence of IC/BPS is increasing as diagnostic criteria become more comprehensive. Conventional pharmacotherapy against IC/BPS has shown suboptimal effects, and consequently, patients with end-stage IC/BPS are subjected to surgery. The novel treatment strategies should have two main functions, anti-inflammatory action and the regeneration of glycosaminoglycan and urothelium layers. Stem cell therapy has been shown to have dual functions. Mesenchymal stem cells (MSCs) are a promising therapeutic option for IC/BPS, but they come with several shortcomings, such as immune activation and tumorigenicity. MSC-derived extracellular vesicles (MSC-EVs) hold numerous therapeutic cargos and are thus a viable cell-free therapeutic option. In this review, we provide a brief overview of IC/BPS pathophysiology and limitations of the MSC-based therapies. Then we provide a detailed explanation and discussion of therapeutic applications of EVs in IC/BPS as well as the possible mechanisms. We believe our review will give an insight into the strengths and drawbacks of EV-mediated IC/BPS therapy and will provide a basis for further development.
Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis
Stem Cells Transl Med. 2022 Oct 21;11(10):1010-1020.
Jung Hyun Shin, Chae-Min Ryu, Hwan Yeul Yu, Juhyun Park, Ah Reum Kang, Jeong Min Shin, Ki-Sung Hong, Eun Young Kim, Hyung-Min Chung, Dong-Myung Shin, Myung-Soo Choo
Source
Department of Urology, Ewha Womans University, Mokdong Hospital, Seoul, Korea.
Abstract
There are still no definite treatment modalities for interstitial cystitis (IC). Meanwhile, stem cell therapy is rising as potential alternative for various chronic diseases. This study aimed to investigate the safety of the clinical-grade mesenchymal stem cells (MSCs) derived from human embryonic stem cells (hESCs), code name MR-MC-01 (SNU42-MMSCs), in IC patients. Three female IC patients with (1) symptom duration >6 months, (2) visual pain analog scale (VAS) ≥4, and (3) one or two Hunner lesions <2 cm in-office cystoscopy within 1 month were included. Under general anesthesia, participants received cystoscopic submucosal injection of SNU42-MMSCs (2.0 × 107/5 mL) at the center or margin of Hunner lesions and other parts of the bladder wall except trigone with each injection volume of 1 mL. Follow-up was 1, 3, 6, 9, and 12 months postoperatively. Patients underwent scheduled follow-ups, and symptoms were evaluated with validated questionnaires at each visit. No SNU42-MMSCs-related adverse events including immune reaction and abnormalities on laboratory tests and image examinations were reported up to 12-month follow-up. VAS pain was temporarily improved in all subjects. No de novo Hunner lesions were observed and one lesion of the first subject was not identifiable on 12-month cystoscopy. This study reports the first clinical application of transurethral hESC-derived MSC injection in three patients with IC. hESC-based therapeutics was safe and proved to have potential therapeutic efficacy in IC patients. Stem cell therapy could be a potential therapeutic option for treating IC.
Personal cell therapy for interstitial cystitis with autologous stromal vascular fraction stem cells
Ther Adv Urol. 2019 Aug 17;11:1756287219868590.
Source
Cell Surgical Network, 72780 Country Club Drive #301, Rancho Mirage, CA 92270, USA.
Abstract
Background: The objective of this study was to evaluate whether autologous stem-cell-based therapy may mitigate the symptoms of interstitial cystitis.
Methods: Stromal vascular fraction (SVF) rich in stem cells and derived from autologous adipose tissue was deployed into 109 men and women with interstitial cystitis/painful bladder syndrome as a surgical procedure. This stem-cell-rich biologic product was injected both systemically and regionally into pelvic floor targets. Patients were queried about quality of life and symptom and bother subjective outcomes tests every 3 months for 2 years.
Results: A total of 78 patients reported a positive response at 1 year. Symptom and bother metrics were statistically improved at 1 year. There were minimal adverse events associated with the harvesting, procurement, and clinical deployment of SVF.
Conclusion: Interstitial cystitis is a complex clinical problem that is known for its resistance to conventional therapies. SVF as an autologous personalized regenerative strategy shows good safety and efficacy and may potentially have a role in the mitigation of interstitial cystitis.
Periurethral injection of autologous fat for the treatment of sphincteric incontinence
J Urol. 1994 Mar;151(3):607-11.
Source
Squire Urologic Clinic, Columbia-Presbyterian Medical Center, New York, New York.
Abstract
A total of 15 women with stress incontinence and 6 men with post-prostatectomy sphincteric incontinence underwent periurethral injection of autologous fat while under local anesthesia. The fat was harvested from the abdominal wall by liposuction. Preoperative evaluation consisted of a micturition diary, questionnaire, semiquantitative pad test, cystoscopy and urodynamics. Sequential injections were performed at 1 to 3-month intervals. Results were assessed by subjective patient scores, pad tests and clinical evaluation performed at intervals. Followup was 12 to 30 months (mean 18). Only 1 man and none of the women with urethral hypermobility had lasting improvement. Of the 15 women 12 had intrinsic sphincteric deficiency (type 3 stress incontinence) and they were our most successful group. Of the 12 women 10 (83%) were improved (mean score of 8.8-7 before injection compared to 1.87 after injection) at 1 month following the initial injection. Of the 9 patients who continued with the treatment 7 (78%) noticed lasting improvement objectively and subjectively after 1 to 4 injections (mean 2.4). We believe that this technique shows sufficient promise as an alternative therapy for sphincteric incontinence to warrant continued clinical investigation.
Periurethral injection of autologous adipose-derived stem cells for the treatment of stress urinary incontinence in patients undergoing radical prostatectomy
Int J Urol. 2010 Jan;17(1):75-82.
Tokunori Yamamoto, Momokazu Gotoh, Ryohei Hattori, Kazuhiro Toriyama, Yuzuru Kamei, Hideki Iwaguro, Yoshihisa Matsukawa, Yasuhito Funahashi
Source
Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Abstract
Objectives: To report a novel cell therapy using autologous adipose tissue-derived stem cells (ADSC) for stress urinary incontinence caused by urethral sphincteric deficiency and the outcomes in two initial cases undergoing periurethral injection of stem cells for the treatment of urinary incontinence after radical prostatectomy.
Methods: Two patients with moderate stress incontinence after radical prostatectomy were enrolled. After liposuction of 250 mL of adipose tissue from the abdomen, we isolated ADSC from this tissue by using the Celution system. Subsequently, the isolated ADSC and a mixture of stem cells and adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. Short-term outcomes during a 12-week follow-up were assessed by a 24-h pad test, a validated patient questionnaire, urethral pressure profile, transrectal ultrasonography, and magnetic resonance imaging.
Results: Urinary incontinence progressively improved after 2 weeks of injection up to 12 weeks in terms of decreased leakage volume in a 24-h pad test, decreased frequency and amount of incontinence, and improved quality of life as per the questionnaire. In urethral pressure profile, both maximum urethral closing pressure and functional profile length increased. Ultrasonography and magnetic resonance imaging showed sustained presence of the injected adipose tissue. Enhanced ultrasonography showed a progressive increase in the blood flow to the injected area. No significant adverse events were observed peri- and postoperatively.
Conclusion: This preliminary study showed that periurethral injection of the autologous ADSC is a safe and feasible treatment modality for stress urinary incontinence.
Post-TUR-P stress urinary incontinence successfully treated by periurethral injection of autologous fat to the prostate
Hinyokika Kiyo. 1995 Jul;41(7):553-6.
Source
Department of Urology, Tokyo Medical and Dental University School of Medicine.
Abstract
A 77-year-old man had been suffering from stress urinary incontinence for 2 years since he had received transurethral resection of prostate (TUR-P) for benign prostatic hypertrophy. A 60-min pad test yielded 3 g of urine. Prostatic urethra was widely open and the external sphincteric injury was suggested because of the short membraneous urethra on the urethrogram. Urethral pressure profile indicated his maximal urethral closing pressure (MUCP) of 24 cmH2O and functional urethral length of 1.6 cm and cystometry demonstrated an underactive bladder, indicating that his incontinence was caused by sphincteric injury. Autologous fat injection therapy was performed in the lithotomy position under spinal anesthesia. Fifteen ml of subcutaneous fat was obtained from his lower abdomen by liposuction through a 15G needle, and 10 ml was injected submucosally from the perineum at 6 o'clock area of the prostatic apex under the guidance of transrectal echography using a 15G needle. The patient became completely dry after the procedure. MUCP and FUL increased to 35 cmH2O and 1.9 cm, respectively, although longer follow up is necessary. The advantage of autologous fat injection to the prostate for post-TUR-P SUI patients is briefly discussed.
Stem-cell therapy in stress urinary incontinence
Tzu Chi Med J. 2022 Sep 5;35(2):111-119.
Source
Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and Tzu Chi University, Hualien, Taiwan.
Abstract
The incidence of urinary incontinence (UI) is approximately 10%-40% in women, affecting one to two hundred million women worldwide. Stress UI (SUI) is characterized by involuntary urination due to increased abdominal stress and urine leakage without bladder contraction. Surgical treatments include midurethral slings, bulking agents, and Burch colposuspension to restore urethral continence. Nevertheless, an optimal treatment for all types of incontinence has not yet been established. Stem-cell therapy has emerged as a novel treatment for many diseases. Stem cells can self-renew and can differentiate into other cell types. Adult stem cells are suitable for clinical applications because they can be easily obtained noninvasively or minimal invasively. Stem-cell therapy for SUI has been studied preclinically and clinically. Muscle-derived progenitors have been used to treat SUI by promoting the regeneration of rhabdomyosphincters. The human trial used transurethral injection of autologous muscle-derived stem cells to improve sphincter contractility and function. Other sources of stem cells have also been studied in SUI treatment, such as umbilical cord blood, amniotic fluid, bone marrow, urine, and adipose tissue. The success rate of stem-cell therapy for SUI ranges from 13% to 100%. This review aimed to summarize the current status of stem-cell treatments for SUI, with respect to clinical trials, cell types, transplantation routes, and dosage volume and frequency.
Stem Cell Therapy for Male Urinary Incontinence
Urol Int. 2013;90(3):249-52.
Source
Department of Surgery, Division of Urology, San Paolo Hospital, Savona, Italy.
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.