The first published report showing germ cell differentiation from PSCs in vitro was on female gamete derivation from mouse ESCs
[1]. Hübner et al. generated oocyte-like structures, which were randomly formed through EB formation, followed by two-dimensional culture. These non-directed differentiation protocols, or random differentiation, allowed even male ES cells to differentiate into oocyte-like structures. Similarly, Lacham-Kaplan et al. obtained presumptive ovary-like structures from male ESC-derived EBs using the conditioned medium from neonatal testis cells. The obtained structures contained oocyte-like cells expressing oocyte markers (
Fig-
α and
ZP3), indicating the possible production of female germ cells from male PSCs
[42][78]. However, these results were inconsistent with the proposed methods and lacked demonstration of functionality
[11][48]; thus, further research is required. As previously mentioned, Hayashi et al. showed that in vitro-derived PGCLCs could further differentiate into functional oocytes in reconstituted ovaries after transplantation into female mice
[4]. Combining these methods, Hayashi and colleagues, in 2016, finally derived MII oocytes from mouse ESCs in an entirely in vitro system
[43][79]. They derived EpiLCs from mouse ESCs and further differentiated the EpiLCs into PGCLCs, which were then aggregated with E12.5 gonadal somatic cells. These aggregates were cultured for approximately 5 weeks in three steps: in vitro differentiation, in vitro growth, and in vitro maturation
[43][44][79,80]. The aggregates of PGCLCs and gonadal somatic cells formed a follicular structure that successfully simulated the in vivo ovarian environment and performed the key events of oogenesis in vitro, including the formation of cumulus-oocyte complexes and development of MII oocytes
[43][44][79,80]. These in-vitro-generated oocytes could be fertilized in vitro with wild-type sperm and developed into 2-cell embryos, giving rise to healthy fertile pups after transfer to pseudopregnant surrogate mice. However, the successful full-term development rate was as low as 3.5%. This in-vitro-oocyte generation method was also valid for iPSC lines reprogrammed from mouse embryonic fibroblasts
[43][79]. Overall, this platform for in vitro gametogenesis by aggregating PSC-derived PGCLCs with gonadal somatic cells faithfully reconstitutes the in vivo-like gonadal environment in both males and females
[32][36][43][44][68,72,79,80]. However, this approach still shows meiosis and epigenetic imperfections compared with their in vivo counterparts and requires embryonic somatic cells
[32][43][68,79], which cannot be used in the clinic. Nevertheless, this differentiation method provides a useful in vitro system for studying the interaction between gametes and gonadal somatic cells
[45][46][81,82].
Recently, oocyte-like cells were directly induced without specification into PGCLCs
[47][83]. Hamazaki et al. generated follicle structures from mouse ESCs and iPSCs aggregated with E12.5 female gonadal somatic cells through forced expression of eight transcription factors important for primordial-to-primary-follicle transition (PPT), such as
Nobox,
Figla,
Tbpl2,
Sohlh1,
Stat3,
Dynll1,
Sub1, and
Lhx8. Oocyte-like cells of the follicle structures could develop into MII oocytes, which were competent for fertilization with sperm and early embryonic development until the 8-cell stage. Overexpression of these eight transcription factors was not sufficient for the induction of oocyte-like cells from somatic cells (MEFs), suggesting that a pluripotent state is required for the induction of germ cells by overexpression of the eight transcription factors. However, it is still unknown whether different transcription factor combinations may induce germ cell specification in somatic cells.
Furthermore, follicle-like cells (FLCs) were first derived from human PSCs by forced expression of DAZL and BOULE, which are involved in in vivo germ cell specification as discussed above
[17][48][54,84]. Germ cell commitment from hESCs was first induced by BMP4 and BMP8a treatment followed by meiosis induction by lentiviral overexpression of DAZL and BOULE with the subsequent addition of GDF9 and BMP15. Follicle-like structures with oocyte-like cells surrounded by multilayered cell aggregates appeared on day 9 after differentiation. These oocyte-like cells expressed ZP2, NOBOX, AMH, and VASA and were found to have primordial oocyte identity, as confirmed by transcriptome analysis. In addition, transplantation of FLCs into kidney capsules resulted in the formation of primordial follicle-like structures, indicating that hESC-derived FLCs are functional ovarian follicles. This in vitro FLC derivation system could be used to elucidate the early mechanism of human germline development and folliculogenesis, the details of which are still elusive.
3. Germ Cell Derivation via Synthetic Embryo Formation
In addition to direct differentiation from PSCs, synthetic embryo formation is an emerging technique for the derivation of germ cells in vitro. Aggregation of two or three types of blastocyst-derived stem cells, including ESCs, trophoblast stem cells (TSCs), and extra-embryonic endoderm (XEN) cells, can form early embryo-like structures or synthetic embryos, mimicking natural embryos
[49][50][51][52][85,86,87,88]. In 2017, Zernicka-Goetz and colleagues first generated synthetic embryos, ETS-embryos, by aggregating ESCs and TSCs, which were then cultured in a 3D-extracellular matrix (ECM) scaffold
[49][85]. ETS-embryos successfully formed a proamniotic cavity and underwent key spatiotemporal morphogenesis of peri- and post-implantation stages, as seen at E6.5 natural embryos, leading to the specification of PGCs expressing
Stella,
Prdm14,
Tfap2c,
Nanos3, and
Ddx4. PGC specification in ETS-embryos was found to be induced by BMP-SMAD signaling, similar to natural embryogenesis.
Moreover, ETX embryos formed by the incorporation of ESCs, TSCs, and XEN cells developed to form gastruloid-like natural E7.0 mid-gastrular embryos
[50][86]. ETX gastruloids showed more efficient mesodermal specification than ETS-embryos and asymmetric patterning, that is, anterior and posterior axis followed by PGC specification as shown by
Stella- and
Prdm14-positive populations at the posterior portion of the boundary of ESC and TSC compartments
[50][86]. Similarly, ETX embryos generated under a nonadherent-suspension-shaking culture system also showed asymmetric patterning of PGC specification
[51][87]. However, these synthetic embryos showed limited developmental potential only in the early post-implantation stage. Therefore, it is not yet known whether subsequent germline differentiation beyond early PGC specification through synthetic embryo formation is possible. However, these studies demonstrated that differentiation via synthetic embryo formation can be another way to generate PGCs from PSCs in vitro.
Recently, Liu et al. reported the successful generation of a human blastocyst-like structure (iBlastoid) via reprogramming of fibroblasts
[53][89]. During pluripotential reprogramming, unwanted cell types, such as trophoblasts and primitive endoderm and epiblast cells, emerged in the same dish by day 21 post-induction. After 3D culture of these heterogeneous cell populations in the AggreWell system for 6 days, aggregates developed into E5–7 human blastocyst-like structures, that is, iBlastoids. Under attachment culture of iBlastoids to test peri-implantation development, iBlastoids did not show any morphological signs of implantation or gastrulation. Although human PGCs have not been derived through synthetic embryo (iBlastoid) formation, we cannot rule out the possibility of this method as an alternative method to generate PGCs in vitro by reprogramming somatic cells.
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