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Pluripotent Stem Cells in Reproductive Medicine: Formation of the Human Germ Line in Vitro

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Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

The germ cell lineage and germ line inheritance have fascinated ­biologists for centuries. Clinically, the function of germ cells in sexually reproducing organisms is to ensure reproductive fitness and to guard against extinction. However, the consequence of abnormal germ cell development can lead to devastating outcomes, including germ cell tumors, spontaneous recurrent miscarriage, fetal demise, infant morbidity and mortality, and birth defects. To overcome abnormal germ cell development, it has been proposed that germ cells could be generated from pluripotent stem cells in vitro. The technology for creating germ cells in this manner remains theoretical. However, recent advances suggest that the field is progressing toward this goal. In particular, the identification, isolation, and characterization of the initial step in human germ cell development has recently been reported by multiple groups. Furthermore, the birth of live, healthy, fertile young has now been achieved following fertilization of murine in vitro–derived germ cells. This remarkable achievement in the mouse has stemmed from years of studies aimed at understanding the first step in murine germ cell development, the formation of primordial germ cells (PGCs). This chapter describes the events in human PGC development in vivo and how this information should instruct PGC differentiation from human pluripotent stem cells in vitro.

Keywords

  • Primordial germ cells
  • Human embryonic stem cells
  • Nuclear ­remodeling
  • Chromatin dynamics

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References

  1. Hajkova, P., Ancelin, K., Waldmann, T., et al. (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature. 452, 877–881.

    PubMed  CrossRef  CAS  Google Scholar 

  2. Hajkova, P., Erhardt, S., Lane, N., et al. (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev. 117, 15–23.

    PubMed  CrossRef  CAS  Google Scholar 

  3. Seki, Y., Hayashi, K., Itoh, K., et al. (2005) Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev Biol. 278, 440–458.

    PubMed  CrossRef  CAS  Google Scholar 

  4. Chuva de Sousa Lopes, S.M., Hayashi, K., Shovlin, T.C., et al. (2008) X Chromosome Activity in Mouse XX Primordial Germ Cells. PLoS Genet. 4, e30.

    PubMed  CrossRef  Google Scholar 

  5. Sugimoto, M. and Abe, K. (2007) X chromosome reactivation initiates in nascent primordial germ cells in mice. PLoS Genet. 3, 1309–1317.

    CrossRef  CAS  Google Scholar 

  6. Yamazaki, Y., Mann, M., Lee, S., et al. (2003) Reprogramming of primordial germ cells begins before migration into the genital ridges, making these cells inadequate donors for reproductive cloning. Proc Natl Acad Sci USA. 100, 12207–12212.

    PubMed  CrossRef  CAS  Google Scholar 

  7. Witschi, E. (1948) Migration of the germ cells of human embryos from the yolk sac to the primitive gonadal folds. Contrib Embryol. 32, 67–80.

    Google Scholar 

  8. Lawson, K.A., Dunn, N.R., Roelen, B.A.J., et al. (1999) Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev. 13, 424–436.

    PubMed  CrossRef  CAS  Google Scholar 

  9. Ohinata,Y., Ohta, H., Shigeta, M., et al. (2009) A signaling principle for the specification of the germ cell lineage in mice. Cell Tissue Res. 137, 571–584.

    CAS  Google Scholar 

  10. Gaskell, T.L., Esnal, A., Robinson, L.L., et al. (2004) Immunohistochemical profiling of germ cells within the human fetal testis: identification of three subpopulations. Biol Reprod. 71, 2012–2021.

    PubMed  CrossRef  CAS  Google Scholar 

  11. Francavilla, S., Cordeschi, G., Properzi, G., et al. (1990) Ultrastructure of fetal human gonad before sexual differentiation and during early testicular and ovarian development. J Submicrosc Cytol Pathol. 22, 389–400.

    CAS  Google Scholar 

  12. Culty, M. (2009) Gonocytes, the forgotten cells of the germ cell lineage. Birth Defects Res C. 87, 1–26.

    CrossRef  CAS  Google Scholar 

  13. Koopman, P., Münsterberg, A., Capel, B., et al. (1990) Expression of a candidate sex-­determining gene during mouse testis differentiation. Nature 29, 450–452.

    CrossRef  Google Scholar 

  14. Lovell-Badge, R. and Robertson, E. (1990) XY female mice resulting from a heritable ­mutation in the primary testis-determining gene, Tdy. Development. 109, 635–646.

    PubMed  CAS  Google Scholar 

  15. Bendsen, E., Byskov, A., Laursen, S., et al. (2003) Number of germ cells and somatic cells in human fetal testes during the first weeks after sex differentiation. Hum Reprod. 18, 13–18.

    PubMed  CrossRef  CAS  Google Scholar 

  16. Hilscher, B., Hilscher, W., Bulthoff-Ohnolz, B., et al. (1974) Kinetics of gametogenesis. I. Comparative histological and autoradiographic studies of oocytes and transitional prospermatogonia during oogenesis and prespermatogenesis. Cell Tissue Res. 154, 443–470.

    PubMed  CrossRef  CAS  Google Scholar 

  17. Heyn, R., Makabe, S. and Motta, P. (1998) Ultrastructural dynamics of human testicular cords from 6–16 weeks of embryonic development. Study by transmission and high resolution scanning electron microscopy. Ital J Anat Embryol. 103(4 Suppl 1), 17–29.

    PubMed  CAS  Google Scholar 

  18. Huhtaniemi, I. and Pelliniemi, L. (1992) Fetal Leydig cells: cellular origin, morphology, life span, and special functional features. Proc Soc Exp Biol Med. 201, 125–140.

    PubMed  CrossRef  CAS  Google Scholar 

  19. Bendsen, E., Byskov, A., Andersen, C., Westergaard, L. (2008) Number of germ cells and somatic cells in human fetal ovaries during the first weeks after sex differentiation. Hum Reprod. 21, 30–35.

    CrossRef  Google Scholar 

  20. Pauls, K., Schorle, H., Jeske, W., et al. (2006) Spatial expression of germ cell markers during maturation of human fetal male gonads: an immunohistochemical study. Hum Reprod. 21, 397–404.

    PubMed  CrossRef  CAS  Google Scholar 

  21. Ohinata, Y., Payer, B., O’Carroll, D., et al. (2005) Blimp1 is a critical determinant of the germ cell lineage in mice. Nature. 436, 207–213.

    PubMed  CrossRef  CAS  Google Scholar 

  22. Vincent, S., Dunn, R., Sciammas, R., et al. (2005) The zinc finger transcriptional represssor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of ­primordial germ cells in the mouse. Development. 132, 1315–1325.

    PubMed  CrossRef  CAS  Google Scholar 

  23. Yamaji, M., Seki, Y., Kurimoto, K., et al. (2008) Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet. 40, 1016–1022.

    PubMed  CrossRef  CAS  Google Scholar 

  24. Hayashi, K. and Surani, A. (2009) Resetting the epigenome beyond pluripotency in the ­germline. Cell Stem Cell. 4, 493–498.

    PubMed  CrossRef  CAS  Google Scholar 

  25. Clark, A.T., Bodnar, M.S., Fox, M., et al. (2004) Spontaneous differentiation of germ cells from human embryonic stem cells in vitro. Hum Mol Genet. 13, 727–739.

    PubMed  CrossRef  CAS  Google Scholar 

  26. Kee, K., Gonsalves, J., Clark, A. (2006) RA RP. Bone morphogenetic proteins induce germ cell differentiation from human embryonic stem cells. Stem Cells Differ. 15, 831–837.

    CrossRef  CAS  Google Scholar 

  27. West, F., Machacek, D., Boyd, N., et al. (2008) Enrichment and differentiation of human germ-like cells mediated by feeder cells and basic fibroblast growth factor signaling. Stem Cells. 26, 2768–2776.

    PubMed  CrossRef  CAS  Google Scholar 

  28. Chen, H., Kuo, H., Chien, C., et al. (2007) Derivation characterization and differentiation of human embryonic stem cells: comparing serum-containing versus serum free media and ­evidence of germ cell differentiation. Hum Reprod. 2, 567–577.

    Google Scholar 

  29. Bucay, N., Yebra, M., Cirulli, V., et al. (2008) A novel Approach for the derivation of putative promordial germ cells and sertoli cells from human embryonic stem cells. Stem Cells. 27, 68–77.

    CrossRef  Google Scholar 

  30. Tilgner, K., Atkinson, S., Golebiewska, A., et al. (2008) Isolation of primordial germ cells from differentiating human embryonic stem cells. Stem Cells. 26, 3075–3085.

    PubMed  CrossRef  CAS  Google Scholar 

  31. Park, T., Galic, Z., Conway, A., et al. (2009) Derivation of primordial germ cells from human embryonic and induced pluripotent stem cells is significantly improved by coculture with human fetal gonadal cells. Stem Cells. 27, 783–795.

    PubMed  CrossRef  CAS  Google Scholar 

  32. Ara, T., Nakamura, Y., Egawa, T., et al. (2003) Impaired colonization of the gonads by ­primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1). Proc Natl Acad Sci USA. 100, 5319–5323.

    PubMed  CrossRef  CAS  Google Scholar 

  33. Perrett, R.M., Turnpenny, L., Eckert, J.J., et al. (2008) The early human germ cell lineage does not express sox2 during in vivo development or upon in vitro culture. Biol Reprod. 78, 852–858.

    PubMed  CrossRef  CAS  Google Scholar 

  34. Kerr, C.L., Hill, C.M., Blumenthal, P.D. and Gearhart, J.D. (2007) Expression of pluripotent stem cell markers in the human fetal testis. Stem Cells. 26, 412–421.

    PubMed  CrossRef  Google Scholar 

  35. Kerr, C.L., Hill, C.M., Blumenthal, P.D. and Gearhart, J.D. (2008) Expression of pluripotent stem cell markers in the human fetal ovary. Hum Reprod. 23, 589–599.

    PubMed  CrossRef  CAS  Google Scholar 

  36. Fox, N., Damjanov, I., Martinez-Hernandez, A., et al. (1981) Immunohistochemical localization of the Early Embryonic Antigen (SSEA1) in postimplantation mouse embryos and fetal and adult tissues. Dev Biol. 83, 391–398.

    PubMed  CrossRef  CAS  Google Scholar 

  37. Mathews, D., Donovan, P., Harris, J., et al. (2009) Pluripotent stem cell-derived gametes: truth and (potential) consequences. Cell Stem Cell. 5, 11–14.

    PubMed  CrossRef  CAS  Google Scholar 

  38. Daley, G.Q. (2007) Gametes from embryonic stem cells: a cup half empty or half full? Science. 316, 409–410.

    PubMed  CrossRef  CAS  Google Scholar 

  39. Anderson, R., Fulton, N., Cowan, G., et al. (2007) Conserved and divergent patterns of expression of DAZL, VASA and OCT4 in the germ cells of the human fetal ovary and testis. BMC Dev Biol. 7, 136.

    PubMed  CrossRef  Google Scholar 

  40. Castrillon, D.H., Quade, B.J., Wang, T.Y., et al. (2000) The human VASA gene is specifically expressed in the germ cell lineage. Proc Natl Acad Sci USA. 97, 9585–9590.

    PubMed  CrossRef  CAS  Google Scholar 

  41. Kee, K., Angeles, V., Flores, M., Nguyen, H., Reijo Pera R. (2009) Human DAZL, DAZ and BOULE genes modulate primordial germ cell and haploid gamete formation. Nature. 462,222–225.

    PubMed  CrossRef  Google Scholar 

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Correspondence to Amander T. Clark .

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Gkountela, S., Lindgren, A., Clark, A.T. (2011). Pluripotent Stem Cells in Reproductive Medicine: Formation of the Human Germ Line in Vitro . In: Appasani, K., Appasani, R. (eds) Stem Cells & Regenerative Medicine. Stem Cell Biology and Regenerative Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-860-7_22

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