Advanced Drug Delivery Reviews 82–83 (2015) 117–122

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Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr

Potential of stem cell treatment in detrusor dysfunction☆ Karl-Erik Andersson ⁎ WFIRM, Wake Forest University School of Medicine, Winston Salem, NC, USA AIAS, Aarhus Institute for Advanced Sciences, Aarhus University, Aarhus, Denmark

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a b s t r a c t The current treatments of bladder dysfunctions, such as bladder overactivity and impaired ability to empty, have limitations, and new treatment alternatives are needed. Stem cell transplantation and tissue engineering have shown promising results in preclinical studies. Stem cells were originally thought to act by differentiating into various cell types, thereby replacing damaged cells and restoring functional deficits. Even if such a mechanism cannot be excluded, the current belief is that a main action is exerted by the stem cells secreting bioactive factors that direct other stem cells to the target organ. In addition, stem cells may exert a number of other effects that can improve bladder dysfunction, since they may have antiapoptotic, antifibrotic, and immunomodulatory properties, and can induce neovascularization. Tissue engineering for bladder replacement, which has had varying success in different animal species, has reached the proof-of-concept state in humans, but recent research suggests that the present approaches may not be optimal. Further studies on new approaches, using animal models with translational predictability, seem necessary for further progress. © 2014 Elsevier B.V. All rights reserved.

Available online 23 October 2014 Keywords: Overactive bladder Bladder outflow obstruction Regenerative medicine Tissue engineering Mesenchymal stem cells Mechanism of action

Contents 1. Introduction . . . . . . . . . . . 2. Stem cell sources . . . . . . . . . 3. Mechanisms of stem cell actions . . 4. Stem cells in bladder dysfunction. . 5. Stem cell use in bladder engineering 6. Conclusions . . . . . . . . . . . References . . . . . . . . . . . . . .

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1. Introduction Bladder dysfunctions, such as bladder over- and underactivity, are common clinical conditions caused by a spectrum of disorders with different pathophysiologies. A common functional disturbance is the overactive bladder syndrome (OAB) with or without associated detrusor overactivity (DO) [1], and many recent studies have focused on the inability to empty the bladder (UAB) [2–4]. There are many relatively effective alternatives for the treatment of OAB [5], but none for UAB [2,3]. Therapies that target the pathophysiologies of OAB/UAB, being curative or aiming at restoring function ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Regenerative Medicine Strategies in Urology”. ⁎ AIAS, Aarhus Institute of Advanced Studies, Aarhus University, Høegh-Guldbergs Gade 6B, Building 1632, 8000 Aarhus C, Denmark. Tel.: +45 510 717 3765. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.addr.2014.10.017 0169-409X/© 2014 Elsevier B.V. All rights reserved.

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and halting progression, are currently not available. Treatment of bladder dysfunction using stem cell transplantation and tissue engineering, may have the potential to overcome the limitations of current treatments. This short review is focusing on the possible mechanisms of action of stem cells from different sources, on the preclinical application of stem cell treatment of various types of bladder dysfunction, and on the clinical use of stem cells for bladder tissue engineering.

2. Stem cell sources Among the 4 main broad categories of stem cells (embryonic stem cells, amniotic fluid or placenta derived stem cells, induced pluripotent stem cells, adult stem cells), only adult stem cells i.e., bone marrowderived stem cell (BM-MSCs), adipose-derived stem cells (ADSCs), and skeletal muscle-derived stem cells or muscle precursor cells (Sk-MSCs), seem to have been used in experimental studies to

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treat bladder dysfunctions. Human urine-derived stem cells (USCs) were shown to be able to differentiate into various lineages, e.g., endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic and neurogenic, which implies the possibility of using them for urological applications, including reconstruction [6,7]. All MSCs, including BM-MSCs, ADSCs and Sk-MSCs exhibit similar biological properties and capabilities, however, their availability differs depending on the therapeutic purpose. For example, while BM-MSCs and Sk-MSCs require a long expansion time with complicated isolation procedures, ADSCs are easily available and can be prepared within hours. BM-MSCs are rare in bone marrow, and harvesting these cells can induce significant morbidity to patients [8]. Mesenchymal stem cells (MSCs) are pluripotent, non-hematopoeitic, stromal cells that differentiate into various cell types, including myocytes, osteoblasts, chondrocytes, adipocytes, and neurons [9,10]. They have properties which make them suited both for cellular therapies and tissue engineering, and as vehicles for gene and drug delivery [9,10]. Among their potentially useful properties are ability to e.g., differentiate to replace damaged cells, recruit endogenous progenitor cells, reduce inflammation, prevent fibrosis, promote angiogenesis [9–11]. MSCs hold niche specificity, i.e., the microenvironment and the factors that control it (the niche) is specific, implying that MSCs from different tissues require different niches for differentiation [12]. MSCs also have different gene expression profiles [13]. This means that a certain type of MSCs can be more appropriate than others for treating a particular dysfunction, such as bladder dysfunction, since they may have the potential to differentiate and secrete bioactive factors relevant to the target organ [14]. Muscle precursor cells (MPCs) or Sk-MSCs, which are predecessors of satellite cells, are considered not to be restricted to myogenic or mesenchymal tissues [15,16]. The main advantage of Sk-MSCs is that they are a source of autologous transplantation and can be obtained relatively easily and safely during surgery. Tamaki et al. [17,18] showed, in a mouse model of severe skeletal muscle damage, that after transplantation of Sk-MSCs by differentiation into skeletal muscle cells, vascular cells (vascular smooth muscle cells, pericytes, and endothelial cells), and peripheral nervous cells (Schwann cells and perineurium), could cause significant functional recovery. ADSCs are mesenchymal stromal cells found in the perivascular space of adipose tissue. They have the advantage of abundant and easy access when compared with other stem cell types [19]. They express similar stem cell surface markers and differentiation potentials similar to those of MSCs [19], and have been shown to have efficacy in preclinical studies of detrusor dysfunction [20–22]. 3. Mechanisms of stem cell actions The mechanisms by which stem cells may act include differentiation, migration and homing, and paracrine effects [23,24]. The therapeutic efficacy of stem cells was originally thought to derive from their ability to differentiate into various cell types. Several studies have shown that stem cells isolated from the embryo, bone marrow, amniotic fluid and adipose tissue can differentiate into “bladder” smooth muscle cells, and also that ADSCs and BM-SCs can differentiate into urothelial cells [25,26]. However, it should be pointed out that the evidence presented in most of these studies was based on the detection of smooth muscle or urothelial markers in cultured stem cells that were maintained in certain conditioned media or co-cultured with native bladder cells. The few in vivo studies that presented evidence of smooth muscle differentiation in the bladder should also be interpreted with caution. Nitta et al. [27] reported on the reconstitution of neurogenic bladder dysfunction with skeletal muscle derived stem cells (Sk-MSCs), in which several different cell types including Schwann cells, perineurial cells and pericytes were suggested to have been differentiated from the transplanted cells. A large body of literature exists concerning the roles of recruited stem cells in a number of different organ systems, including injured bladders [22,28,29]. Several investigators [14,30,31] have suggested that

differentiation may not be a main mechanism of action, and there seems to be reasonable evidence to assume that paracrine release of cytokines and growth factors by transplanted MSCs or their neighboring cells can be responsible for observed effects [14]. Most probably the differentiation pathway plays a minor role in the therapeutic effect exerted by stem cell transplantation. It has been shown that MSCs possess migratory capacity. When transplanted systemically, they can be home to sites of injury, possibly in response to signals that are upregulated under injury conditions [32], such as inflammation, ischemia, or local damage. In this regard, secretory factors from the MSCs have been shown to exert therapeutic effects by the modulation of local and systemic inflammatory responses, stimulation of local tissue regeneration, and/or recruitment of host cells [10]. Thus, MSCs themselves may not be able to substitute damaged cells directly, but by the secretion of growth factors that contribute to reducing e.g., fibrosis through paracrine mechanisms. Supporting the importance of paracrine factors, Albersen et al. [20] found that penile injection of both ADSC and ADSC-derived lysate could improve the recovery of erectile function in a rat model of neurogenic ED. BM-MSCs or ADSCs have been demonstrated to secrete many growth factors, including hepatic growth factor, nerve growth factor, brain-derived growth factor, glial-derived growth factor, insulin-like growth factor, and vascular endothelial growth factor [33]. BM-MSCs may play an essential part in the antifibrosis effects in injured organs. This is managed by paracrine mechanisms rather than by cell incorporation [29]. For example, hepatic growth factor secreted by MSCs, plays an essential part in the angiogenesis and regeneration of tissues, and acts as a potent antifibrotic agent [29]. BM-MSCs and ADSCs may also provide antioxidant chemicals, free radical scavengers and heat shock proteins in ischemic tissue [10,34]. 4. Stem cells in bladder dysfunction Studies of stem cells injected into the bladder have demonstrated positive effects in experimental voiding dysfunctions such as detrusor overactivity with or without bladder outflow obstruction (BOO). Huang et al. [21] studied the effects of adipose derived stem cells injected into the bladder or the tail vein of healthy male rats where hyperlipidemia was induced by a high fat diet. They found that the diet made the rats obese, that the bladder wall content of smooth muscle and nerves decreased, and that urodynamically the micturition interval was shortened. This was assumed to be caused by reduced bladder blood flow. Compared to rats injected with saline, animals receiving stem cells had improved blood vessel and nerve density, and a reduction of micturition frequency. Since tracking of the cells using EdU (5-ethynyl-2′-deoxyuridine) revealed a sparse staining, the authors concluded that the therapeutic effect “was likely mediated primarily by paracrine release of cytokines and growth factors”. Chen et al. [35] evaluated the feasibility and effectiveness of using BM-MCs in the treatment of chronic ischemia-induced bladder detrusor dysfunction in an experimental rat model. The cells were injected into the common iliac artery and then the iliac arteries were ligated bilaterally and doxazosin mesylate was administered intragastrically. Eight weeks later, urodynamic and histologic examinations were performed on experimental animals. Both urodynamically and morphologically the cell treated animal were improved and the authors concluded that transplanted stem cells could regenerate in the bladder tissue, increase the percentage of smooth muscle content and nerve cells, and improve bladder detrusor contraction function. Since α-adrenoceptor blockade by itself has similar positive effects on the ischemic bladder, it may not be possible to attribute the effects demonstrated only to the injected cells [36,37]. Zhang et al. [38] determined the efficacy of and mechanisms by which ADSCs, injected into the detrusor or via tail vein, may ameliorate diabetes induced bladder dysfunction in rats fed with a high-fat diet and treated with low-dose streptozotocin to induce type II diabetes. By

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cystometry they could demonstrate that 1 month after ADSC injection, all the rats in a diabetes + saline (detrusor injection) group had abnormal voiding, whereas only 60% in a diabetes + tail vein injection and 40% diabetes + detrusor injection groups, had voiding dysfunction. For tracking the ADSCs, EdU labeling was used, and it was demonstrated that EdU-expressing ADSCs were predominantly localized in the lamina propria. Since some of the EdU-positive nuclei appeared to reside within cells expressing smooth muscle actin, it was suggested that a small fraction of the transplanted ADSCs may have differentiated into SMCs. Based on this finding, the authors suggested that paracrine release of cytokines and growth factors by transplanted ADSCs or their neighboring cells were responsible for the observed effects. Nitta et al. [27] disrupted the bladder branch of the pelvic plexus (BBPP) and attempted to reconstitute the nerves and blood vessels using Sk-MSCs obtained from the right soleus and gastrocnemius muscles after enzymatic digestion and cell sorting. Autologous cells were used for transplantation around the damaged region, and medium alone and CD45 cells served as control groups. Stem cells obtained from green fluorescent protein (GFP) transgenic mouse muscles were transplanted into a nude rat model in order to determine the morphological contribution of the transplanted cells. Assessment of bladder function was performed by measuring intravesical pressure after electrical stimulation of the BBPP. Comparing the data obtained at 4 weeks after surgery, the transplantation group showed significantly higher functional recovery (78%) than the two controls (28% and 24%). Numerous GFP positive donor-derived cells were demonstrated around the bladder neck and surrounding tissues, and GFP positive nerve-like tissues, assumed to be regenerated nerves, were found on the recipient bladder surface. GFP positive cells were also found to be incorporated into blood vessels and in the damaged BBPP after differentiation into Schwann cells and perineurium, vascular smooth muscle, and pericytes. These results seem to be very promising, but need confirmation. Most studies on the effects of stem cells on bladder dysfunction have been performed on the rat BOO model. Four weeks after producing BOO in rats, Nishijima et al. [20] relieved the obstruction and then injected bone marrow cells from GFP transgenic rats (n = 6; cells not characterized for stem cell properties) or culture medium (control, n = 6) into the bladder walls of normal female rats. Another 4 weeks later the rats were sacrificed and the authors were able to demonstrate (isovolumetric cystometry) improved bladder contractility compared to that found in untreated, obstructed rats. They also observed GFP cells in bladder smooth muscle tissue, and concluded that the transplanted bone marrow cells improved contractility by differentiating into “smooth muscle-like” cells. Since it has been shown that after the relief of obstruction in the rat BOO model, up to 80% of the animals recover without treatment [39,40], it is remarkable, considering the small number of animals investigated, that clear differences could be demonstrated. Woo et al. [22] induced BOO in mice and 3 days after operation BMSCs were injected intravenously. After 4 weeks, mice with BOO showed smooth muscle hypertrophy of the detrusor on hematoxylin and eosin staining, and increased collagen deposition between muscle fascicles on Masson's trichrome staining compared to controls. In twothirds of the BOO plus MSC group bladder architecture more closely resembled that in controls with decreased hypertrophy and fibrosis. Immunohistochemical staining revealed GFP positive MSCs in the bladder of 10 out of 15 mice that survived to evaluation. MSCs were identified in the detrusor compartment of bladder specimens, but were not observed in skin, lung or kidney samples. Song et al. [41] induced BOO in 6-week old female rats and injected after 4 weeks of obstruction a single injection of adipose-derived MSCs labeled with GFP, or saline, into the bladder, or were given solifenacin intravenously daily for 2 weeks. Two or 4 weeks later cystometry and histological studies were performed. In the MSC treated group urodynamic parameters improved more than in animals given solifenacin. Cell-treated rats also improved morphologically, but no

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signs of tissue engraftment were found. The authors suggested unleashing/mobilizing primitive endogenous cells as a novel mechanism for the paracrine effect of MSCs, and suggested that this could explain their long-term stable therapeutic efficacy. Lee et al. [28] investigated if human mesenchymal stem cells (MSCs) are capable of inhibiting collagen deposition and improving cystometric parameters in rats with BOO. They labeled human MSCs with nanoparticles containing superparamagnetic iron oxide (SPION), and 2 weeks after induction of BOO the cells were injected into the bladder wall. MR images were taken immediately after transplantation and at 4 week posttransplantation. The MR images showed a clear hypointense signal located in the bladder induced by the SPION-labeled MSCs. The expression of collagen and TGF-β protein increased after BOO, but returned to the original levels after MSC transplantation. Maximal voiding pressure and residual urine volume increased after BOO, but they recovered after MSC transplantation. The authors concluded that MSCs transplanted in rat BOO models inhibited bladder fibrosis and mediated recovery of bladder dysfunction. The same group [29], examined the capability of human MSCs overexpressing hepatic growth factor to inhibit collagen deposition in the rat model of bladder BOO. As mentioned, hepatic growth factor is known for its antifibrotic effect and the most promising agent for treating bladder fibrosis. Two weeks after the onset of BOO, hepatic growth factor cells were injected into the bladder wall, and after 4 weeks, bladder tissues were harvested and Masson's trichrome staining was performed. The mean bladder weight in BOO rats was 5.8 times that of normal controls, while in animals grafted with hepatic growth factor cells, the weight was lowered to four times of the control. The mean percentage of collagen area increased in BOO rats, while in the animals transplanted with hepatic growth factor cells, the collagen area decreased to the normal control level. The expression of collagen and TGF-β protein increased after BOO, while the expression of HGF and c-met protein increased in the group with hepatic growth factor cell transplantation. Inter-contraction interval decreased after BOO, but it recovered after hepatic growth factor cell transplantation. Maximal voiding pressure increased after BOO, and it recovered to levels of the normal control after transplantation. Residual urine volume increased after BOO, but was not reversed by transplantation. It is obvious that stem cell treatment can affect the remodeling of the bladder that occurs after the initiation of obstruction in the rat BOO model, and that this treatment may have a beneficial effect against both morphological and functional changes. In many of the studies cited, the authors speculated on the use of MSCs as a new treatment to prevent the morphological and functional effects of BOO in humans. However, assuming that MSC treatment has positive effects also in human BOO, relevant questions are 1) when should treatment be instituted? 2) can cell therapy reverse established morphological changes? In most of the BOO studies cited above, stem cells were given early on in the remodeling process initiated by the urethral obstruction, i.e., at times points when the process is still dynamic. Studies on the clinical application of MSCs in humans with various diseases are available, including orthopedic injuries, graft versus host disease following bone marrow transplantation, cardiovascular diseases, autoimmune diseases, and liver diseases [42]. However, the effects of stem cell therapy for bladder dysfunction, e.g., in patients with OAB, BOO associated DO, or in patients with UAB have so far not been published. 5. Stem cell use in bladder engineering Use of tissue engineering as a possibility to overcome the disadvantages of currently used approaches for bladder replacement or repair, has been suggested by several investigators [43–47]. Organ or tissue reconstruction by tissue engineering uses two major approaches, one involving either natural or synthetic biomaterials that encourage the in vivo regenerative process by serving as a solid support

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matrix (scaffold) for the in-growth of native cells. The other involves biomaterials with a cell seeded approach that utilizes autologous sources of patient cells and where the newly created tissue is transplanted back to the host for the completion of the regeneration process. Stem cells, endogenous or exogenous, are necessary for both approaches. Tissue engineering has been largely focused on the construction of bladder wall for augmentation, and many strategies have utilized free (scaffold-free) grafts from engineered cells, as well as grafts with scaffolds with and without cell seeding. Although many researchers have been able to demonstrate the formation of engineered tissue with a structure similar to that of native bladder tissue, restoration of physiologic voiding using these constructs has not been demonstrated. The main reasons for this may be that development of proper innervation, vascularization, and correct muscle alignment has not been obtained [46]. Cell-seeded scaffolds are thought to provide better outcomes than bare scaffolds, for which tissue regeneration is dependent on in growth of the surrounding tissue [44,48], however, this was questioned in a systematic review of publications in the field [49], showing that acellular and cellular constructs resulted in similar final bladder volumes after augmentation. The concept of utilizing endogenous cells for in situ tissue regeneration has gained increasing interest [59]. Although validated, the classical tissue engineering strategy, which involves extensive cell expansion steps, is time-consuming and requires laborious efforts before implantation. In order to bypass this ex vivo process, Ko et al. [50] suggested use of the body's own regenerating capacity by mobilizing host endogenous stem cells or tissue-specific progenitor cells to the site of injury. This approach was considered to hold great potential to provide new therapeutic options for functional tissue regeneration. However, to be successful, it relies on development of a target-specific biomaterial scaffolding systems that can create an appropriate microenvironment, direct cells to the target sites, and guide them to proliferate and differentiate into the cell type of interest. The main requirements for producing an engineered tissue are the presence of adequate stem/progenitor cells, an appropriate extracellular matrix or carrier construct, an adequate blood supply, and the presence of regulatory signals. The tissue engineering approach to urinary bladder regeneration requires a favorable environment. The source of cells in cell-seeded scaffolds can be from an autologous, allogeneic, or heterologous (xenogeneic) source. The best option is to use autologous cells in order to eliminate the risk of rejection [51]. BM-SCs seeded on small intestinal submucosa (SIS) facilitated the regeneration of partially cystectomized bladder [52–54]. Hair SCs and ADSCs seeded on bladder acellular matrix (BAM) have demonstrated the potential to regenerate bladder [55–57]. Stem cells are effective not only in SIS or BAM but also as part of synthetic scaffolds. Sharma et al. [58] reported that BM-SCs seeded on poly (1,8-octanediol-co-citrate) thin film supported partial bladder regeneration. Tian et al. [26] showed that myogenically differentiated BM-SCs seeded on poly-llactic acid scaffold exhibited bladder engineering potential. A synthetic material of poly-lactic-glycolic acid seeded with myogenically differentiated human ADSC showed the recovery of bladder capacity and compliance when grafted in hemi-cystectomized rats [59]. Some promising results in the preclinical research on the use of stem cells and biomaterials in the regeneration of urinary tissues have been obtained [49], which motivated the approach to be applied in humans. Atala et al. [43] were the first to use autologous bladder biopsyderived cells for bladder replacement in myelomeningocele patients with high-pressure or poorly compliant bladders. After growing and expanding urothelial and muscle cells in culture, the urothelial cells were seeded on the inside and the muscle cells on the outside of a biodegradable bladder-shaped scaffold made of collagen or a composite of collagen and polyglycolic acid. The autologous engineered bladder constructs were used for reconstruction and implanted either with or without an omental wrap about 7 weeks after the biopsy. An improved

bladder function could be demonstrated over 5 years after cystoplasty. Biopsies from the engineered bladder showed an adequate structural architecture and phenotype. Caione et al. [60] performed bladder augmentation using acellular SIS in 5 patients with poor bladder capacity and compliance after complete extrophy repair. They found that bladder capacity and compliance increased when studied after 6 and 18 months. Biopsies from the bladders showed decreased muscle/ collagen ratio compared to normal controls. These pilot studies evoked high expectations. However, negative experiences were reported by Joseph et al. [61], who performed a phase II prospective study in children with neurogenic bladder due to spina bifida requiring enterocystoplasty for detrusor pressure 40 cm H2O or greate, despite maximum antimuscarinic medication. Following open bladder biopsy, urothelial and smooth muscle cells were grown ex vivo and seeded onto a biodegradable scaffold to form a regenerative augment as the foundation for bladder tissue regeneration. Primary and secondary outcomes at 12 months included change in bladder compliance, bladder capacity and safety. Long-term assessment was done with similar outcomes at 36 months. It was found that compliance improved in 4 patients at 12 months and in 5 patients at 36 months, although the difference was not clinically or statistically significant. There was no clinical or statistical improvement in bladder capacity at 12 or 36 months in any patient. Adverse events occurred in all patients and serious adverse events such as bowel obstruction and/or bladder rupture occurred in 4 patients. The authors concluded that their autologous cell seeded biodegradable scaffold did not improve bladder compliance or capacity, and that serious adverse events surpassed an acceptable safety standard. The reasons for the discrepancy in results between the study of Atala et al. [43] and that of Joseph et al. [61] are not known and the difference in results is somewhat surprising since the studies were similar in design and used the same cell types, omental wrapping and bladder cycling techniques. In a systematic review of preclinical studies in the current literature, Sloff et al. [49] evaluated the potential of tissue engineering of the bladder, and compared the outcomes with the available clinical evidence. The preclinical studies included showed a remarkable heterogeneity in characteristics and design, but the authors found that bladder augmentation through tissue engineering resulted in a normal bladder volume in healthy animals. Furthermore, experiments in large animal models (pigs and dogs) approximated the desired bladder volume more accurately than in smaller species. The authors found that the initial clinical experiences were based on seemingly predictive healthy animal models with a promising outcome. However, the positive findings in preclinical studies were not confirmed in the clinical trials, which may be explained by the patients having neuropathic bladders. They therefore concluded that the translational predictability of a model with healthy animals might be questioned, and that even if preclinical research in healthy animals show the feasibility of bladder augmentation by tissue engineering, new approaches should also be evaluated in models with dysfunctional/diseased bladders.

6. Conclusions Stem cells for the treatment of bladder dysfunction still awaits clinical application, but it is clear that the preclinical experiences seem promising and suggest that stem cells can e.g., affect the remodeling of the bladder that occurs after initiation of obstruction in the rat BOO model and prevent both morphological and functional changes. However, the translational value of results from the models used for testing this approach remains to be established. Stem cells, endogenous or exogenous, are necessary for organ or tissue reconstruction by tissue engineering. Bladder augmentation by tissue engineering is feasible, as shown both in preclinical models and patients, but so far the clinical success has not been convincing. Further

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studies on new approaches, using animal models with translational predictability, are necessary for further progress. [29]

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Potential of stem cell treatment in detrusor dysfunction.

The current treatments of bladder dysfunctions, such as bladder overactivity and impaired ability to empty, have limitations, and new treatment altern...
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