ADR-12684; No of Pages 8 Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

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Regenerative medicine for the treatment of reproductive system disorders: Current and potential options☆ Hooman Sadri-Ardekani ⁎, Anthony Atala Wake Forest Institute for Regenerative Medicine (WFIRM), Wake Forest School of Medicine, Winston-Salem, NC, USA Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, USA

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Available online xxxx Keywords: Reproductive medicine Male Female Regenerative medicine Tissue engineering

a b s t r a c t Regenerative medicine has opened new avenues for treating patients with severe reproductive system disorders, such as congenital abnormalities, cancer, trauma, infection, inflammation and iatrogenic injuries. Over the past two decades, scientists have advanced the field of reproductive tissue engineering to restore normal sexual function and preserve fertility in both female and male patients. In this review, we summarize recent advances in the use of cell, tissue, and organ-based regenerative medicine strategies for clinical application in reproductive system disorders. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Female reproductive system . . . . . . . . . . . . . . . . . . . 2.1. Vagina . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Cervix . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Uterus . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Ovary . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Oogonial Stem Cells (OSCs) . . . . . . . . . . . 2.4.2. Ovary transplantation . . . . . . . . . . . . . . 2.4.3. In vitro maturation (IVM) of ovarian follicles . . . 2.4.4. Hormone replacement therapy . . . . . . . . . . 3. Male reproductive system . . . . . . . . . . . . . . . . . . . . 3.1. Penis . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Testis . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Spermatogonial Stem Cell (SSC) autotransplantation 3.2.2. Androgen replacement . . . . . . . . . . . . . 3.2.3. Engineering vas deferens . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction For many years, hormonal and surgical treatments have been used to help patients suffering from reproductive system disorders. In the

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21st century, regenerative medicine has become a promising concept in the development of new therapies for all fields of medicine, including reproduction [1]. The field of regenerative medicine includes several different areas of biomedical technology, including biomaterials, tissue

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Regenerative Medicine Strategies in Urology”. ⁎ Corresponding author at: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. E-mail address: [email protected] (H. Sadri-Ardekani).

http://dx.doi.org/10.1016/j.addr.2014.10.019 0169-409X/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: H. Sadri-Ardekani, A. Atala, Regenerative medicine for the treatment of reproductive system disorders: Current and potential options, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.019

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engineering and stem cell therapy. Three main strategies have been used for tissue engineering: 1) Use of extracellular matrices (ECM) without cells, allowing the natural ability of the body to generate new tissue; 2) Use of ECM seeded with cells for implantation; 3) Direct injection of cells either with or without carriers such as hydrogels (Fig. 1). The ECMs used for tissue engineering may either be synthetic, or derived from natural tissues [2,3]. A variety of different cell types may also be used, including: 1) Tissue specific stem cells; 2) Mesenchymal stem cells; and 3) Pluripotent stem cells, such as embryonic stem cells, induce pluripotent stem cells (iPS), or amniotic and placental stem cells. The source of these cells can be either autologous or allogeneic (Fig. 1). Autologous cells derived from a small biopsy are the preferred cell type. The biopsy is obtained from the patient, and the cells isolated from this biopsy tissue are expanded in vitro. However, for some patients, this is not possible as there is insufficient functional tissue to obtain a biopsy. Therefore other sources of cells, such as stem cells (either autologous or allogeneic) might be used for these patients [2,3]. The ultimate goal of regenerative medicine strategies for the treatment of reproductive system disorders is to restore normal sexual function and preserve fertility. In this review, we summarize the most recent advances in using cell, tissue, and organ-based regenerative medicine strategies for clinical applications in treating reproductive system disorders. 2. Female reproductive system 2.1. Vagina Vaginal agenesis is a genital tract anomaly that occurs in 1 out of 5000 females [4]. Congenital vagina malformations such as Mayer–

Rokitansky–Kuester–Hauser (MRKH) syndrome, cloacal malformation, or thick transverse vaginal septum can adversely affect vaginal anatomy and consequently result in sexual dysfunction [5]. Extensive surgery in the pelvis due to cancer, severe trauma, or transgender operations can also create the need for vaginal reconstruction [6–8]. A recent systematic review of optimal management of isolated vaginal agenesis due to MRKH or androgen insensitivity syndrome (AIS) showed that the existing data in the literature is not consistent [9] However, overall data of 7 different vaginoplasty techniques revealed that the conservative method of using dilation had the fewest complications, with success rates ranging between 43% and 94.5%, with an average vaginal length of 6.65 cm [9]. If dilation fails or the defect is large, surgical vaginoplasty methods are required. The main challenge is the lack of sufficient native tissue to reconstruct the vagina. The feasibility of tissue engineering of vaginal organ was investigated using rabbit cells [10]. Rabbit vaginal epithelial and smooth muscle cells (SMC) were expanded in vitro and seeded on polyglycolic acid (PGA) scaffolds at a density of 10–20 million cells/cm2 [10]. The seeded scaffolds were then implanted subcutaneously in nude mice. Evaluation of implants by immunohistochemistry, Western blot and organ bath electrical stimulation after 6 weeks revealed formation of tissue that was phenotypically and functionally similar to native vagina [10]. In another study, radiographic analysis of neovagina in rabbits six months after total vaginal replacement, demonstrated wide, patent vaginal structures, without strictures [7]. Several materials have now been used to engineer vaginal tissue, including amniotic membrane [11], oxidized cellulose [12], peritoneum [13], small intestinal submucosa [14], autologous buccal mucosa [15] and autologous in vitro cultured tissue [16]. A 28 year old patient with MRKH syndrome had a 1 cm2 full-thickness mucosal biopsy taken from the vaginal vestibule. Cells were isolated from the sample,

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Fig. 1. Schematic diagram showing the application of autologous or allogeneic tissue based therapies for the treatment of male and female reproductive system disorders.

Please cite this article as: H. Sadri-Ardekani, A. Atala, Regenerative medicine for the treatment of reproductive system disorders: Current and potential options, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.019

H. Sadri-Ardekani, A. Atala / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

expanded for 2 weeks and seeded on a hyaluronic acid embedded gauze used to bridge a 2 cm × 12 cm vaginal segment. At six weeks post-implantation, colposcopy and vaginal biopsy showed normal epithelium [16]. The first surgical implantation of a three-dimensional (3-D) engineered vaginal organ in humans has recently been reported [17]. Four MRKH patients with ages ranging from 13 to 18 years old received autologous engineered vaginas 5–6 weeks after obtaining tissue biopsies for creating vaginal tissue in the laboratory [17]. Vaginoscopy 6 months after surgery showed that the margin between the engineered segments and the native tissues was indistinguishable. Annual serial deep-tissue biopsies showed a tri-layered structure consisting of vaginal tissue with an epithelial cell-lined lumen surrounded by submucosa and muscle. The MRIs, which showed the extent of the vaginal aplasia before surgery, showed the maintenance of

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normal organ caliber after surgery (Fig. 2). Long-term follow up (up to 8 years) showed no postoperative surgical complications and a normal range of function, as determined using the Female Sexual Function Index (FSFI) [17]. Further clinical studies are required to definitively establish the efficacy of tissue engineered vaginas, by extending the number of patients included in the next phases of clinical trials, as well as by conducting controlled studies that compare results with currently established surgical techniques. 2.2. Cervix More than 12% of births in the USA are preterm (defined as b37 weeks gestation), representing approximately 500,000 births per year [18]. Preterm births are a common cause of morbidity and

Fig. 2. Preoperative and postoperative MRI images (A) Preoperative MRI images show an absence of vaginal organs. (B) MRIs 1 year after surgery show engineered vaginal organs. (C) MRI images up to 8 years after surgery (boxes within the MRIs show engineered vaginal organs).

Please cite this article as: H. Sadri-Ardekani, A. Atala, Regenerative medicine for the treatment of reproductive system disorders: Current and potential options, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.019

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mortality in newborn infants [19]. In the United States, hospital care related to preterm births costs $26 billion annually [20]. Maintaining the anatomic shape of the cervix during fetal and uterine growth is crucial for a normal pregnancy during adulthood. The relative risk of preterm delivery increases (from 1.98 to 13.99) as the length of the cervix decreases (from 40 mm to 13 mm), as determined by vaginal ultrasound measurement during pregnancy [21]. The feasibility of using a tissue engineering strategy for the development of 3-D cervical constructs has been investigated previously [22]. In this study, cervical cells were isolated from two pre-menopausal women who were undergoing hysterectomy for benign gynecological conditions. The isolated cervical cells were seeded onto porous silk scaffolds and cultured for 8 weeks. Human cervical cells proliferated on these 3-D scaffolds and synthesized an ECM with biochemical constituents and morphology similar to native tissue, as evaluated by immunohistochemistry, biochemical characterization, gene expression and mechanical testing [22]. This study suggests that a robust 3-D construct of cervical ECM may be used to replace an impaired cervix. However, further investigation is required before advancing this technology to the clinic. 2.3. Uterus The prevalence of uterine factor infertility (UFI) is approximately 3– 5% of the general population [23]. UFI can be congenital, disease-related or iatrogenic. It has been estimated that of the 62 million women of reproductive age in US, 9 million have some form of UFI [23,24]. Adoption or surrogacy is an option for these women, if not disallowed for personal, societal, or religious reasons [25]. Infertility researchers have targeted uterus transplant as a potential therapeutic option for UFI [26]. Recently, the first clinical pregnancy following uterus allotransplantation in a 23year-old MRKH patient has been reported [27,28]. The patient had her first menstrual bleed 1 month after transplantation and had one biochemically and one clinically recognized pregnancy; both after embryo transfers [28]. Unfortunately, the gestational sac failed to develop in each of these cases. Pregnancy resulting in a live birth after uterine transplantation still remains challenging [28,29]. The paucity of compatible tissue for uterus allotransplantation and the adverse effects of maintaining immunosuppression, emphasize the importance of engineering functional uterine tissue using autologous cells. This has been investigated in a rabbit model [30], where autologous rabbit uterine smooth muscle cells and epithelial cells were harvested and expanded in vitro. These cells were seeded onto pre-configured uterine-shaped biodegradable polymer scaffolds, which were then used for subtotal uterine tissue replacement in the corresponding autologous animals [30]. Six months after implantation, morphological, immunocytochemical, and Western blot analyses confirmed the presence of normal uterine tissue components in the tissue construct [30]. Biomechanical analyses and organ bath studies showed that the functional characteristics of these tissues were similar to those of normal uterine tissue [30]. Another approach that has been tried was the production of myofibroblast-rich tissue capsules as autologous grafts for mimicking the hollow, smooth muscle-walled uterus [31]. In this research, boiled blood clots molded into tubular shapes (0.5 cm diameter × 2.5 cm long) were implanted into the peritoneal cavities of 33 rats (used as an in vivo bioreactor; two implants per rat); while additional seven rats were used as controls [31]. After 2 to 3 weeks, the tubular templates were removed, and the encapsulating myofibroblast-rich tissue, which resulted from the foreign body response to the biomaterial, was harvested for grafting. Finally, a segment (1.5–2.0 × 0.75–1.0 cm, equivalent to approximately one-third of the total area) was excised from one horn of the uterus and replaced with the myofibroblast tissue [31]. Twelve weeks after grafting, the thickness of the grafted tissue increased, while histological and immunofluorescence evaluation showed normal uterus morphology. The grafted uterine horns also supported embryos to the late stages (19 days) of gestation [31]; however, birth of healthy offspring was not reported in this study. In another recent

study, uterine tissue was constructed using collagen membranes loaded with collagen-targeting basic fibroblast growth factor (bFGF). These engineered constructs were used for repairing uterus horns in a rat model [32]. The structure and function of bFGFcontaining regenerated uterine horns were similar to native tissue (sham operated) and were superior to other experimental groups, including spontaneously regenerated uterus [32]. Ninety days after surgery, pregnancies were observed in some of the regenerated uterine horns, which were maintained to the late gestational stage. The pregnancy rate of bFGF containing regenerated uterus was much higher (86.67%) than the spontaneous regeneration group (33.33%), and was close to that of the sham operated group (100%) [32]. This study demonstrated a significant improvement in the histology and function of regenerated uterine horns treated with bFGF; although no viable births were reported. 2.4. Ovary The main role of ovaries is to produce oocytes and secrete female hormones. Ovarian sex steroids are important for preparing the uterus for implantation of fertilized oocytes. These hormones also have a major role in breast development, bone health and sexual function. Premature Ovarian Failure (POF) also known as Primary Ovarian Insufficiency (POI) can be idiopathic [33] or induced by chemotherapy [34] and radiotherapy [35]. These patients are not able to produce normal levels of hormones or release oocytes. Direct loss of oocytes or somatic cell depletion may explain the mechanism of ovarian failure [34]. 2.4.1. Oogonial Stem Cells (OSCs) For decades, it was believed that women are born with a limited number of oocytes, without a capacity for renewal [36]. Recent studies have challenged this belief by identifying mitotically active germ cells that have been shown to undergo differentiation into oocytes in both in vitro and in vivo studies [37]; producing offspring in 82% (18/22) of naturally mated mice [38]. In 2012, White and colleagues [39] isolated viable DDX4-COOH positive cells by Fluorescence-Activated Cell Sorting (FACS) from the ovarian cortical tissue of 6 women (22–33 years of age) undergoing sex reassignment surgery. The FACS sorted cells were cultured in vitro with Mouse Embryonic Fibroblasts (MEFS), resulting in the spontaneous generation of immature oocytes [39]. Later, these DDX4-positive cells were transduced with a Green Fluorescent Protein (GFP) expression vector and the GFP positive cells were injected into human ovarian cortical tissue [39]. After 72 h of ex vivo culture, the engineered human ovarian cortical tissue was transplanted into Nonobese Diabetic (NOD)-Severe Combined immunodeficient (SCID) female mice. After 7–14 days, it was found that the GFP positive large cells resembled oocytes [39]. However, there are still several questions remaining: What do these putative OSCs do in the ovary? Where do they come from? Most importantly, it is not clear if these putative OSCs could give rise to viable oocytes in the adult ovary, and could they be used to restore fertility? If the existence of OSCs in human ovary is confirmed, this would be beneficial for POF patients and female cancer survivors. 2.4.2. Ovary transplantation Following ovary transplantation in sheep two decades ago [40], the first successful series of human ovary transplantation (both fresh and frozen) was reported 10 years later [41–43]. Silber and colleagues performed a large series of nine consecutive successful fresh ovary transplants in identical twins discordant for POF, in the age range of 24–40 years [44]. All recipients had normal hormonal cycling and menstruation 77–142 days post-transplant. The transplantations resulted in 12 natural pregnancies and 9 healthy babies [44,45]. The post-thaw oocyte viability after ovarian tissue cryopreservation has been improved (N89%) by using vitrification methods, compared to traditional slow freezing (b 50%) [46]. For vitrification, the ovary cortex is cut into pieces of 1 × 10 × 10 mm (l × w × h). The ultra-thinness of the tissue is not

Please cite this article as: H. Sadri-Ardekani, A. Atala, Regenerative medicine for the treatment of reproductive system disorders: Current and potential options, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.019

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only crucial for the cryopreservation, but also for rapid revascularization after grafting [47]. By using frozen ovarian tissue for transplantation, at least 8 centers have reported pregnancies resulting in 17 live births from 12 patients (9 cancer survivors, 1 POF, 1 Polyangitis and 1 Sickle Cell) [42,43, 48–52]. Cryopreserved ovarian tissue can be used either for autotransplantation, which gives a chance for natural conception or for in vitro maturation of follicles for producing mature oocytes for use in in vitro fertilization (IVF). Recently Kawamura and colleagues [53] demonstrated an in vitro activation method for infertility treatment of POF patients. Under laparoscopic surgery, both ovaries were removed from 27 infertile POF patients (37.3 ± 5.8 years of age; 6.8 ± 2.1 years duration of amenorrhea), followed by fragmentation to disrupt Hippo signaling and then drug treatment (PTEN inhibitor and PI3K activator) to stimulate Akt signaling [53]. Histological evaluation showed residual follicles in 13 of 27 patients. Autografting was performed in these patients [53]. Trans-vaginal ultrasound monitoring revealed follicles growing in 8 of the 13 patients and mature oocytes were retrieved form 5 patients for IVF cycles [53]. One pregnancy and live birth after embryo transfer (using Intra Cytoplasmic Sperm Injection; ICSI) was reported in one of the patients [53]. 2.4.3. In vitro maturation (IVM) of ovarian follicles For cancer survivors that have the risk of reintroducing malignant cells at the time of ovary autotransplantation, in vitro maturation of cryopreserved ovarian follicles can be an ideal alternative. Traditionally, culture methods have been used for oocyte IVM using two different approaches: (a) culturing whole slices of ovarian tissue (organ culture) and (b) culturing isolated follicles [54]. In two-dimensional (2-D) culture systems, somatic cells detach from the oocyte and spread onto the culture surface, thereby disrupting somatic cell and oocyte communication [47]. Recent advances in 3-D culture methods using hydrogels have enabled mimicking of the native ovarian environment by maintaining follicular architecture, cell–cell interactions and paracrine signaling. These 3-D ovarian systems have been used in mouse models [55,56]. Shikanov and colleagues [55] used a Fibrin-Alginate Interpenetrating Network (FA-IPN; composed of fibrin and alginate gels) for in vitro culture of ovarian follicles. Oocytes obtained from FA-IPN culture system demonstrated a high rate (82%) of Metaphase II (MII). They hypothesized that the degradable component of this FA-IPN is particularly critical for clinical translation in order to support the greater than 106 fold increases in volume that human follicles normally undergo in vivo [56]. 2.4.4. Hormone replacement therapy Lack of ovarian hormones results in various pathological conditions such as urogenital complications and osteoporosis [57]. Although current pharmacological hormone replacement therapy (HRT) is able to compensate for the loss of ovarian hormone production, hormone delivery through traditional methods result in high serum concentrations that can lead to complications including increased incidence of heart disease and cancer, depending on the type of HRT regimen [58]. Cellbased hormone delivery may be an alternative that would provide physiologically normal levels of hormones that would not cause adverse effects. The most pressing challenge for cell-based HRT has been the lack of an appropriate means for delivering these cells into the body. Cell encapsulation techniques using biomaterials such as alginate may represent an elegant solution to this problem [59]. In a recent study, theca and granulosa cells isolated from rat ovaries were encapsulated in multilayer alginate microcapsules to recapitulate the native follicular structure. These constructs secreted adequate levels of 17 β-estradiol (E2), progesterone (P4), activin and inhibin ex-vivo for a period of 30 days. Using this technique as a regenerative medicine based approach for HRT may prove a safe and effective strategy for the treatment of low hormone conditions [60].

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3. Male reproductive system 3.1. Penis Congenital and acquired genitourinary tract anomalies of the penis require surgical reconstruction. Lack of sufficient normal autologous tissue is the main limitation for many surgeons addressing different conditions such as ambiguous genitalia, epispadias, hypospadias, micropenis, aphallia, severe chordee, impotence, female to male genital reassignment, and traumatic or iatrogenic penile defects [61–63]. The possibility of developing tissue composed of corporal cells in vivo has also been investigated [64]. Human corporal SMC and endothelial cells (EC) were seeded on biodegradable polymer scaffolds at concentrations of 20 × l06 and 10 × l06 cells per cm3 respectively. These constructs were then implanted in the subcutaneous space of nude mice [64]. Histological evaluation showed the formation of vascularized corpus cavernosum comprised of these two cell types (28 and 42 days, respectively) in vivo, post-implantation [64]. To achieve a 3-D corporal structure, naturally derived polymer scaffold from rabbit corporal tissue was used in combination with primary human cavernosal SMC and endothelial cells [65]. Engineered corporal tissues were maintained in culture for up to 4 weeks and then implanted into nude mice [65]. The matrices showed a stable collagen concentration 8 weeks post-implantation [65]. Immunocytochemical studies using α-actin and factor VIII antibodies confirmed the presence of corporal SMC and EC in vivo [65]. Organ bath studies also showed that the cell-seeded corporal tissue matrices responded to electrical field stimulation [65]. In a follow up study, structural parameters were evaluated up to 6 months post-implantation in a rabbit penile defect model [66], where the engineered corporal bodies showed structural integrity on cavernosography. The presence of sperm after copulation was confirmed in rabbits with the engineered corpora [66]. In all of these studies, it was shown that a short segment of the penile corporal body (approximately one-third of the penile corpora) can be replaced using naturally-derived collagen matrices with autologous cells [64–66]. To improve the results of previous studies, engineering of the entire length of both penile corpora was attempted [67]. Here, the matrices were seeded with the autologous corporal SMC and EC, using a novel multistep cell seeding protocol [68] and the cell seeded matrices were used to replace the entire pendular penile corpora in 12 male rabbits [67] At 1, 3 and 6 months following implantation of the engineered corpora, the rate of sperm presentation on vaginal swabs and pregnancy rates of mated female rabbits were found to be 83% and 30%, respectively. Untreated rabbits showed no evidence of intravaginal sperm and no pregnancies occurred. [67]. These studies demonstrate that penile corpora cavernosa tissue can be engineered and transplanted to restore function. 3.2. Testis 3.2.1. Spermatogonial Stem Cell (SSC) autotransplantation Every day in the United States on average, about five men become azoospermic due to the adverse effect of cancer treatments [69]. In adult men and adolescent boys suffering from cancer and who are at risk of infertility, sperm cryopreservation is the simple and the most effective method to preserve their fertility [70]. However, less than one fourth of these patients use sperm banking [71]. Lack of knowledge about sperm banking is one of the major reasons of low percentage of sperm storage [71]. However, since production of sperm does not start in prepubescent boys [72], sperm banking is not an option for these cancer patients. On average, more than 14 boys younger than 15 years of age are diagnosed with cancer every day and more than 80% of them will recover from their cancer [73]. Therefore, long-term infertility will be a critical issue for many of these childhood cancer survivors that have no option for sperm banking. Unlike the controversy surrounding the existence of OSCs in the ovary after birth [74,75], it is well known that SSCs are presented in the testis of most species, includes non-

Please cite this article as: H. Sadri-Ardekani, A. Atala, Regenerative medicine for the treatment of reproductive system disorders: Current and potential options, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.019

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human primates and human [76]. SSCs are rare cells that are located in the basement membrane of seminiferous tubules (Fig. 3) in the testis that play a primary role in spermatogenesis [76]. Normally, SSCs are able to divide and differentiate to haploid germ cells (sperm) and sustain fertility in men [76]. Brinster and colleagues [77] have established the feasibility of isolating and transplanting SSCs to restore fertility in mice. This has given great hope to physicians and researchers for finding an effective alternative for sperm banking in adult males, and may also represent a solution for restoring fertility in prepubescent boys following cancer treatment. Nagano and colleagues [78] isolated human SSCs from 6 infertile men, that were xenotransplanted to busolfan treated nude mice. The number of human SSCs was shown to engraft into mouse testis, but their numbers decrease significantly one month after transplantation. However, some SSCs remained in the mouse testis for up to 6 months without any evidence of differentiation [78]. Recently, a xenotransplantation study of prepubescent human SSCs showed similar results to the previous study on adult human SSCs [79]. The feasibility of SSC transplantation in a non-human primate model was demonstrated by Hermann and colleagues [80]. Here, ejaculatory lenti viral positive sperm was found in the testes of N75% of adult (9 out of 12) and 60% of matured prepubescent (2 out of 5) recipient macaques monkeys for up to 63 weeks (average of 40.1 ± 4.9 weeks) after lenti virusmarked SSC autotransplantation. [76] Auto transplantation (70.5%;12 out of 17) was two times more successful than allotransplantation (33.3%; 2 out of 6) in terms of presence of sperm in the ejaculate. [80] The competence of these sperm to fertilize eggs and develop preimplantation embryos was confirmed by performing ICSI. Full pregnancies and live births were not observed in this study [80]. Translating the above results from non-human primate models to human fertility clinics seems imminent. In the above study, an average of 88 ± 17.1 and 45.8 ± 14.5 million viable cells was used for transplantation [80]. It is known that increasing the number of cells corresponds linearly with the transplantation success rate [81]. The number of SSCs in testis is very low (0.03% of germ cells and 1.25% of spermatogonial cells in mice; unknown in human) [82,83], and the size of testicular biopsy from premature boys undergoing cancer treatment is also very small (around 100 mm3) [76]. Although human SSC autotransplantation has not been tried yet, it is expected that successful human SSC autotransplantation requires in vitro expansion of these cells prior to transplantation. Recently, in a study involving the isolation and culture of human testicular cells from 6 different adult men who underwent orchiectomy as part of their prostate cancer treatment, human SSCs could be maintained and proliferated in vitro for longer than 20 weeks [84].

Fig. 3. Localization of Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) [brown] in undifferentiated spermatogonial cells in a human testicular section (normal testis tissue from 61 year old Caucasian donor received via National Disease Research InterchangeNDRI) (counterstained with hematoxylin [blue]). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

The number of SSC increased more than 18,000-fold over 64 days of in vitro culture. In a follow up study using testicular tissue from 2 boys aged 6.5 and 8 years, who were diagnosed with Hodgkin's lymphoma, isolated SSCs were able to propagate in vitro for at least 15.5 to 20 weeks [85]. Before performing the first clinical trial of SSC autotransplantation in human, several safety issues need to be addressed. First, especially in non-solid cancer survivors (mainly hematopoietic malignancies), the transplanted cells should be free of any malignant cell contamination that may reintroduce the cancer to the recipient. In a study on culturing acute lymphoblastic leukemia (ALL) cells in combination with testicular cells from 3 different patients, ALL cells were undetectable beyond 26 days of culture even at extremely high initial concentration (40% ALL cells) [86]. However, it will be beneficial to test more cell lines from different types of leukemia to ensure complete purging of malignant cells. Second, the genetic integrity of stored, isolated and propagated SSCs is very important, as it can influence the next generation of offspring. It has been shown that in vitro expanded mouse SSCs showed normal karyotype and stable androgenetic imprinting over 24 months [87]. It has been shown that the genetic stability of in vitro propagated human SSCs was preserved, however some changes in the methylation status (epigenetics) of human SSCs during culture has been reported [88]. 3.2.2. Androgen replacement Testosterone is a complicated and critical hormone that plays multiple roles in vivo [89]. Patients with testicular dysfunction and hypogonadal disorders may need androgen replacement therapy in order to restore and maintain physiological levels of serum testosterone and its metabolites. Testosterone therapy can increase muscle strength, stabilize bone density, improve osteoporosis, and restore secondary sexual characteristics, including libido and erectile function [90]. However, long-term exogenous testosterone therapy is not optimal and can cause multiple problems, including excessive erythropoiesis, bone density changes and even infertility [91]. To address these problems, an effective method to provide sufficient endogenous testosterone is required. In an animal model, isolated Leydig cells from rats that were cultured and stimulated with human chorionic gonadotropin (HCG) showed a high level of testosterone production [92]. In this study, engineered alginate-poly-L-lysine-encapsulated Leydig cell microspheres (with an average diameter of 0.7 mm ± 0.06 mm) were injected into castrated rats. Approximately 10% of a normal adult rat Leydig cell population was injected into each castrated animal. The serum testosterone levels increased and were maintained up to 40% of normal level for a maximum period of 43 days, without any HCG stimulation [92]. Bilateral testicular agenesis or atrophy often requires placement of testicular prostheses and androgen supplementation [93]. In this regard, the possibility of creating hormone releasing testicular prostheses has been investigated [94]. Isolated chondrocytes from bovine articular cartilage were seeded on testicular shaped polymer scaffolds. Implanted engineered testis prostheses loaded with 100 μg testosterone enanthate were able to maintain the physiologic levels of testosterone in vivo for at least 16 weeks in recipient mice [94]. For a better outcome, combinations of Leydig cell technology and engineered testicular prosthesis need to be further explored. 3.2.3. Engineering vas deferens Congenital bilateral absence of the vas deferens (CBAVD) as a cause of obstructive azoospermia is common in about 1% of infertile men [95]. As CBAVD men have normal spermatogenesis, Assisted Reproduction Techniques (ARTs) make it possible for them to become biological fathers [96]. However, conception requires the female partner to undergo hormonal stimulation and an IVF/ICSI procedure. A solution to this problem would be replacing the vas deferens. A novel approach for the tissue engineering of vas deferens has been tried in a rabbit model

Please cite this article as: H. Sadri-Ardekani, A. Atala, Regenerative medicine for the treatment of reproductive system disorders: Current and potential options, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.019

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[31]. Polyethylene tubes (with 0.86 mm diameter and 6 cm length) were implanted into the peritoneal cavities (as an in vivo bioreactor) of 16 rabbits [31]. After 2 to 3 weeks, the tubes were removed and the encapsulating myofibroblast-rich tissue that resulted from the foreign body response to the biomaterial was harvested for grafting as vas deferens in the rabbits [31]. At 2, 4, 6 and 8 months postimplantation, morphological and immunohistochemical evaluations showed that the structure of engineered vas deferens was similar to native vas deferens tissue [31]. In addition, the presence of sperm in the ejaculate indicated normal function of the engineered vas deferens. However, more research on large animal models is required before this approach can be used in humans. 4. Conclusion The application of regenerative medicine technologies is currently being considered for treating several types of disorders of the female and male reproductive systems. Most of the effort towards engineering of reproductive tissues has occurred within the last two decades. Although animal models have shown the tremendous potential of regenerative medicine based therapies in this field, translation of these approaches to humans has been initiated in selected areas. Safety and effectiveness of engineered reproductive tissues are the most critical issues that need to be addressed prior to and during clinical trials. Acknowledgments We would like to thank Drs. John D. Jackson, Prafulla K. Chandra and Thomas D. Shupe for the editorial assistance. References [1] J.R. Fuchs, B.A. Nasseri, J.P. Vacanti, Tissue engineering: a 21st century solution to surgical reconstruction, Ann. Thorac. Surg. 72 (2001) 577–591. [2] J.L. Olson, A. Atala, J.J. Yoo, Tissue engineering: current strategies and future directions, Chonnam Med. J. 47 (2011) 1–13. [3] A. Atala, F.K. Kasper, A.G. Mikos, Engineering complex tissues, Sci. Transl. Med. 4 (2012) 160rv112. [4] N. Kimberley, J.M. Hutson, B.R. Southwell, S.R. Grover, Vaginal agenesis, the hymen, and associated anomalies, J. Pediatr. Adolesc. Gynecol. 25 (2012) 54–58. [5] J.C. Lankford, P. Mancuso, R. Appel, Congenital reproductive abnormalities, J. Midwifery Women's Health 58 (5) (2013) 546–551. [6] D. Habek, T. Kulas, Nonobstetrics vulvovaginal injuries: mechanism and outcome, Arch. Gynecol. Obstet. 275 (2007) 93–97. [7] R.E. De Filippo, C.E. Bishop, L.F. Filho, J.J. Yoo, A. Atala, Tissue engineering a complete vaginal replacement from a small biopsy of autologous tissue, Transplantation 86 (2008) 208–214. [8] J. Wefer, N. Sekido, K.D. Sievert, N. Schlote, L. Nunes, R. Dahiya, U. Jonas, E.A. Tanagho, Homologous acellular matrix graft for vaginal repair in rats: a pilot study for a new reconstructive approach, World J. Urol. 20 (2002) 260–263. [9] S.K. McQuillan, S.R. Grover, Dilation and surgical management in vaginal agenesis: a systematic review, Int. Urogynecol. J. 25 (2014) 299–311. [10] R.E. De Filippo, J.J. Yoo, A. Atala, Engineering of vaginal tissue in vivo, Tissue Eng. 9 (2003) 301–306. [11] K.E. Morton, C.J. Dewhurst, Human amnion in the treatment of vaginal malformations, Br. J. Obstet. Gynaecol. 93 (1986) 50–54. [12] J. Dornelas, Z.I. Jarmy-Di Bella, T. Heinke, M.M. Kajikawa, C.C. Takano, E.V. Zucchi, M.J. Girao, Vaginoplasty with oxidized cellulose: anatomical, functional and histological evaluation, Eur. J. Obstet. Gynecol. Reprod. Biol. 163 (2012) 204–209. [13] J.H. Zhou, J. Sun, C.B. Yang, Z.W. Xie, W.Q. Shao, H.M. Jin, Long-term outcomes of transvestibular vaginoplasty with pelvic peritoneum in 182 patients with Rokitansky's syndrome, Fertil. Steril. 94 (2010) 2281–2285. [14] J.X. Ding, X.Y. Zhang, L.M. Chen, K.Q. Hua, Vaginoplasty using acellular porcine small intestinal submucosa graft in two patients with Meyer–von-Rokitansky–Kuster– Hauser syndrome: a prospective new technique for vaginal reconstruction, Gynecol. Obstet. Investig. 75 (2013) 93–96. [15] W.C. Lin, C.Y. Chang, Y.Y. Shen, H.D. Tsai, Use of autologous buccal mucosa for vaginoplasty: a study of eight cases, Hum. Reprod. 18 (2003) 604–607. [16] P.B. Panici, F. Bellati, T. Boni, F. Francescangeli, L. Frati, C. Marchese, Vaginoplasty using autologous in vitro cultured vaginal tissue in a patient with Mayer–vonRokitansky–Kuster–Hauser syndrome, Hum. Reprod. 22 (2007) 2025–2028. [17] A.M. Raya-Rivera, D. Esquiliano, R. Fierro-Pastrana, E. Lopez-Bayghen, P. Valencia, R. Ordorica-Flores, S. Soker, J.J. Yoo, A. Atala, Tissue-engineered autologous vaginal organs in patients: a pilot cohort study, Lancet 384 (2014) 329–336. [18] T.N. Raju, The problem of late-preterm (near-term) births: a workshop summary, Pediatr. Res. 60 (2006) 775–776.

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Please cite this article as: H. Sadri-Ardekani, A. Atala, Regenerative medicine for the treatment of reproductive system disorders: Current and potential options, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.019

Regenerative medicine for the treatment of reproductive system disorders: current and potential options.

Regenerative medicine has opened new avenues for treating patients with severe reproductive system disorders, such as congenital abnormalities, cancer...
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