Journal List > Korean J Urol > v.56(4) > 1006253

Alwaal, Hussein, Lin, and Lue: Prospects of stem cell treatment in benign urological diseases

Abstract

Stem cells (SCs) are undifferentiated cells that are capable of self-renewal and differentiation and that therefore contribute to the renewal and repair of tissues. Their capacity for division, differentiation, and tissue regeneration is highly dependent on the surrounding environment. Several preclinical and clinical studies have utilized SCs in urological disorders. In this article, we review the current status of SC use in benign urological diseases (erectile dysfunction, Peyronie disease, infertility, and urinary incontinence), and we summarize the results of the preclinical and clinical trials that have been conducted.

INTRODUCTION

Stem cells (SCs) are undifferentiated cells that are capable of self-renewal and differentiation and that therefore contribute to the renewal and repair of tissues [1]. Their capacity for division, differentiation, and tissue regeneration is highly dependent on the surrounding environment [1]. SCs are difficult to classify owing to a lack of defined morphologic and molecular characteristics. However, they can be classified according to their differentiation potential as follows [2]:
(1) Totipotent SCs: These SCs have the highest potential and can differentiate into any tissue type, regardless of origin. The zygote and morula are examples of this SC type.
(2) Pluripotent SCs: These SCs can differentiate into cells from the 3 different germ cell layers and gonadal ridge but not into extra-embryonic tissues. An example is embryonic SCs (ESCs), which are a derivative of the inner cell mass of the blastocyst.
(3) Multipotent SCs: These SCs are capable of self-renewal and can differentiate into organ-specific cell types. Examples include hematopoietic SCs, mesenchymal SCs, and neural SCs.
(4) Unipotent SCs: These SCs can give rise to only one defined cell type, epithelial cells.
(5) Induced pluripotent SCs: These SCs are "reprogrammed" cells, i.e., differentiated cells that are manipulated in the laboratory to express genes that are normally present in ESCs and that therefore behave like ESCs. Induced pluripotent SCs can differentiate into cells of all organs and tissues.
When tissue damage occurs, SCs, which are normally quiescent, become stimulated to undergo cellular division and enhance cellular regeneration. The microenvironment of SCs, also known as the niche, is crucial for this process. The niche properties, including proximity to the bloodstream, the presence of certain cytokines and growth factors, and low oxygen tension and other physiochemical properties, allow optimal interaction between SCs and their neighboring stromal or epithelial cells and the extracellular matrix [3].

ERECTILE DYSFUNCTION

Erectile dysfunction (ED) is defined as the inability to attain or maintain a penile erection for satisfactory sexual intercourse [2]. ED can significantly impair the quality of life and relationships of men and their partners [4]. The estimated prevalence of ED is about 20% of men aged 40 years and older, with a higher prevalence among older men [5]. There are several management options for ED, including lifestyle modifications, pharmacotherapy (including oral phosphodiesterase-5 inhibitors [PDE5Is], intraurethral alprostadil, intracorporal injections, vacuum devices, and surgery [including penile revascularization and penile implants]). Despite the efficiency of many of these modalities, limitations to their use exist, including different drug interactions (especially PDE5Is with cardiovascular medications), intolerance to side effects, cost, and that not all patients achieve a satisfactory outcome [6]. Apart from a successful revascularization, these modalities offer symptomatic relief rather than a cure for the disease, spurring interest in developing a curative treatment for ED, including SC therapy [7].

1. Mechanism of ED varies according to the cause

Aging is associated with increased resistance to penile blood flow and diminished response to cavernosal nerve stimulation [8]. In addition, nitric oxide (NO) levels decrease as a result of high levels of reactive oxygen species, causing endothelial dysfunction [9]. Structural changes also may occur with aging, including replacement of smooth muscles with collagen fibers and degeneration of elastic fibers [10].
Metabolic syndrome constitutes diabetes mellitus (DM), hypertension, and dyslipidemia. DM is associated with decreased cavernosal NO, endothelial cells, and smooth muscles [11]. Hyperlipidemia is associated with lower levels of cavernosal NO, with subsequent neuronal and endothelial dysfunction [12].
Following radical prostatectomy (RP) for prostate cancer treatment, cavernous nerve injury may ensue. Although nerve-sparing RP results in a lower incidence of postsurgery ED, about 20% of patients still experience ED at 2 years following a nerve-sparing procedure [13]. This may be attributed to neurapraxia, diminished NO production, smooth muscle apoptosis, and penile fibrosis [14]. Radiation-based therapies are thought to cause ED via a similar mechanism [15].

2. Potential role of SC therapy in ED

Several cell types have been studied in the treatment of ED. ESCs improve erectile function in neurogenic ED [16]. However, ethical concerns have limited further research using this cell type. One study showed that vascular endothelial growth factor (VEGF)-transfected endothelial progenitor SCs improved erection in diabetic rats [17]. Similarly, several preclinical studies have shown the beneficial effect of bone marrow-derived SCs (BMSCs) on erectile function in different rat models, including models of DM, cavernous nerve injury, and aging [18,19,20]. Another SC type used in ED treatment research is skeletal muscle-derived SCs (SKMSC). These SCs can be easily obtained through muscle biopsy and have been shown to improve erectile function in cavernous nerve injury and aging ED rat models [21,22]. Neural crest SCs have shown the potential to differentiate into smooth muscle cells and endothelial cells in the rat penis [23]. Adipose tissue-derived SCs (ADSCs) are the most widely used type of SC in ED [7]. They improve erectile function by promoting angiogenesis and through direct transformation to endothelial cells, smooth muscle cells, and neurons and also through the release of stimulatory cytokines such as VEGF and fibroblast growth factor [24,25,26]. Testicular and human urine SCs have been also studied [27].

3. Methods of SC delivery

SC performance may be potentiated by modifying the characteristics of the cells by manipulating their genes or by incubating them with scaffolds, growth factors, or other substances. The therapeutic effect of SC injection may be via migration of these cells to the injury site [28]. Different routes have been suggested for delivery of SCs. Intravenous injection of ADSCs showed improvement of erectile function [28]. Moreover, intracorporal SC delivery for ED treatment is popular, being easy and successful. The regenerative effect of SCs is achieved by either secreting growth factors into the bloodstream or migrating to major pelvic ganglia [7]. Direct injection of SCs into the major pelvic ganglia has not been studied extensively despite their regenerative effect because of difficulties in the injection process [16,29]. Periprostatic injection with or without simultaneous intracorporal injection has also been tried [30,31,32]. Intraperitoneal injection of SCs was less effective than intracorporal injection in restoring erectile function in a cavernous nerve injury mouse model [33].

PEYRONIE'S DISEASE

Peyronie's disease (PD) is an acquired connective tissue disease of the tunica albuginea of the corpus cavernosum, characterized by extensive fibrosis and plaque formation. PD can result in significant physical and psychological morbidity; men may suffer incapacitating pain and deformities that may prevent intercourse and reduce satisfaction, with adverse impacts on partner relationships [34].

1. Mechanism of PD

The exact pathogenesis of PD is unknown. The most widely accepted theory is repeated microvascular trauma to the erect penis resulting in inflammation, disruption of the elastic fibers, and deposition of fibrin [35]. Some studies related vascular trauma to osteoid formation via osteoblast-like cells originating from the vascular lumen [36]. More recent reports showed that upregulation of certain genes, namely, osteoblast specific factor 1, may be responsible for plaque calcification [37]. Another theory is cavernosal hypoxia, which induces collagen deposition and fibrosis. This may explain the penile morphological changes and the development of PD following RP [38]. Transforming growth factor (TGF)-β1 may play an important role in the induction of collagen production by fibroblasts and myofibroblasts in the development of PD plaques [35]. Prolonged inflammation causes the formation of dense fibrotic plaques, which may progress to calcification or ossification. The exact mechanism by which tissue mineralization occurs remains uncertain [39].

2. Potential role of SC therapy in PD

Regenerative urology represents a novel method with potential benefits in the treatment of PD with the use of mesenchymal SC therapy [40]. The external location of the penis makes administration of local SC therapy technically feasible and easy. Moreover, pluripotent mesenchymal SCs are readily available, and their use avoids the ethical issues associated with the use of embryonic SCs. Also, autologous cells may be used, avoiding the issue of antigenic incompatibility [41]. ADSCs may be the most widely used of the mesenchymal SCs, as they are abundant and easily accessible [41]. The exact mechanism of action of ADSCs remains unclear; SCs may differentiate and replace the damaged tissue, increase the local production of cytokines and growth factors, decrease inflammation and oxidative stress, or modulate the extracellular matrix [42]. One interesting finding is that ADSCs seem to migrate to the site of injury, probably in response to cytokine signaling [43]. In rats treated with intratunical injections of TGF-β1, an established model for PD, ADSCs inhibited the development of PD. ADSCs decreased disordered collagen type III and elastin tissues (common in PD plaques) [44], which could be the basis for future research for their use in the treatment of PD in humans and the hope of interrupting the disease pathogenesis before it actually manifests.

INFERTILITY

1. Mechanism of infertility

Anticancer treatment, in the form of surgery, cytotoxic chemotherapy, novel targeted therapy, immunological therapy, and radiotherapy, may cause persistent damage to germ cells, somatic cells critical to germ cell survival and maturation such as Sertoli cells, and Leydig cells, which are critical for testosterone production. The extent of damage depends on the type of cancer, age, and treatment modality [45]. Cytotoxic therapy disrupts spermatogenesis by targeting spermatogonial SCs [46].

2. Potential role of SCs in the treatment of infertility

Isolation and cryopreservation of spermatogonial SCs from the prepubertal testicle prior to cytotoxic therapy may provide hope for children facing a sterilizing therapy. This technique requires a testicular biopsy followed by cryopreservation. Afterwards, spermatogonial SCs may be used for induction of in vitro spermatogenesis or autologous transplantation into the patient's own testes. This procedure was successfully replicated in many animal models [47].

URINARY INCONTINENCE

Urinary incontinence (UI) is defined as the involuntary loss of urine. It affects nearly 200 million people around the world. UI affects women 2 to 3 times more than men until the age of 80 years, after which the prevalence becomes equal in men and women. Nearly 50% of women above the age of 20 years will experience UI, and 50% of those will suffer from stress urinary incontinence (SUI). Other types of incontinence include urge UI and mixed UI. Oral pharmacotherapy usually fails in ameliorating SUI, and more effective, although invasive, surgical options such as a urethral sling may become necessary. Therefore, there is a need to develop less invasive alternative treatments for this common condition, and SC therapy represents a promising avenue [48].
The urethra is a multilayered structure composed of the epithelium, connective tissue, striated and smooth muscles, and small blood vessels [49]. Striated and smooth muscle cells were found to be markedly reduced in animal models of SUI [49], and because SCs can differentiate into either muscle type, several studies have utilized SCs in the treatment of SUI to replenish those cells [50]. Furthermore, SCs secrete musculogenic and angiogenic growth factors that can further enhance their regenerative effect [50]. ADSCs were also found to improve urethral connective tissue, likely through the production and processing of elastin and collagen [51].

1. Preclinical studies

The initial concept behind cell-based therapy for SUI involved the use of skeletal myoblasts to replace the deficient urethral sphincter [52]. The idea then evolved into the use of SCs to substitute for myoblasts. Yiou et al. [53] are credited with the first utilization of SKMSCs in SUI in 2002. From there, SKMSCs were utilized exclusively in SUI preclinical studies until 2010 (Table 1). Since then, five preclinical studies have utilized BMSCs [54,55,56,57,58]. One of those studies was not a typical SC study in that the SCs were seeded in a degradable silk scaffold, which was then used as a sling for the urethra [57]. Umbilical cord blood SCs were also used in one preclinical trial [59]. More recently, seven preclinical studies utilized ADSCs in SUI [51,60,61,62,63,64,65], including one study in which ADSCs with silk fibroin microspheres were used as a bulking agent [65]. Human amniotic fluid-derived SCs have been used in 3 studies of mouse SUI models [66,67,68]. All SC types used have produced improvement in SUI.
Most preclinical studies on SC treatment for SUI used rats as an animal model. However, several studies utilized mice [66,67,68], including the first study by Yiou et al. [53], and one study used monkeys [69]. Different techniques have been performed to establish SUI animal models. A sphincteric injury model has been developed using cauterization, injection of myotoxin, or electrocoaugulation. Pudendal or sciatic nerve injury models have also been developed by using crush injury or transection. The delivery, vaginal distension, and ovariectomy animal model is the most widely used animal model for birth injury [48,70,71,72]. All these models suffer from their short durability of 2 to 3 weeks [73,74,75]. Administration of SCs in SUI preclinical studies has been through periurethral injection. In one study by Lin et al. [51], both periurethral and intravenous routes were utilized, and both routes demonstrated improvement of urinary continence.
Functional and histological assessments are used to assess the outcome of SC use in SUI. Functional assessment is typically achieved by either measuring leak point pressure by use of the Crede or vertical tilt table method or through electrical stimulation of the urethral sphincter neurovascular bundle [48]. The purpose of histological assessment is to locate the SCs, identify SC differentiation, and assess for tissue improvement. Histological assessment is typically done by sacrificing the animal and harvesting the urethral tissue, followed by staining with H&E or trichrome. To identify possible differentiation of the transplanted SCs, immunohistochemical and immunoelectron microscopy were done in several studies [48].

2. Clinical studies

Five clinical trials, done by the same group of researchers, have examined the effect of injected SKMSCs in male and female UI between 2007 and 2008. Those studies reported 80% to 90% improvement in UI [61,76,77,78,79,80]. However, two of those trials were later retracted, citing ethical concerns [79,80]. Carr et al. [81] showed that 5 out of 8 women with SUI achieved total continence using SKMSCs. Lee et al. [59] demonstrated 70% to 80% improvement of continence in 39 female patients with SUI by using cord blood SCs. A small case series utilizing ADSCs for SUI was later retracted for unknown reasons [82]. Using SKMSCs in 12 female patients with SUI, Sebe et al. [83] showed improvement in 10 of 12 women, but worsening of SUI in 2 patients. The typical injection method in clinical trials has been transurethrally, although Carr et al. [81] utilized both transurethral and periurethral routes and showed improvement in incontinence with both routes. In a small pilot study of 3 male patients with SUI, Yamamoto et al. [84] showed an improvement in SUI by using ADSCs at 6 months. Another study using ADSCs showed 60% improvement in SUI in 8 of 11 male patients at 1 year [85]. A Polish study with a longer follow-up of 2 years reported 75% improvement in 16 female patients with SUI with the use of SKMSCs, with 50% of patients achieving complete continence [86]. Most recently, Kuismanen et al. [87] showed improvement of SUI in 3 of 5 female patients at 1 year of follow-up with the use of ADSCs with collagen gel as a bulking agent. Functional assessment in clinical trials has been through measuring pad weights, bladder diaries, and quality of life assessment, in addition to urodynamic study findings such as peak flow rate, postvoid residuals, and maximal urethral closing pressure [48].

3. Future directions

ADSCs represent an easier SC type to obtain given the availability of adipose tissue and ease of acquisition. Therefore, future use of SCs in UI would probably utilize ADSCs more than other SC types. Current SUI animal models have the disadvantage of short durability. Development of more durable, chronic-type SUI animal models is important to accurately determine the therapeutic effects of SCs. The development of induced pluripotent SCs represents a milestone in SC research, and utilization of this technology in urology should be a future goal. More clinical trials recruiting a larger number of patients are needed, and they should adhere to the highest standards of ethical considerations.

Figures and Tables

Table 1

Stem cell studies for urinary incontinence

kju-56-257-i001
Source Year of publication Animal model/patients Stem cell type Injection method
Yiou et al. [53] 2002 Sphincter injury mice Autologous SKMSC Periurethral
Lee et al. [88] 2003 Sciatic nerve transection rats Allogeneic SKMSC Periurethral
Yiou et al. [89] 2003 Sphincter injury rats Autologous SKMSC Periurethral
Cannon et al. [90] 2003 Sciatic nerve transection rats Allogeneic SKMSC Periurethral
Chermansky et al. [91] 2004 Sphincter cauterization rats Allogeneic SKMSC Periurethral
Lee et al. [92] 2004 Pudendal nerve transection rats Allogeneic SKMSC Periurethral
Yiou et al. [93] 2005 Sphincter injury rats Autologous SKMSC Periurethral
Kwon et al. [94] 2006 Sciatic nerve transection rats Allogeneic SKMSC Periurethral
Kim et al. [95] 2007 Sciatic nerve transection nude rats Human SKMSC Periurethral
Mitterberger et al. [76] 2007 123 Female patients Autologous SKMSC Transurethral
Mitterberger et al. [77] 2008 63 Male patients Autologous SKMSC Transurethral
Mitterberger et al. [78] 2008 20 Female patients Autologous SKMSC Transurethral
Carr et al. [81] 2008 8 Female patients Autologous SKMSC Transurethral/periurethral
Hoshi et al. [96] 2008 Periurethral injury rats Allogeneic & xenogeneic rodent SKMSC Periurethral
Furuta et al. [97] 2008 Pudendal nerve transection nude rats Human SKMSC Periurethral
Lin et al. [51] 2010 Vagina distension rats Autologous ADSC Periurethral & IV
Fu et al. [60] 2010 Vagina distension rats Allogeneic ADSC Periurethral
Kinebuchi et al. [55] 2010 Sphincter injury rats Autologous BMSC Periurethral
Lim et al. [98] 2010 Sphincter injury rats Human CBSC Periurethral
Lee et al. [59] 2010 39 Female patients Allogeneic CBSC Periurethral
Zou et al. [57] 2010 Sciatic nerve transection rats BMSC on scaffold Sling surgery
Xu et al. [99] 2010 Pudendal nerve transection rats Allogeneic SKMSC Periurethral
Zhao et al. [63] 2011 Pudendal nerve transection rats Autologous ADSC Periurethral
Kim et al. [56] 2011 Pudendal nerve transection rats Allogeneic BMSC Periurethral
Corcos et al. [54] 2011 Pudendal nerve transection rats Allogeneic BMSC Periurethral
Wu et al. [62] 2011 Pudendal nerve transection rats Allogeneic ADSC Periurethral
Watanabe et al. [61] 2011 Pelvic nerve transection rats Allogeneic ADSC Periurethral
Sebe et al. [83] 2011 12 Female patients Autologous SKMSC Endourethral
Yamamoto et al. [84] 2012 3 Male patients Autologous ADSC Transurethral
Kim et al. [66] 2012 Pudendal nerve transection mice Human AFSC Periurethral
Li et al. [64] 2012 Vagina distension rats Autologous ADSC Periurethral
Chun et al. [67] 2012 Pudendal nerve transection mice Human AFSC Periurethral
Badra et al. [69] 2013 Pudendal nerve transection monkeys Autologous SKMSC Periurethral
Stangel-Wojcikiewicz et al. [86] 2014 16 Female patients Autologous SKMSC Transurethral
Dissaranan et al. [58] 2014 Vagina distension rats Allogeneic BMSC Periurethral
Gotoh et al. [85] 2014 11 Male patients Autologous ADSC Transurethral
Shi et al. [65] 2014 Pudendal nerve transection rats Autologous ADSC with silk fibroin microspheres Periurethral
Chun et al. [68] 2014 Pudendal nerve transection mice Human AFSC Periurethral
Kuismanen et al. [87] 2014 5 Female patients Autologous ADSC with collagen gel Transurethral

SKMSC, skeletal muscle-derived stem cell; ADSC, adipose tissue-derived stem cell; BMSC, bone marrow-derived stem cell; CBSC, umbilical cord blood stem cell; AFSC, amniotic fluid-derived stem cell; IV, intravenous.

Notes

CONFLICTS OF INTEREST The authors have nothing to disclose.

References

1. Lin CS, Xin ZC, Deng CH, Ning H, Lin G, Lue TF. Recent advances in andrology-related stem cell research. Asian J Androl. 2008; 10:171–175.
2. Alwaal A, Zaid UB, Lin CS, Lue TF. Stem cell treatment of erectile dysfunction. Adv Drug Deliv Rev. 2014; 11. 14. [Epub]. http://dx.doi.org/10.1016/j.addr.2014.11.012.
3. Kiefer JC. Primer and interviews: The dynamic stem cell niche. Dev Dyn. 2011; 240:737–743.
4. Sanchez-Cruz JJ, Cabrera-Leon A, Martin-Morales A, Fernandez A, Burgos R, Rejas J. Male erectile dysfunction and health-related quality of life. Eur Urol. 2003; 44:245–253.
5. Laumann EO, West S, Glasser D, Carson C, Rosen R, Kang JH. Prevalence and correlates of erectile dysfunction by race and ethnicity among men aged 40 or older in the United States: from the male attitudes regarding sexual health survey. J Sex Med. 2007; 4:57–65.
6. Carvalheira AA, Pereira NM, Maroco J, Forjaz V. Dropout in the treatment of erectile dysfunction with PDE5: a study on predictors and a qualitative analysis of reasons for discontinuation. J Sex Med. 2012; 9:2361–2369.
7. Lin CS, Xin Z, Dai J, Huang YC, Lue TF. Stem-cell therapy for erectile dysfunction. Expert Opin Biol Ther. 2013; 13:1585–1597.
8. Carrier S, Nagaraju P, Morgan DM, Baba K, Nunes L, Lue TF. Age decreases nitric oxide synthase-containing nerve fibers in the rat penis. J Urol. 1997; 157:1088–1092.
9. Azadzoi KM, Schulman RN, Aviram M, Siroky MB. Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants. J Urol. 2005; 174:386–393.
10. Wespes E. Erectile dysfunction in the ageing man. Curr Opin Urol. 2000; 10:625–628.
11. Dashwood MR, Crump A, Shi-Wen X, Loesch A. Identification of neuronal nitric oxide synthase (nNOS) in human penis: a potential role of reduced neuronally-derived nitric oxide in erectile dysfunction. Curr Pharm Biotechnol. 2011; 12:1316–1321.
12. Huang YC, Ning H, Shindel AW, Fandel TM, Lin G, Harraz AM, et al. The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model. J Sex Med. 2010; 7(4 Pt 1):1391–1400.
13. Ficarra V, Novara G, Artibani W, Cestari A, Galfano A, Graefen M, et al. Retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. Eur Urol. 2009; 55:1037–1063.
14. Fode M, Ohl DA, Ralph D, Sonksen J. Penile rehabilitation after radical prostatectomy: what the evidence really says. BJU Int. 2013; 112:998–1008.
15. Carrier S, Hricak H, Lee SS, Baba K, Morgan DM, Nunes L, et al. Radiation-induced decrease in nitric oxide synthase: containing nerves in the rat penis. Radiology. 1995; 195:95–99.
16. Bochinski D, Lin GT, Nunes L, Carrion R, Rahman N, Lin CS, et al. The effect of neural embryonic stem cell therapy in a rat model of cavernosal nerve injury. BJU Int. 2004; 94:904–909.
17. Gou X, He WY, Xiao MZ, Qiu M, Wang M, Deng YZ, et al. Transplantation of endothelial progenitor cells transfected with VEGF165 to restore erectile function in diabetic rats. Asian J Androl. 2011; 13:332–338.
18. Qiu X, Lin H, Wang Y, Yu W, Chen Y, Wang R, et al. Intracavernous transplantation of bone marrow-derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats. J Sex Med. 2011; 8:427–436.
19. Fall PA, Izikki M, Tu L, Swieb S, Giuliano F, Bernabe J, et al. Apoptosis and effects of intracavernous bone marrow cell injection in a rat model of postprostatectomy erectile dysfunction. Eur Urol. 2009; 56:716–725.
20. Bivalacqua TJ, Deng W, Kendirci M, Usta MF, Robinson C, Taylor BK, et al. Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction. Am J Physiol Heart Circ Physiol. 2007; 292:H1278–H1290.
21. Hwang JH, Yuk SH, Lee JH, Lyoo WS, Ghil SH, Lee SS, et al. Isolation of muscle derived stem cells from rat and its smooth muscle differentiation [corrected]. Mol Cells. 2004; 17:57–61.
22. Kim Y, de Miguel F, Usiene I, Kwon D, Yoshimura N, Huard J, et al. Injection of skeletal muscle-derived cells into the penis improves erectile function. Int J Impot Res. 2006; 18:329–334.
23. Song YS, Lee HJ, Park IH, Lim IS, Ku JH, Kim SU. Human neural crest stem cells transplanted in rat penile corpus cavernosum to repair erectile dysfunction. BJU Int. 2008; 102:220–224.
24. Qiu X, Fandel TM, Ferretti L, Albersen M, Orabi H, Zhang H, et al. Both immediate and delayed intracavernous injection of autologous adipose-derived stromal vascular fraction enhances recovery of erectile function in a rat model of cavernous nerve injury. Eur Urol. 2012; 62:720–727.
25. Ryu JK, Tumurbaatar M, Jin HR, Kim WJ, Kwon MH, Piao S, et al. Intracavernous delivery of freshly isolated stromal vascular fraction rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. J Sex Med. 2012; 9:3051–3065.
26. Ning H, Liu G, Lin G, Yang R, Lue TF, Lin CS. Fibroblast growth factor 2 promotes endothelial differentiation of adipose tissue-derived stem cells. J Sex Med. 2009; 6:967–979.
27. Ouyang B, Sun X, Han D, Chen S, Yao B, Gao Y, et al. Human urine-derived stem cells alone or genetically-modified with FGF2 Improve type 2 diabetic erectile dysfunction in a rat model. PLoS One. 2014; 9:e92825.
28. Qiu X, Villalta J, Ferretti L, Fandel TM, Albersen M, Lin G, et al. Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction. J Sex Med. 2012; 9:1834–1841.
29. Kim SJ, Choi SW, Hur KJ, Park SH, Sung YC, Ha YS, et al. Synergistic effect of mesenchymal stem cells infected with recombinant adenovirus expressing human BDNF on erectile function in a rat model of cavernous nerve injury. Korean J Urol. 2012; 53:726–732.
30. Choi WY, Jeon HG, Chung Y, Lim JJ, Shin DH, Kim JM, et al. Isolation and characterization of novel, highly proliferative human CD34/CD73-double-positive testis-derived stem cells for cell therapy. Stem Cells Dev. 2013; 22:2158–2173.
31. You D, Jang MJ, Lee J, Jeong IG, Kim HS, Moon KH, et al. Periprostatic implantation of human bone marrow-derived mesenchymal stem cells potentiates recovery of erectile function by intracavernosal injection in a rat model of cavernous nerve injury. Urology. 2013; 81:104–110.
32. You D, Jang MJ, Lee J, Suh N, Jeong IG, Sohn DW, et al. Comparative analysis of periprostatic implantation and intracavernosal injection of human adipose tissue-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. Prostate. 2013; 73:278–286.
33. Ryu JK, Kim DH, Song KM, Yi T, Suh JK, Song SU. Intracavernous delivery of clonal mesenchymal stem cells restores erectile function in a mouse model of cavernous nerve injury. J Sex Med. 2014; 11:411–423.
34. Smith JF, Walsh TJ, Conti SL, Turek P, Lue T. Risk factors for emotional and relationship problems in Peyronie's disease. J Sex Med. 2008; 5:2179–2184.
35. Gonzalez-Cadavid NF, Rajfer J. Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie's disease. Nat Clin Pract Urol. 2005; 2:291–297.
36. Devine CJ Jr. International Conference on Peyronie's disease advances in basic and clinical research. March 17-19, 1993. Introduction. J Urol. 1997; 157:272–275.
37. Gonzalez-Cadavid NF, Magee TR, Ferrini M, Qian A, Vernet D, Rajfer J. Gene expression in Peyronie's disease. Int J Impot Res. 2002; 14:361–374.
38. Tal R, Heck M, Teloken P, Siegrist T, Nelson CJ, Mulhall JP. Peyronie's disease following radical prostatectomy: incidence and predictors. J Sex Med. 2010; 7:1254–1261.
39. Vernet D, Nolazco G, Cantini L, Magee TR, Qian A, Rajfer J, et al. Evidence that osteogenic progenitor cells in the human tunica albuginea may originate from stem cells: implications for peyronie disease. Biol Reprod. 2005; 73:1199–1210.
40. Shindel AW. Sexual dysfunction: The potential of stem cell therapy for Peyronie disease. Nat Rev Urol. 2013; 10:8–9.
41. Lin CS, Lin G, Lue TF. Allogeneic and xenogeneic transplantation of adipose-derived stem cells in immunocompetent recipients without immunosuppressants. Stem Cells Dev. 2012; 21:2770–2778.
42. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007; 25:2739–2749.
43. Zhang H, Ning H, Banie L, Wang G, Lin G, Lue TF, et al. Adipose tissue-derived stem cells secrete CXCL5 cytokine with chemoattractant and angiogenic properties. Biochem Biophys Res Commun. 2010; 402:560–564.
44. Castiglione F, Hedlund P, Van der Aa F, Bivalacqua TJ, Rigatti P, Van Poppel H, et al. Intratunical injection of human adipose tissue-derived stem cells prevents fibrosis and is associated with improved erectile function in a rat model of Peyronie's disease. Eur Urol. 2013; 63:551–560.
45. Schover LR, Brey K, Lichtin A, Lipshultz LI, Jeha S. Oncologists' attitudes and practices regarding banking sperm before cancer treatment. J Clin Oncol. 2002; 20:1890–1897.
46. Meistrich ML, Finch M, da Cunha MF, Hacker U, Au WW. Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Res. 1982; 42:122–131.
47. Yokonishi T, Sato T, Komeya M, Katagiri K, Kubota Y, Nakabayashi K, et al. Offspring production with sperm grown in vitro from cryopreserved testis tissues. Nat Commun. 2014; 5:4320.
48. Lin CS, Lue TF. Stem cell therapy for stress urinary incontinence: a critical review. Stem Cells Dev. 2012; 21:834–843.
49. Delancey JO. Why do women have stress urinary incontinence? Neurourol Urodyn. 2010; 29:Suppl 1. S13–S17.
50. Lin CS. Stem cell therapy for the bladder: where do we stand? J Urol. 2011; 185:779–780.
51. Lin G, Wang G, Banie L, Ning H, Shindel AW, Fandel TM, et al. Treatment of stress urinary incontinence with adipose tissue-derived stem cells. Cytotherapy. 2010; 12:88–95.
52. Chancellor MB, Yokoyama T, Tirney S, Mattes CE, Ozawa H, Yoshimura N, et al. Preliminary results of myoblast injection into the urethra and bladder wall: a possible method for the treatment of stress urinary incontinence and impaired detrusor contractility. Neurourol Urodyn. 2000; 19:279–287.
53. Yiou R, Dreyfus P, Chopin DK, Abbou CC, Lefaucheur JP. Muscle precursor cell autografting in a murine model of urethral sphincter injury. BJU Int. 2002; 89:298–302.
54. Corcos J, Loutochin O, Campeau L, Eliopoulos N, Bouchentouf M, Blok B, et al. Bone marrow mesenchymal stromal cell therapy for external urethral sphincter restoration in a rat model of stress urinary incontinence. Neurourol Urodyn. 2011; 30:447–455.
55. Kinebuchi Y, Aizawa N, Imamura T, Ishizuka O, Igawa Y, Nishizawa O. Autologous bone-marrow-derived mesenchymal stem cell transplantation into injured rat urethral sphincter. Int J Urol. 2010; 17:359–368.
56. 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. 2011; 86:110–116.
57. Zou XH, Zhi YL, Chen X, Jin HM, Wang LL, Jiang YZ, et al. Mesenchymal stem cell seeded knitted silk sling for the treatment of stress urinary incontinence. Biomaterials. 2010; 31:4872–4879.
58. Dissaranan C, Cruz MA, Kiedrowski MJ, Balog BM, Gill BC, Penn MS, et al. Rat mesenchymal stem cell secretome promotes elastogenesis and facilitates recovery from simulated childbirth injury. Cell Transplant. 2014; 23:1395–1406.
59. Lee CN, Jang JB, Kim JY, Koh C, Baek JY, Lee KJ. Human cord blood stem cell therapy for treatment of stress urinary incontinence. J Korean Med Sci. 2010; 25:813–816.
60. Fu Q, Song XF, Liao GL, Deng CL, Cui L. Myoblasts differentiated from adipose-derived stem cells to treat stress urinary incontinence. Urology. 2010; 75:718–723.
61. Watanabe T, Maruyama S, Yamamoto T, Kamo I, Yasuda K, Saka Y, et al. Increased urethral resistance by periurethral injection of low serum cultured adipose-derived mesenchymal stromal cells in rats. Int J Urol. 2011; 18:659–666.
62. Wu G, Song Y, Zheng X, Jiang Z. Adipose-derived stromal cell transplantation for treatment of stress urinary incontinence. Tissue Cell. 2011; 43:246–253.
63. Zhao W, Zhang C, Jin C, Zhang Z, Kong D, Xu W, et al. Periurethral injection of autologous adipose-derived stem cells with controlled-release nerve growth factor for the treatment of stress urinary incontinence in a rat model. Eur Urol. 2011; 59:155–163.
64. Li GY, Zhou F, Gong YQ, Cui WS, Yuan YM, Song WD, et al. Activation of VEGF and ERK1/2 and improvement of urethral function by adipose-derived stem cells in a rat stress urinary incontinence model. Urology. 2012; 80:953.e1–953.e8.
65. Shi LB, Cai HX, Chen LK, Wu Y, Zhu SA, Gong XN, et al. Tissue engineered bulking agent with adipose-derived stem cells and silk fibroin microspheres for the treatment of intrinsic urethral sphincter deficiency. Biomaterials. 2014; 35:1519–1530.
66. Kim BS, Chun SY, Lee JK, Lim HJ, Bae JS, Chung HY, et al. Human amniotic fluid stem cell injection therapy for urethral sphincter regeneration in an animal model. BMC Med. 2012; 10:94.
67. Chun SY, Cho DH, Chae SY, Choi KH, Lim HJ, Yoon GS, et al. Human amniotic fluid stem cell-derived muscle progenitor cell therapy for stress urinary incontinence. J Korean Med Sci. 2012; 27:1300–1307.
68. Chun SY, Kwon JB, Chae SY, Lee JK, Bae JS, Kim BS, et al. Combined injection of three different lineages of early-differentiating human amniotic fluid-derived cells restores urethral sphincter function in urinary incontinence. BJU Int. 2014; 114:770–783.
69. Badra S, Andersson KE, Dean A, Mourad S, Williams JK. Long-term structural and functional effects of autologous muscle precursor cell therapy in a nonhuman primate model of urinary sphincter deficiency. J Urol. 2013; 190:1938–1945.
70. Jiang HH, Damaser M. Animal models of stress urinary incontinence. In : Andersson KE, Michel MC, editors. Urinary tract. Berlin: Springer;2011. p. 45–67.
71. Lin AS, Carrier S, Morgan DM, Lue TF. Effect of simulated birth trauma on the urinary continence mechanism in the rat. Urology. 1998; 52:143–151.
72. Sievert KD, Emre Bakircioglu M, Tsai T, Dahms SE, Nunes L, Lue TF. The effect of simulated birth trauma and/or ovariectomy on rodent continence mechanism. Part I: functional and structural change. J Urol. 2001; 166:311–317.
73. Pauwels E, De Wachter S, Wyndaele JJ. Evaluation of different techniques to create chronic urinary incontinence in the rat. BJU Int. 2009; 103:782–785.
74. Rodriguez LV, Chen S, Jack GS, de Almeida F, Lee KW, Zhang R. New objective measures to quantify stress urinary incontinence in a novel durable animal model of intrinsic sphincter deficiency. Am J Physiol Regul Integr Comp Physiol. 2005; 288:R1332–R1338.
75. Lin YH, Liu G, Li M, Xiao N, Daneshgari F. Recovery of continence function following simulated birth trauma involves repair of muscle and nerves in the urethra in the female mouse. Eur Urol. 2010; 57:506–512.
76. Mitterberger M, Marksteiner R, Margreiter E, Pinggera GM, Colleselli D, Frauscher F, et al. Autologous myoblasts and fibroblasts for female stress incontinence: a 1-year follow-up in 123 patients. BJU Int. 2007; 100:1081–1085.
77. Mitterberger M, Marksteiner R, Margreiter E, Pinggera GM, Frauscher F, Ulmer H, et al. Myoblast and fibroblast therapy for post-prostatectomy urinary incontinence: 1-year followup of 63 patients. J Urol. 2008; 179:226–231.
78. Mitterberger M, Pinggera GM, Marksteiner R, Margreiter E, Fussenegger M, Frauscher F, et al. Adult stem cell therapy of female stress urinary incontinence. Eur Urol. 2008; 53:169–175.
79. Strasser H, Marksteiner R, Margreiter E, Mitterberger M, Pinggera GM, Frauscher F, et al. Transurethral ultrasonography-guided injection of adult autologous stem cells versus transurethral endoscopic injection of collagen in treatment of urinary incontinence. World J Urol. 2007; 25:385–392.
80. Strasser H, Marksteiner R, Margreiter E, Pinggera GM, Mitterberger M, Frauscher F, et al. Autologous myoblasts and fibroblasts versus collagen for treatment of stress urinary incontinence in women: a randomised controlled trial. Lancet. 2007; 369:2179–2186.
81. Carr LK, Steele D, Steele S, Wagner D, Pruchnic R, Jankowski R, et al. 1-year follow-up of autologous muscle-derived stem cell injection pilot study to treat stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2008; 19:881–883.
82. Yamamoto T, Gotoh M, Hattori R, Toriyama K, Kamei Y, Iwaguro H, et al. Periurethral injection of autologous adipose-derived stem cells for the treatment of stress urinary incontinence in patients undergoing radical prostatectomy: report of two initial cases. Int J Urol. 2010; 17:75–82.
83. Sebe P, Doucet C, Cornu JN, Ciofu C, Costa P, de Medina SG, et al. Intrasphincteric injections of autologous muscular cells in women with refractory stress urinary incontinence: a prospective study. Int Urogynecol J. 2011; 22:183–189.
84. Yamamoto T, Gotoh M, Kato M, Majima T, Toriyama K, Kamei Y, et al. Periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: Report of three initial cases. Int J Urol. 2012; 19:652–659.
85. Gotoh M, Yamamoto T, Kato M, Majima T, Toriyama K, Kamei Y, et al. Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose-derived regenerative cells: 1-year outcomes in 11 patients. Int J Urol. 2014; 21:294–300.
86. Stangel-Wojcikiewicz K, Jarocha D, Piwowar M, Jach R, Uhl T, Basta A, et al. Autologous muscle-derived cells for the treatment of female stress urinary incontinence: a 2-year follow-up of a Polish investigation. Neurourol Urodyn. 2014; 33:324–330.
87. Kuismanen K, Sartoneva R, Haimi S, Mannerstrom B, Tomas E, Miettinen S, et al. Autologous adipose stem cells in treatment of female stress urinary incontinence: results of a pilot study. Stem Cells Transl Med. 2014; 3:936–941.
88. Lee JY, Cannon TW, Pruchnic R, Fraser MO, Huard J, Chancellor MB. The effects of periurethral muscle-derived stem cell injection on leak point pressure in a rat model of stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2003; 14:31–37.
89. Yiou R, Yoo JJ, Atala A. Restoration of functional motor units in a rat model of sphincter injury by muscle precursor cell autografts. Transplantation. 2003; 76:1053–1060.
90. Cannon TW, Lee JY, Somogyi G, Pruchnic R, Smith CP, Huard J, et al. Improved sphincter contractility after allogenic muscle-derived progenitor cell injection into the denervated rat urethra. Urology. 2003; 62:958–963.
91. Chermansky CJ, Tarin T, Kwon DD, Jankowski RJ, Cannon TW, de Groat WC, et al. Intraurethral muscle-derived cell injections increase leak point pressure in a rat model of intrinsic sphincter deficiency. Urology. 2004; 63:780–785.
92. Lee JY, Paik SY, Yuk SH, Lee JH, Ghil SH, Lee SS. Long term effects of muscle-derived stem cells on leak point pressure and closing pressure in rats with transected pudendal nerves. Mol Cells. 2004; 18:309–313.
93. Yiou R, Yoo JJ, Atala A. Failure of differentiation into mature myotubes by muscle precursor cells with the side-population phenotype after injection into irreversibly damaged striated urethral sphincter. Transplantation. 2005; 80:131–133.
94. Kwon D, Kim Y, Pruchnic R, Jankowski R, Usiene I, de Miguel F, et al. Periurethral cellular injection: comparison of muscle-derived progenitor cells and fibroblasts with regard to efficacy and tissue contractility in an animal model of stress urinary incontinence. Urology. 2006; 68:449–454.
95. Kim YT, Kim DK, Jankowski RJ, Pruchnic R, Usiene I, de Miguel F, et al. Human muscle-derived cell injection in a rat model of stress urinary incontinence. Muscle Nerve. 2007; 36:391–393.
96. Hoshi A, Tamaki T, Tono K, Okada Y, Akatsuka A, Usui Y, et al. Reconstruction of radical prostatectomy-induced urethral damage using skeletal muscle-derived multipotent stem cells. Transplantation. 2008; 85:1617–1624.
97. Furuta A, Jankowski RJ, Pruchnic R, Egawa S, Yoshimura N, Chancellor MB. Physiological effects of human muscle-derived stem cell implantation on urethral smooth muscle function. Int Urogynecol J Pelvic Floor Dysfunct. 2008; 19:1229–1234.
98. Lim JJ, Jang JB, Kim JY, Moon SH, Lee CN, Lee KJ. Human umbilical cord blood mononuclear cell transplantation in rats with intrinsic sphincter deficiency. J Korean Med Sci. 2010; 25:663–670.
99. Xu Y, Song YF, Lin ZX. Transplantation of muscle-derived stem cells plus biodegradable fibrin glue restores the urethral sphincter in a pudendal nerve-transected rat model. Braz J Med Biol Res. 2010; 43:1076–1083.
TOOLS
Similar articles