Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Gamete derivation from embryonic stem cells, induced pluripotent stem cells or somatic cell nuclear transfer-derived embryonic stem cells: state of the art

Charles A. Easley IV A , Calvin R. Simerly B C and Gerald Schatten B C D
+ Author Affiliations
- Author Affiliations

A Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.

B Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15108, USA.

C Magee Womens Research Institute, Pittsburgh Development Center, Pittsburgh, PA 15108, USA.

D Corresponding author. Email: schattengp@upmc.edu

Reproduction, Fertility and Development 27(1) 89-92 https://doi.org/10.1071/RD14317
Published: 4 December 2014

Abstract

Generating gametes from pluripotent stem cells (PSCs) has many scientific justifications and several biomedical rationales. Here, we consider several strategies for deriving gametes from PSCs from mice and primates (human and non-human) and their anticipated strengths, challenges and limitations. Although the ‘Weismann barrier’, which separates the mortal somatic cell lineages from the potentially immortal germline, has long existed, breakthroughs first in mice and now in humans are artificially creating germ cells from somatic cells. Spermatozoa with full reproductive viability establishing multiple generations of seemingly normal offspring have been reported in mice and, in humans, haploid spermatids with correct parent-of-origin imprints have been obtained. Similar progress with making oocytes has been published using mouse PSCs differentiated in vitro into primordial germ cells, which are then cultured after xenografting reconstructed artificial ovaries. Progress in making human oocytes artificially is proving challenging. The usefulness of these artificial gametes, from assessing environmental exposure toxicity to optimising medical treatments to prevent negative off-target effects on fertility, may prove invaluable, as may basic discoveries on the fundamental mechanisms of gametogenesis.

Additional keywords: embryonic stem cells, gametes, in vitro gametogenesis, iPS, scnt.


References

Bao, S., Tang, F., Li, X., Hayashi, K., Gillich, A., Lao, K., and Surani, M. A. (2009). Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells. Nature 461, 1292–1295.
Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtlOjt77M&md5=97a444fd15417971edee3a68e816382fCAS | 19816418PubMed |

Chuva de Sousa Lopes, S. M., Hayashi, K., Shovlin, T. C., Mifsud, W., Surani, M. A., and McLaren, A. (2008). X chromosome activity in mouse XX primordial germ cells. PLoS Genet. 4, e30.
X chromosome activity in mouse XX primordial germ cells.Crossref | GoogleScholarGoogle Scholar | 18266475PubMed |

Cibelli, J. B., Campbell, K. H., Seidel, G. E., West, M. D., and Lanza, R. P. (2002). The health profile of cloned animals. Nat. Biotechnol. 20, 13–14.
The health profile of cloned animals.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xis12gsg%3D%3D&md5=b3d69d600651d3fd4e4c7d0ae536205dCAS | 11753346PubMed |

Daley, G. Q. (2007). Gametes from embryonic stem cells: a cup half empty or half full? Science 316, 409–410.
Gametes from embryonic stem cells: a cup half empty or half full?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXktlSrsr4%3D&md5=c4426b58e4be5eae8f50d270361f82b8CAS | 17446394PubMed |

Easley, C. A., Miki, T., Castro, C. A., Ozolek, J. A., Minervini, C. F., Ben-Yehudah, A., and Schatten, G. P. (2012a). Human amniotic epithelial cells are reprogrammed more efficiently by induced pluripotency than adult fibroblasts. Cell. Reprogram. 14, 193–203.
Human amniotic epithelial cells are reprogrammed more efficiently by induced pluripotency than adult fibroblasts.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XotlCgt7Y%3D&md5=4be79402abfe5037d02a2dd11a9bf819CAS | 22686477PubMed |

Easley, C. A., Phillips, B. T., McGuire, M. M., Barringer, J. M., Valli, H., Hermann, B. P., Simerly, C. R., Rajkovic, A., Miki, T., Orwig, K. E., and Schatten, G. P. (2012b). Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep. 2, 440–446.
Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhsFSmsL%2FP&md5=18ccedc0c50aa61da6ec22d4bb05535dCAS | 22921399PubMed |

Easley, C. A., Phillips, B. T., Wu, G. J., Schatten, G., and Simerly, C. (2012c). Clinical implications of human spermatogenesis initiation in vitro. J. Med. Sci. 32, 257–263.

Easley, C. A., Simerly, C. R., and Schatten, G. (2013). Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility? Reprod. Biomed. Online 27, 75–80.
Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility?Crossref | GoogleScholarGoogle Scholar | 23664220PubMed |

Easley, C. A., Latov, D. R., Simerly, C. R., and Schatten, G. (2014). Adult somatic cells to the rescue: nuclear reprogramming and the dispensability of gonadal germ cells. Fertil. Steril. 101, 14–19.
Adult somatic cells to the rescue: nuclear reprogramming and the dispensability of gonadal germ cells.Crossref | GoogleScholarGoogle Scholar | 24382340PubMed |

Eguizabal, C., Montserrat, N., Vassena, R., Barragan, M., Garreta, E., Garcia-Quevedo, L., Vidal, F., Giorgetti, A., Veiga, A., and Izpisua Belmonte, J. (2011). Complete meiosis from human induced pluripotent stem cells. Stem Cells 29, 1186–1195.
Complete meiosis from human induced pluripotent stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtFGmt7zK&md5=979ed51cbb77e6da8dd52dcfe6071a5aCAS | 21681858PubMed |

Hayashi, K., and Saitou, M. (2013a). Generation of eggs from mouse embryonic stem cells and induced pluripotent stem cells. Nat. Protoc. 8, 1513–1524.
Generation of eggs from mouse embryonic stem cells and induced pluripotent stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtVyktrrF&md5=bb82bef9832b46ced03ab375cf7d4c6dCAS | 23845963PubMed |

Hayashi, K., and Saitou, M. (2013b). Stepwise differentiation from naïve state pluripotent stem cells to functional primordial germ cells through an epiblast-like state. Methods Mol. Biol. 1074, 175–183.
Stepwise differentiation from naïve state pluripotent stem cells to functional primordial germ cells through an epiblast-like state.Crossref | GoogleScholarGoogle Scholar | 23975813PubMed |

Hayashi, K., and Saitou, M. (2014). Perspectives of germ cell development in vitro in mammals. Anim. Sci. J. 85, 617–626.
Perspectives of germ cell development in vitro in mammals.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXpsVensrk%3D&md5=7971833eeeb4df93062083a21df4d50eCAS | 24725251PubMed |

Hayashi, K., and Surani, M. A. (2009). Resetting the epigenome beyond pluripotency in the germline. Cell Stem Cell 4, 493–498.
Resetting the epigenome beyond pluripotency in the germline.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXnt1GgtL4%3D&md5=d0b288d7f5aa5273a969ba1b0cf62d37CAS | 19497276PubMed |

Hayashi, K., de Sousa Lopes, S. M., and Surani, M. A. (2007). Germ cell specification in mice. Science 316, 394–396.
Germ cell specification in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXktlSku7w%3D&md5=90d19e33b19d273f9363dd55f0c5dae2CAS | 17446386PubMed |

Hayashi, K., Ohta, H., Kurimoto, K., Aramaki, S., and Saitou, M. (2011). Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 146, 519–532.
Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtVKjsb%2FL&md5=401009d2910590dced9c864d2c819e16CAS | 21820164PubMed |

Hayashi, K., Ogushi, S., Kurimoto, K., Shimamoto, S., Ohta, H., and Saitou, M. (2012). Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice. Science 338, 971–975.
Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xhs1GntL%2FP&md5=9cc4a38643d0e0419e646a295e6303a6CAS | 23042295PubMed |

Houk, C. P., Rogol, A., and Lee, P. A. (2010). Fertility in men with Klinefelter syndrome. Pediatr. Endocrinol. Rev. 8, 182–186.
| 21217611PubMed |

Hübner, K., Fuhrmann, G., Christenson, L. K., Kehler, J., Reinbold, R., De La Fuente, R., Wood, J., Strauss, J. F., Boiani, M., and Schöler, H. R. (2003). Derivation of oocytes from mouse embryonic stem cells. Science 300, 1251–1256.
Derivation of oocytes from mouse embryonic stem cells.Crossref | GoogleScholarGoogle Scholar | 12730498PubMed |

Hwang, K., and Lamb, D. J. (2010). New advances on the expansion and storage of human spermatogonial stem cells. Curr. Opin. Urol. 20, 510–514.
New advances on the expansion and storage of human spermatogonial stem cells.Crossref | GoogleScholarGoogle Scholar | 20844436PubMed |

Jahnukainen, K., Ehmcke, J., Hou, M., and Schlatt, S. (2011). Testicular function and fertility preservation in male cancer patients. Best Pract. Res. Clin. Endocrinol. Metab. 25, 287–302.
Testicular function and fertility preservation in male cancer patients.Crossref | GoogleScholarGoogle Scholar | 21397199PubMed |

Kee, K., Angeles, V. T., Flores, M., Nguyen, H. N., and Reijo Pera, R. (2009). Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature 462, 222–225.
Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtlaksr3L&md5=935fff6ba7072b54be22b14ebfa850efCAS | 19865085PubMed |

Ko, K., Huebner, K., Mueller-Keuker, J., and Schoeler, H. R. (2010). In vitro derivation of germ cells from embryonic stem cells. Front. Biosci. (Landmark Ed) 15, 46–56.
In vitro derivation of germ cells from embryonic stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXovFamsbo%3D&md5=dd7d594bf0fb6260b91a74b48a3150fdCAS | 20036805PubMed |

Levine, J., Canada, A., and Stern, C. J. (2010). Fertility preservation in adolescents and young adults with cancer. J. Clin. Oncol. 28, 4831–4841.
Fertility preservation in adolescents and young adults with cancer.Crossref | GoogleScholarGoogle Scholar | 20458029PubMed |

Lokman, M., and Moore, H. (2010). An artificial sperm: next year or never? Hum. Fertil. (Camb.) 13, 272–276.
An artificial sperm: next year or never?Crossref | GoogleScholarGoogle Scholar | 21117938PubMed |

Ma, H., Morey, R., O’Neil, R. C., He, Y., Daughtry, B., Schultz, M. D., Hariharan, M., Nery, J. R., Castanon, R., Sabatini, K., Thiagarajan, R. D., Tachibana, M., Kang, E., Tippner-Hedges, R., Ahmed, R., Gutierrez, N. M., Van Dyken, C., Polat, A., Sugawara, A., Sparman, M., Gokhale, S., Amato, P., Wolf, D. P., Ecker, J. R., Laurent, L. C., and Mitalipov, S. (2014). Abnormalities in human pluripotent cells due to reprogramming mechanisms. Nature 511, 177–183.
Abnormalities in human pluripotent cells due to reprogramming mechanisms.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhtFehsLvM&md5=db5939fdc9a14af97e401bde6601666aCAS | 25008523PubMed |

Nakaki, F., Hayashi, K., Ohta, H., Kurimoto, K., Yabuta, Y., and Saitou, M. (2013). Induction of mouse germ-cell fate by transcription factors in vitro. Nature 501, 222–226.
Induction of mouse germ-cell fate by transcription factors in vitro.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXht1Whs7rL&md5=dafabf3ba894ad3c7762bd8c2521f1f1CAS | 23913270PubMed |

Panula, S., Medrano, J. V., Kee, K., Bergstrom, R., Nguyen, H. N., Byers, B., Wilson, K. D., Wu, J. C., Simon, C., Hovatta, O., and Reijo Pera, R. A. (2011). Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells. Hum. Mol. Genet. 20, 752–762.
Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXpsFyhsg%3D%3D&md5=740fecc35c2f5747349a643c55ed7f84CAS | 21131292PubMed |

Sabour, D., and Schöler, H. R. (2012). Reprogramming and the mammalian germline: the Weismann barrier revisited. Curr. Opin. Cell Biol. 24, 716–723.
Reprogramming and the mammalian germline: the Weismann barrier revisited.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtlSgtLjO&md5=aa4875e3a2df74ed5326c6a8d8445529CAS | 22947493PubMed |

Schatten, G. (1994). The centrosome and its mode of inheritance: the reduction of the entrosome during gametogenesis and its restoration during fertilization. Dev. Biol. 165, 299–335.
The centrosome and its mode of inheritance: the reduction of the entrosome during gametogenesis and its restoration during fertilization.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXhvVylu7Y%3D&md5=8d278edd8a0decc50c13a9e968a71f50CAS | 7958403PubMed |

Schatten, G. P. (2002). Safeguarding ART. Nat. Cell Biol. 4, S19–S22.
Safeguarding ART.Crossref | GoogleScholarGoogle Scholar | 12479610PubMed |

Schatten, G. (2012). Cellular promiscuity: explaining cellular fidelity in vivo against unrestrained pluripotency in vitro. EMBO Rep. 14, 4.
Cellular promiscuity: explaining cellular fidelity in vivo against unrestrained pluripotency in vitro.Crossref | GoogleScholarGoogle Scholar | 23229589PubMed |

Silber, S. J. (2010). Sperm retrieval for azoospermia and intracytoplasmic sperm injection success rates: a personal overview. Hum. Fertil. (Camb.) 13, 247–256.
Sperm retrieval for azoospermia and intracytoplasmic sperm injection success rates: a personal overview.Crossref | GoogleScholarGoogle Scholar | 21117935PubMed |

Strome, S., and Lehmann, R. (2007). Germ versus soma decisions: lessons from flies and worms. Science 316, 392–393.
Germ versus soma decisions: lessons from flies and worms.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXktlSku78%3D&md5=bdb276bb4fca931d246a9b1c35fea800CAS | 17446385PubMed |

Wallace, W. H. (2011). Oncofertility and preservation of reproductive capacity in children and young adults. Cancer 117, 2301–2310.
Oncofertility and preservation of reproductive capacity in children and young adults.Crossref | GoogleScholarGoogle Scholar | 21523750PubMed |

Weismann, A. (1892). ‘Das Keimplasma: eine Theorie der Vererbung.’ (Fischer: Jena.)

West, F. D., Mumaw, J. L., Gallegos-Cardenas, A., Young, A., and Stice, S. L. (2011). Human haploid cells differentiated from meiotic competent clonal germ cell lines that originated from embryonic stem cells. Stem Cells Dev. 20, 1079–1088.
Human haploid cells differentiated from meiotic competent clonal germ cell lines that originated from embryonic stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXmslaju7w%3D&md5=6a0e1f2b6b5331a300cb68bed3a41083CAS | 20929355PubMed |

White, Y. A., Woods, D. C., Takai, Y., Ishihara, O., Seki, H., and Tilly, J. L. (2012). Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat. Med. 18, 413–421.
Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xislygu7g%3D&md5=d69ea5f6cc312a3738e11066af113e20CAS | 22366948PubMed |

Woodruff, T. K. (2010). The Oncofertility Consortium: addressing fertility in young people with cancer. Nat. Rev. Clin. Oncol. 7, 466–475.
The Oncofertility Consortium: addressing fertility in young people with cancer.Crossref | GoogleScholarGoogle Scholar | 20498666PubMed |

Wyns, C., Curaba, M., Vanabelle, B., Van Langendonckt, A., and Donnez, J. (2010). Options for fertility preservation in prepubertal boys. Hum. Reprod. Update 16, 312–328.
Options for fertility preservation in prepubertal boys.Crossref | GoogleScholarGoogle Scholar | 20047952PubMed |

Zhao, X. Y., Li, W., Lv, Z., Liu, L., Tong, M., Hai, T., Hao, J., Wang, X., Wang, L., Zeng, F., and Zhou, Q. (2010). Viable fertile mice generated from fully pluripotent iPS cells derived from adult somatic cells. Stem Cell Rev. 6, 390–397.
Viable fertile mice generated from fully pluripotent iPS cells derived from adult somatic cells.Crossref | GoogleScholarGoogle Scholar | 20549390PubMed |

Zou, K., Yuan, Z., Yang, Z., Luo, H., Sun, K., Zhou, L., Xiang, J., Shi, L., Yu, Q., Zhang, Y., Xiang, J., Shi, L., Yu, Q., Zhang, Y., Hou, R., and Wu, J. (2009). Production of offspring from a germline stem cell line derived from neonatal ovaries. Nat. Cell Biol. 11, 631–636.
Production of offspring from a germline stem cell line derived from neonatal ovaries.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXlt1Sktrg%3D&md5=0993046b466a1869fc28980595bbffdcCAS | 19363485PubMed |