In vitro Differentiation of Germ Cells from Stem Cells

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In vitro Differentiation of Germ Cells from Stem Cells Xinbao Ding1, Jian Wang1 and Ji Wu1,2,3,* 1

Key Laboratory for the Genetics of Developmental & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China; 2Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750004, China; 3Shanghai Key Laboratory of Reproductive Medicine, Shanghai 200025, China Abstract: Stem cells are unique cell types with the ability of self-renewal and differentiation, which mainly include embryonic stem cells, induced pluripotent stem cells, and adult stem cells. Recently, Ji Wu several research groups have reported that stem cells can differentiate into germ cells under appropriate conditions in vitro. Advances in this field have revealed new perspectives for reproductive and regenerative medicine. Here, we review the progress of in vitro gamete production from stem cells.

Keywords: Stem cells, differentiation, germ cells. INTRODUCTION Germ cells are responsible for the transmission of genetic information from one generation to the next. In mammals, the germ cell lineage is induced by extrinsic and intrinsic signaling molecules. Primitive germline cells, which are referred to as primordial germ cells (PGCs), are derived from the proximal part of the epiblast cell population. Bone morphogenetic proteins (Bmps), including Bmp4, Bmp2, and Bmp8b, and Wnt signaling are essential for PGC specification in mouse embryos [1-6]. After specification, PGCs migrate through the dorsal mesentery, enter the female and male genital ridge, and subsequently differentiate into oogonia and gonocytes, respectively. Meiosis is a specialized type of cell division to produce germ cells with a haploid number of chromosomes. In mammals, meiotic initiation occurs in female germ cells during fetal development and in male germ cells after birth. It is generally accepted that RA (retinoic acid) induction of Stra8 (Stimulated by retinoic acid gene 8) is necessary and sufficient for meiotic initiation in mammals [7-9]. However, a recent study has demonstrated that RA induction of Rec8 occurs in parallel with induction of Stra8 and independently of Stra8 functions to activate meiosis [10]. Stem cells are undifferentiated cells that have the potential of self-renewal and differentiation into specialized cell types. In mammals, stem cells mainly include embryonic stem cells (ESCs) [11-13], induced pluripotent stem cells (iPSCs) [14-16], and adult stem cells (ASCs) in various tissues. ESCs and iPSCs are pluripotent stem cells with the capacity to differentiate into any cell type of the body. *Address correspondence to this author at the Bio-X Institutes, Shanghai Jiao Tong University, No. 800. DongchuanRoad, Minhang District, Shanghai, 200240, China; Tel: 86-21-34207263; Fax: 86-21-34204051; E-mail: [email protected] 1874-4672/16 $58.00+.00

Spermatogonial stem cells (SSCs, also known as male germline stem cells) [17, 18] and female germline stem cells (FGSCs, also known as oogonial stem cells [OSCs]) [19-23] are unipotent stem cells located in the seminiferous tubules of the testes and the cortex of ovaries, which have the capacity to differentiate into sperms and oocytes, respectively. Several reports have documented that PGC-, sperm-, and oocyte-like cells can be differentiated from various types of stem cells in vitro. Here, we describe recent progress in the derivation of germ cells from ESCs, iPSCs, and ASCs including SSCs and FGSCs. GERM CELLS DIFFERENTIATED FROM ESCs AND iPSCs Hubner et al. firstly reported the ability of ESCs to differentiate into oocytes in vitro. They found that mouse ESCs of both sexes would spontaneously form follicle-like structures under feeder-free and leukemia inhibitory factor-free culture conditions without any other inducing factors. The oocyte-like cells extruded from these structures entered meiosis and later developed into blastocysts [24]. However, Novak et al. found that the oocytes generated from mouse ESCs did not progress through meiosis [25]. Lacham-Kaplan et al. showed that male mouse ESCs form ovarian-like structures containing putative oocytes in embryoid bodies (EBs) when cultured in newborn mouse testicular cell-conditioned medium [26]. Qing et al. found that ovarian granulosa cells induce both male and female mouse ESCs to differentiate into oocyte-like cells expressing meiosis- and oocytespecific genes [27]. Alexandre et al. demonstrated that both putative follicle-like structures and sperm-like cells existed in the same EBs from one male mouse ESC line. A putative blastocyst-like structure was also shown [28]. However, aberrant gene expression and sexually incompatible genomic imprinting are observed in oocytes differentiated from male © 2016 Bentham Science Publishers

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mouse ESCs [29]. Aflatoonian et al. revealed that PGCs and post-meiotic spermatids are easily detected in EBs formed by human ESCs after treatment with RA, but there is no development of oocytes in a follicle-like structure [30]. Similarly, Alexandre et al. used an RA differentiation protocol to produce sperm- and oocyte-like cells from mouse ESCs [28]. Hu et al. demonstrated that more PGC- and oocyte-like cells are produced by treatment with RA rather than porcine follicular fluid [31]. Eguizabal et al. obtained post-meiotic cells from both male and female iPSCs using a three-step differentiation protocol in the presence of RA [32]. Using a dual fluorescence reporter system in which mouse ESCs express green fluorescent protein (GFP) under the control of the gene promoter of Pou5f1, an oocyte marker, and red fluorescent protein (Discosoma sp red [DsRed]) driven by the gene promoter of Foxl2, a granulosa cell marker, Woods et al. observed follicle-like structures containing GFP-positive cells surrounded by DsRed-positive cells in vitro [33]. Toyooka et al. firstly differentiated sperm-like cells from mouse ESCs using a knock-in ESC line in which GFP or lacZ expression was driven by endogenous Ddx4, which is specifically expressed in the germ cell lineage, to visualize germ cell production during in vitro differentiation. Differentiation of Ddx4-positive germ cells in EBs was greatly enhanced by Bmp4-producing feeders. These germ cells participated in spermatogenesis when transplanted into reconstituted testicular tubules [34]. Treatment with BMPs, including BMP4, BMP7, and BMP8b, also induces differentiation of germ cells positive for DDX4 and SYCP3 from human ESCs [35]. In addition, Geijsen et al. described the capacity of mouse ESCs to differentiate into mature male gametes. They isolated PGCs from EBs using stage-specific embryonic antigen 1, a marker of PGCs, and derived continuously growing lines of embryonic germ cells with erasure of the methylation imprints of Igf2r and H19 genes. EBs also support the maturation of PGCs into haploid male gametes, resulting in the formation of blastocysts [36]. Nayernia et al. used two fusion genes, Stra8-EGFP and protamine 1 (Prm1)DsRed, harboring EGFP- and DsRed-coding regions under the control of Stra8 and Prm1 gene promoters, respectively, to monitor the development of SSCs from ESCs. These SSCs are able to undergo meiosis, generate haploid male gametes in vitro, and are functional, as shown by fertilization after intracytoplasmic injection into mouse oocytes and generation of offspring [37]. Easley et al. showed that human ESCs and iPSCs can directly differentiate into male germ cell lineages in vitro, including postmeiotic spermatid-like cells, under standardized mouse SSC culture conditions [38]. Miryounesi et al. found that Sertoli cells induce meiosis of mouse ESCs, which is comparable to the effect of RA [39]. Lim et al. developed a three-step medium and calcium alginate-based threedimensional (3D) culture system to enhance the differentiation of human ESCs into SSC-like cells and haploid germ cells. Firstly, EBs derived from ESCs are treated with BMP4 and RA to specify SSC-like cells. Secondly, the germ cells are purified based on GFRA1 expression and expanded in germ cell-specific medium. Finally, a 3D co-culture system using calcium alginate encapsulation and testicular somatic cells is applied to induce differentiation into haploid germ cells [40]. Yamauchi et al. investigated the effects of mouse gonadal cell-conditioned medium and growth factors on germ cell

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differentiation of monkey ESCs via EB formation. They found that both conditions promoted this process and revealed that the addition of BMP4 to differentiating ESCs increases the expression of SCP1, a meiotic marker gene [41]. Silva et al. examined the temporal profile of genes expressed at various stages of male germ cell differentiation from ESCs induced by RA and testosterone [42]. Furthermore, it has been reported that SSCs can be reprogrammed to pluripotent stem cells (multipotent adult germline stem cells, maGSCs) in vitro with a differentiation potential comparable to ESCs and iPSCs [43-45]. Nolte et al. developed an alternative method to generate haploid male germ cells in vitro. They first reprogrammed SSCs into maGSCs, followed by differentiation into germ cells using RA and a double-selection strategy [46]. Recently, Wang et al. demonstrated that female embryonic stem-like cells (fESLCs) can be generated from stably proliferating FGSCs cultured in ESC medium. These fESLCs exhibit properties similar to those of ESCs in terms of marker expression and differentiation potential [47]. However, it is unknown whether these fESLCs can differentiate into germ cells. Kee et al. used a GFP-conjugated DDX4 reporter to quantify and isolate PGCs derived from both human male and female ESCs. By silencing and overexpressing several genes encoding germ cell-specific cytoplasmic RNA-binding proteins, they found that DAZL (deleted in azoospermia-like) functions in PGC formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes [48]. Yu et al. also found that ectopic expression of Dazl in mouse ESCs induces both motile-tailed sperms and oocytes in vitro without EB formation [49]. Wei et al. demonstrated that PGC derivation is more faithfully recapitulated using the EB method rather than attachment culture. They also found that Bmp4 and Wnt3a promote PGC derivation, whereas Bmp8b and activin A have no observable effect [50]. West et al. showed that signaling from MEF (mouse embryonic fibroblast) feeders and basic fibroblast growth factor induce a highly enriched population of germ-like cells from human ESCs [51]. Furthermore, human fetal gonadal cells significantly improve the efficiency of human ESC and iPSC differentiation into PGCs [52]. Using the same strategy as Geijsen et al [36], Tilgner et al. purified PGCs from human ESCs. These cells express a high level of DDX4 and show removal of parental imprints and chromatin modifications that support their PGC identity [53]. Panula et al. compared the potential of human iPSCs derived from adult and fetal somatic cells to form primordial and meiotic germ cells [54]. They found that BMPs induce differentiation of PGCs from iPSCs, and DAZL, BOULE, and DAZ induce the formation of the synaptonemal complex, which is similar to the results of Kee et al. and Yu et al. [48, 49]. Hayashi et al. demonstrated that male mouse ESCs and iPSCs can differentiate into PGClike cells through epiblast-like cells using cytokines such as Bmp4 and Bmp8b. These PGC-like cells have global transcription and epigenetic profiles similar to those of endogenous PGCs. They also have the capacity for spermatogenesis and offspring production when transplanted into the seminiferous tubules of W/Wv neonatal mice lacking endogenous germ cells [55]. Using a similar strategy, they generated PGC-like cells from female mouse ESCs and iPSCs.

In vitro Differentiation of Germ Cells from Stem Cells

After transplantation into reconstituted ovaries, reaggregation of PGC-like cells with embryonic day 12.5 gonads under the ovarian bursa generated oocytes with the capacity for fertilization resulting in offspring [56]. Without cytokines, epiblast-like cells derived from ESCs can also be directly induced into a PGC state rapidly and efficiently by simultaneous overexpression of Prdm1 (also known as B lymphocyte induced maturation protein 1, Blimp1) [57], Prdm14 [58], and Tfap2c (also known as AP2) [59] in vitro [60]. In principle, these transcriptional factors are sufficient for PGC specification and unprecedented resetting of the epigenome towards a basal state [61]. Kimura et al. demonstrated that inhibition of extracellular signal-regulated kinase (ERK) signaling by a MAPK/ERK kinase inhibitor in mouse ESCs efficiently induces PGC-like cells [62]. Li et al. derived PGC-like cells (iPGCLCs) from mouse iPSCs via induced epiblast-like cells as demonstrated by monitoring the expression of EGFP under the control of Stra8 gene promoter (Stra8-EGFP). These iPGCLCs express numerous marker genes and undergo spermatogenesis upon transplantation into the testis of infertile W/Wv mice. Furthermore, iPGCLCs can be either induced to germline stem cell-like cells or reverted back to embryonic germ cell-like cells [63]. GERM CELLS DIFFERENTIATED FROM NONGERMLINE ASCs Dyce et al. differentiated stem cells isolated from the skin of porcine fetuses into oocyte-like cells in vitro [64]. These fetal skin stem cells formed follicle-like aggregates when cultured with porcine follicular fluid and exogenous gonadotrophin. Some oocyte-like cells extruded from these aggregates would spontaneously develop into parthenogenetic embryo-like structures, which is similar to the findings of Hubner et al. [24]. They also found that skin-derived stem cells from both male and female porcine fetuses can generate oocytes in vitro [65]. Subsequently, the same group differentiated porcine skin-derived stem cells into PGC-like cells in vitro [66]. Shen et al. demonstrated that midkine, a heparinbinding growth factor, promotes the proliferation of PGClike cells derived from stem cells in porcine fetal skin by inhibition of DAZL gene expression. Similar to the finding that DAZL initiates meiosis of PGCs [67], they also found that overexpression of DAZL promotes meiosis and decreases PGC-like cell proliferation [68]. Moreover, similar to ESCs [48, 49], Park et al. showed that exogenous expression of DAZL enhances in vitro-derived porcine germ cell formation from stem cells in porcine fetal skin and their subsequent meiosis [69]. Danner et al. showed that a clonal cell line derived from adult pancreatic stem cells forms aggregates. These 3D aggregates produced terminally differentiated oocyte-like cells based on morphological criteria and molecular markers at the outside margin [70]. Using Stra8EGFP transgenic mice, Nayernia et al. demonstrated that bone marrow-derived stem cells can transdifferentiate into male germ cells under stimulation by RA [71]. GERM CELLS DIFFERENTIATED FROM GERMLINE STEM CELLS Carlomagno et al. used a rat SSC line to elucidate the role of Bmp4 in SSC differentiation in vitro. They found that Bmp4 up-regulates the expression of Kit, an early marker of

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differentiating spermatogonia, and affects cell adhesion pathways [72]. Lee et al. isolated SSC-like cells from testicular tissue of non-obstructive azoospermic patients and differentiated these cells into haploid germ cells in vitro by encapsulation in differentiation medium containing calcium alginate [73]. Using a 3D agar culture system, Elhija et al. differentiated testicular germ cells into spermatozoa in vitro [74]. Riboldi et al. demonstrated that co-cultured Sertoli cells induce meiosis of CD49f+ (a marker of SSCs) cells from testicular sperm samples of azoospermic patients and generate haploid cells in vitro [75], which is similar to the findings of Miryounesi et al in ESCs [39]. Recently, Yang et al. reported that the combined use of RA and stem cell factor efficiently differentiate human SSCs from cryptorchidism patients into functional round spermatids, as shown by fertilization after round spermatid microinjection into mouse oocytes [76]. Organ culture is an alternative strategy to differentiate SSCs into sperms in vitro. Gohbara et al. used AcrGFP and Gsg2 (haspin)-GFP mice to monitor mouse spermatogenesis in an organ culture system. Acr and Gsg2 are expressed at the mid and end stages of meiosis onward, respectively. They demonstrated that some cells in this culture system undergo complete meiosis to form round spermatids [77]. The same group subsequently found that the efficiency of meiosis completion and the formation of spermatids and sperm are increased by the addition of knockout serum replacement instead of fetal bovine serum to the organ culture medium [78]. This system was examined further to demonstrate that SSCs injected into the seminiferous tubules within recipient testes proceed through meiosis to form reproductively functional haploid gametes [79]. The authors also showed their system can be used to correct spermatogenic defects in vitro. They found that the addition of recombinant c-kit ligand (Kitl) and colony stimulating factor-1 to the medium of organ cultures induces spermatogenesis to proceed through meiosis in Sl/Sld mouse testes that contain only primitive spermatogonia as germ cells and lack any sign of spermatogenesis owing to mutations of the Kitl gene in Sertoli cells [80]. FGSCs are newly documented germline stem cells in postnatal mammalian ovaries. They provide alternative strategy to study mammalian oogenesis in vitro. Zou et al. firstly isolated FGSCs from neonatal and adult mouse ovaries. FGSCs in long-term culture maintain their capacity to produce normal oocytes and fertile offspring after transplantation into ovaries [19]. Using a similar strategy, germline stem cells with the capacity to differentiate into large cells exhibiting the morphological and molecular characteristics of oocytes were also found in the mouse ovary [20]. White et al. isolated OSCs from the ovaries of reproductive-age women. These cells had the capacity to spontaneous differentiate into oocytes in vitro and enter meiosis [22]. Their subsequent study showed that Bmp4-mediated signaling in adult mouse OSCs drives the differentiation of these cells into oocytes through Smad1/5/8 activation and up-regulation of key meiosis-initiating genes including Msx1/2 [81] and Stra8 in vitro [82]. Zhou et al. obtained FGSCs from 5-dayold female rat ovaries. They developed a three-step system to differentiate FGSCs into germinal vesicle stage oocytes in vitro, although further studies are required to determine their functional quality [23].

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PROSPECTS Infertility rates are obviously increasing worldwide because of the influence of disease, environmental pollution, and many other factors. Assisted reproductive technology has been widely used to treat infertility. However, it is still difficult to treat the infertility of patients lacking gametes without the capacity of fertilization. Surprisingly, some progress in the differentiation of stem cells into germ cells has made it possible to obtain functional gametes including sperm and metaphase II stage oocytes in vitro. To date, many studies have demonstrated that stem cells, including ESCs, iPSCs, and ASCs, have the potential to differentiate into PGCs, male and female presumptive gametes. The process of differentiating ESCs and SSCs into gametes has been well studied in vitro (Fig. 1). However, some remaining problems

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stem cells in vitro. Secondly, it is necessary to evaluate whether accurate epigenetic modifications and imprinting are established in gametes obtained from stem cells in vitro. Finally, such differentiation processes need to be reproducible and efficient to meet clinical needs. Apart from their practical use in clinical applications, stem cells are an ideal model to study the mechanisms of germ cell formation and gametogenesis. Drug screening using gametes generated from stem cells in vitro is another potential application. For example, contraceptives can be screened by observing the cytotoxic and functional effects of candidate drugs. Moreover, stem cell-derived gametes can be used to analyze the effects of environmental pollutants on germ cell development. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS This work was supported by National Basic Research Program of China (grant numbers 2013CB967401; http://www.most.gov.cn)and the National Nature Science Foundation of China (grant numbers81370675, 81200472 and 81121001; http://www.nsfc.gov.cn), and Shanghai Jiao Tong University Medicine-Engineering Fund (grant numberYG2013ZD04; http://www.sjtu.edu.cn). REFERENCES [1]

Fig. (1). Overview of germ cells differentiation from stem cells in vitro. PGCs, SSCs, and FGSCs can be converted to pluripotent stem cells, EGCs, maGSCs, and fESLCs, respectively, in vitro without genetic manipulation. Pluripotent stem cells including ESCs, iPSCs, maGSCs, EGCs, and fESLCs can generate gametes through epiblast cells, PGCs, and SSCs or FGSCs. The differentiation processes documented are indicated by the solid lines, whereas the processes requiring further confirmation are shown by the dotted lines. Abbreviations: maGSC, multipotent adult germline stem cell; EGC, embryonic germ cell; ESC, embryonic stem cell; iPSC, induced pluripotent stem cell; fESLC, female embryonic stem-like cell; PGC, primordial germ cell; SSC, spermatogonial stem cell; FGSC, female germline stem cell.

require resolution. Firstly, meiosis is a specialized type of cell division to produce haploid gametes. While sperm- and oocyte-like cells have been generated from stem cells in vitro, the frequency of complete meiosis varies in each study. In mice, female germ cells enter meiosis at around 13.5 days post-coitus (dpc) and arrest in the diplotene stage beginning at 17.5 dpc [83]. Subsequently, the individual oocytes are enclosed by pre-granulosa cells to form primordial follicles [84-86] and recruited to differentiate into functional oocytes. Recently, Dokshin et al. demonstrated that growth and differentiation into oocytes are dissociable from the chromosomal events of meiosis [87]. However, it is difficult to regulate these two events during oocyte-like cell generation from

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Accepted: April 27, 2015

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