Skip to main content
SpringerLink
Log in

The reciprocal relationship between primordial germ cells and pluripotent stem cells

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Primordial germ cells (PGCs) are induced in the epiblast early in mammalian development. They develop their specific fate separate from somatic cells by the generation of a unique transcriptional profile and by epigenetic modifications of histones and DNA. PGCs are related to pluripotent cells in many respects, both on a molecular and a cell biological level. Mimicking their in vivo development, PGCs can be derived in culture from pluripotent cells. Vice versa, PGCs can be converted in vitro into pluripotent embryonic germ cells. Recent evidence indicates that the derivation of pluripotent embryonic stem cells from explanted inner cell mass cells may pass through a germ cell-like state, but that this intermediate is not obligatory. In this review, we discuss PGC development and its relevance to pluripotency in mammalian embryos. We outline possibilities and problems connected to the application of in vitro-derived germ cells in reproductive medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. De Felici M, Farini D (2012) The control of cell cycle in mouse primordial germ cells: old and new players. Curr Pharm Des 18:233–244

    Article  PubMed  Google Scholar 

  2. Ohinata Y, Ohta H, Shigeta M, Yamanaka K, Wakayama T, Saitou M (2009) A signaling principle for the specification of the germ cell lineage in mice. Cell 137:571–584

    Article  PubMed  CAS  Google Scholar 

  3. Hopf C, Viebahn C, Puschel B (2011) BMP signals and the transcriptional repressor BLIMP1 during germline segregation in the mammalian embryo. Dev Genes Evol 221:209–223

    Article  PubMed  CAS  Google Scholar 

  4. de Sousa Lopes SM, Hayashi K, Surani MA (2007) Proximal visceral endoderm and extraembryonic ectoderm regulate the formation of primordial germ cell precursors. BMC Dev Biol 7:140

    Article  PubMed  Google Scholar 

  5. Saga Y (2008) Mouse germ cell development during embryogenesis. Curr Opin Genet Dev 18:337–341

    Article  PubMed  CAS  Google Scholar 

  6. Saitou M (2009) Germ cell specification in mice. Curr Opin Genet Dev 19:386–395

    Article  PubMed  CAS  Google Scholar 

  7. Saitou M (2009) Specification of the germ cell lineage in mice. Front Biosci 14:1068–1087

    Article  PubMed  CAS  Google Scholar 

  8. Saitou M, Kagiwada S, Kurimoto K (2012) Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139:15–31

    Article  PubMed  CAS  Google Scholar 

  9. McLaren A (2000) Establishment of the germ cell lineage in mammals. J Cell Physiol 182:141–143

    Article  PubMed  CAS  Google Scholar 

  10. McLaren A, Lawson KA (2005) How is the mouse germ-cell lineage established? Differentiation 73:435–437

    Article  PubMed  CAS  Google Scholar 

  11. Tam PP, Snow MH (1981) Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morphol 64:133–147

    PubMed  CAS  Google Scholar 

  12. Ohinata Y, Payer B, O'Carroll D, Ancelin K, Ono Y, Sano M, Barton SC, Obukhanych T, Nussenzweig M, Tarakhovsky A et al (2005) Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436:207–213

    Article  PubMed  CAS  Google Scholar 

  13. Yamaji M, Seki Y, Kurimoto K, Yabuta Y, Yuasa M, Shigeta M, Yamanaka K, Ohinata Y, Saitou M (2008) Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet 40:1016–1022

    Article  PubMed  CAS  Google Scholar 

  14. Lin Y, Wong K, Calame K (1997) Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science 276:596–599

    Article  PubMed  CAS  Google Scholar 

  15. Kurimoto K, Yamaji M, Seki Y, Saitou M (2008) Specification of the germ cell lineage in mice: a process orchestrated by the PR-domain proteins, Blimp1 and Prdm14. Cell Cycle 7:3514–3518

    Article  PubMed  CAS  Google Scholar 

  16. Seki Y, Yamaji M, Yabuta Y, Sano M, Shigeta M, Matsui Y, Saga Y, Tachibana M, Shinkai Y, Saitou M (2007) Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development 134:2627–2638

    Article  PubMed  CAS  Google Scholar 

  17. Seki Y, Hayashi K, Itoh K, Mizugaki M, Saitou M, Matsui Y (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

    Article  PubMed  CAS  Google Scholar 

  18. Kurimoto K, Yabuta Y, Ohinata Y, Shigeta M, Yamanaka K, Saitou M (2008) Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes Dev 22:1617–1635

    Article  PubMed  CAS  Google Scholar 

  19. Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, Zhang Y (2006) JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125:483–495

    Article  PubMed  CAS  Google Scholar 

  20. Yabuta Y, Kurimoto K, Ohinata Y, Seki Y, Saitou M (2006) Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol Reprod 75:705–716

    Article  PubMed  CAS  Google Scholar 

  21. Hawkins RD, Hon GC, Yang C, Antosiewicz-Bourget JE, Lee LK, Ngo QM, Klugman S, Ching KA, Edsall LE, Ye Z et al (2011) Dynamic chromatin states in human ES cells reveal potential regulatory sequences and genes involved in pluripotency. Cell Res 21:1393–1409

    Article  PubMed  CAS  Google Scholar 

  22. Smallwood A, Esteve PO, Pradhan S, Carey M (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21:1169–1178

    Article  PubMed  CAS  Google Scholar 

  23. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326

    Article  PubMed  CAS  Google Scholar 

  24. Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange UC, Cesari F, Lee C, Almouzni G, Schneider R, Surani MA (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452:877–881

    Article  PubMed  CAS  Google Scholar 

  25. Hajkova P (2011) Epigenetic reprogramming in the germline: towards the ground state of the epigenome. Philos Trans R Soc Lond B Biol Sci 366:2266–2273

    Article  PubMed  CAS  Google Scholar 

  26. Hackett JA, Zylicz JJ, Surani MA (2012) Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet 28(4):164–174

    Article  PubMed  CAS  Google Scholar 

  27. Popp C, Dean W, Feng S, Cokus SJ, Andrews S, Pellegrini M, Jacobsen SE, Reik W (2010) Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463:1101–1105

    Article  PubMed  CAS  Google Scholar 

  28. Hajkova P, Jeffries SJ, Lee C, Miller N, Jackson SP, Surani MA (2010) Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science 329:78–82

    Article  PubMed  CAS  Google Scholar 

  29. Bartolomei MS, Ferguson-Smith AC (2011) Mammalian genomic imprinting. Cold Spring Harb Perspect Biol 3:a002592

    Google Scholar 

  30. Sasaki H, Matsui Y (2008) Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 9:129–140

    Article  PubMed  CAS  Google Scholar 

  31. Mochizuki K, Matsui Y (2010) Epigenetic profiles in primordial germ cells: global modulation and fine tuning of the epigenome for acquisition of totipotency. Dev Growth Differ 52:517–525

    Article  PubMed  CAS  Google Scholar 

  32. Resnick JL, Bixler LS, Cheng L, Donovan PJ (1992) Long-term proliferation of mouse primordial germ cells in culture. Nature 359:550–551

    Article  PubMed  CAS  Google Scholar 

  33. Matsui Y, Zsebo K, Hogan BL (1992) Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70:841–847

    Article  PubMed  CAS  Google Scholar 

  34. Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, Blumenthal PD, Huggins GR, Gearhart JD (1998) Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci USA 95:13726–13731

    Article  PubMed  CAS  Google Scholar 

  35. Durcova-Hills G, Adams IR, Barton SC, Surani MA, McLaren A (2006) The role of exogenous fibroblast growth factor-2 on the reprogramming of primordial germ cells into pluripotent stem cells. Stem Cells 24:1441–1449

    Article  PubMed  CAS  Google Scholar 

  36. Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N, Ikeuchi M, Nagy A, Mak TW, Nakano T (2003) Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development 130:1691–1700

    Article  PubMed  CAS  Google Scholar 

  37. Leitch HG, Blair K, Mansfield W, Ayetey H, Humphreys P, Nichols J, Surani MA, Smith A (2010) Embryonic germ cells from mice and rats exhibit properties consistent with a generic pluripotent ground state. Development 137:2279–2287

    Article  PubMed  CAS  Google Scholar 

  38. Moe-Behrens GH, Klinger FG, Eskild W, Grotmol T, Haugen TB, De Felici M (2003) Akt/PTEN signaling mediates estrogen-dependent proliferation of primordial germ cells in vitro. Mol Endocrinol 17:2630–2638

    Article  PubMed  CAS  Google Scholar 

  39. Deng W, Xu Y (2009) Genome integrity: linking pluripotency and tumorgenicity. Trends Genet 25:425–427

    Article  PubMed  CAS  Google Scholar 

  40. Durcova-Hills G, Tang F, Doody G, Tooze R, Surani MA (2008) Reprogramming primordial germ cells into pluripotent stem cells. PLoS One 3:e3531

    Article  PubMed  Google Scholar 

  41. Ng HH, Surani MA (2011) The transcriptional and signalling networks of pluripotency. Nat Cell Biol 13:490–496

    Article  PubMed  CAS  Google Scholar 

  42. Young RA (2011) Control of the embryonic stem cell state. Cell 144:940–954

    Article  PubMed  CAS  Google Scholar 

  43. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956

    Article  PubMed  CAS  Google Scholar 

  44. Tee WW, Pardo M, Theunissen TW, Yu L, Choudhary JS, Hajkova P, Surani MA (2010) Prmt5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency. Genes Dev 24:2772–2777

    Article  PubMed  CAS  Google Scholar 

  45. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    Article  PubMed  CAS  Google Scholar 

  46. Kanatsu-Shinohara M, Inoue K, Lee J, Yoshimoto M, Ogonuki N, Miki H, Baba S, Kato T, Kazuki Y, Toyokuni S et al (2004) Generation of pluripotent stem cells from neonatal mouse testis. Cell 119:1001–1012

    Article  PubMed  CAS  Google Scholar 

  47. Kanatsu-Shinohara M, Lee J, Inoue K, Ogonuki N, Miki H, Toyokuni S, Ikawa M, Nakamura T, Ogura A, Shinohara T (2008) Pluripotency of a single spermatogonial stem cell in mice. Biol Reprod 78:681–687

    Article  PubMed  CAS  Google Scholar 

  48. Ko K, Tapia N, Wu G, Kim JB, Bravo MJ, Sasse P, Glaser T, Ruau D, Han DW, Greber B et al (2009) Induction of pluripotency in adult unipotent germline stem cells. Cell Stem Cell 5:87–96

    Article  PubMed  CAS  Google Scholar 

  49. Conrad S, Renninger M, Hennenlotter J, Wiesner T, Just L, Bonin M, Aicher W, Buhring HJ, Mattheus U, Mack A et al (2008) Generation of pluripotent stem cells from adult human testis. Nature 456:344–349

    Article  PubMed  CAS  Google Scholar 

  50. Seandel M, James D, Shmelkov SV, Falciatori I, Kim J, Chavala S, Scherr DS, Zhang F, Torres R, Gale NW et al (2007) Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature 449:346–350

    Article  PubMed  CAS  Google Scholar 

  51. Ko K, Wu G, Arauzo-Bravo MJ, Kim J, Francine J, Greber B, Muhlisch J, Joo JY, Sabour D, Fruhwald MC, et al. (2012) Autologous pluripotent stem cells generated from adult mouse testicular biopsy. Stem Cell Rev and Rep, doi:10.1007/s12015-011-9307-x

  52. Golestaneh N, Kokkinaki M, Pant D, Jiang J, DeStefano D, Fernandez-Bueno C, Rone JD, Haddad BR, Gallicano GI, Dym M (2009) Pluripotent stem cells derived from adult human testes. Stem Cells Dev 18:1115–1126

    Article  PubMed  Google Scholar 

  53. Kossack N, Meneses J, Shefi S, Nguyen HN, Chavez S, Nicholas C, Gromoll J, Turek PJ, Reijo-Pera RA (2009) Isolation and characterization of pluripotent human spermatogonial stem cell-derived cells. Stem Cells 27:138–149

    Article  PubMed  CAS  Google Scholar 

  54. Mizrak SC, Chikhovskaya JV, Sadri-Ardekani H, van Daalen S, Korver CM, Hovingh SE, Roepers-Gajadien HL, Raya A, Fluiter K, de Reijke TM et al (2010) Embryonic stem cell-like cells derived from adult human testis. Hum Reprod 25:158–167

    Article  PubMed  CAS  Google Scholar 

  55. Tapia N, Arauzo-Bravo MJ, Ko K, Scholer HR (2011) Concise review: challenging the pluripotency of human testis-derived ESC-like cells. Stem Cells 29:1165–1169

    Article  PubMed  CAS  Google Scholar 

  56. Ko K, Reinhardt P, Tapia N, Schneider RK, Arauzo-Bravo MJ, Han DW, Greber B, Kim J, Kliesch S, Zenke M et al (2011) Brief report: evaluating the potential of putative pluripotent cells derived from human testis. Stem Cells 29:1304–1309

    Article  PubMed  Google Scholar 

  57. Zhu S, Wei W, Ding S (2011) Chemical strategies for stem cell biology and regenerative medicine. Annu Rev Biomed Eng 13:73–90

    Article  PubMed  CAS  Google Scholar 

  58. Efe JA, Ding S (2011) The evolving biology of small molecules: controlling cell fate and identity. Philos Trans R Soc Lond B Biol Sci 366:2208–2221

    Article  PubMed  CAS  Google Scholar 

  59. Park TS, Galic Z, Conway AE, Lindgren A, van Handel BJ, Magnusson M, Richter L, Teitell MA, Mikkola HK, Lowry WE 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

    Article  PubMed  CAS  Google Scholar 

  60. Daley GQ (2007) Gametes from embryonic stem cells: a cup half empty or half full? Science 316:409–410

    Article  PubMed  CAS  Google Scholar 

  61. Saitou M, Yamaji M (2010) Germ cell specification in mice: signaling, transcription regulation, and epigenetic consequences. Reproduction 139:931–942

    Article  PubMed  CAS  Google Scholar 

  62. Nayernia K, Nolte J, Michelmann HW, Lee JH, Rathsack K, Drusenheimer N, Dev A, Wulf G, Ehrmann IE, Elliott DJ et al (2006) In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev Cell 11:125–132

    Article  PubMed  CAS  Google Scholar 

  63. Geijsen N, Horoschak M, Kim K, Gribnau J, Eggan K, Daley GQ (2004) Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature 427:148–154

    Article  PubMed  CAS  Google Scholar 

  64. Toyooka Y, Tsunekawa N, Akasu R, Noce T (2003) Embryonic stem cells can form germ cells in vitro. Proc Natl Acad Sci USA 100:11457–11462

    Article  PubMed  CAS  Google Scholar 

  65. Hubner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, De La Fuente R, Wood J, Strauss JF 3rd, Boiani M, Scholer HR (2003) Derivation of oocytes from mouse embryonic stem cells. Science 300:1251–1256

    Article  PubMed  Google Scholar 

  66. Lewitzky M, Yamanaka S (2007) Reprogramming somatic cells towards pluripotency by defined factors. Curr Opin Biotechnol 18:467–473

    Article  PubMed  CAS  Google Scholar 

  67. Stadtfeld M, Hochedlinger K (2010) Induced pluripotency: history, mechanisms, and applications. Genes Dev 24:2239–2263

    Article  PubMed  CAS  Google Scholar 

  68. Kee K, Angeles VT, Flores M, Nguyen HN, Reijo Pera RA (2009) Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature 462:222–225

    Article  PubMed  CAS  Google Scholar 

  69. Panula S, Medrano JV, Kee K, Bergstrom R, Nguyen HN, Byers B, Wilson KD, Wu JC, Simon C, Hovatta O et al (2012) Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells. Hum Mol Genet 20:752–762

    Google Scholar 

  70. Yu Z, Ji P, Cao J, Zhu S, Li Y, Zheng L, Chen X, Feng L (2009) Dazl promotes germ cell differentiation from embryonic stem cells. J Mol Cell Biol 1:93–103

    Article  PubMed  CAS  Google Scholar 

  71. Hayashi K, Surani MA (2009) Self-renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development 136:3549–3556

    Article  PubMed  CAS  Google Scholar 

  72. Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M (2011) Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 146:519–532

    Article  PubMed  CAS  Google Scholar 

  73. Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008) The ground state of embryonic stem cell self-renewal. Nature 453:519–523

    Article  PubMed  CAS  Google Scholar 

  74. Nichols J, Smith A (2011) The origin and identity of embryonic stem cells. Development 138:3–8

    Article  PubMed  CAS  Google Scholar 

  75. Zwaka TP, Thomson JA (2005) A germ cell origin of embryonic stem cells? Development 132:227–233

    Article  PubMed  CAS  Google Scholar 

  76. Nichols J, Silva J, Roode M, Smith A (2009) Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136:3215–3222

    Article  PubMed  CAS  Google Scholar 

  77. Xu X, Pantakani DV, Luhrig S, Tan X, Khromov T, Nolte J, Dressel R, Zechner U, Engel W (2011) Stage-specific germ-cell marker genes are expressed in all mouse pluripotent cell types and emerge early during induced pluripotency. PLoS One 6:e22413

    Article  PubMed  CAS  Google Scholar 

  78. Tang F, Barbacioru C, Bao S, Lee C, Nordman E, Wang X, Lao K, Surani MA (2010) Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-Seq analysis. Cell Stem Cell 6:468–478

    Article  PubMed  CAS  Google Scholar 

  79. Dudley B, Palumbo C, Nalepka J, Molyneaux K (2010) BMP signaling controls formation of a primordial germ cell niche within the early genital ridges. Dev Biol 343:84–93

    Article  PubMed  CAS  Google Scholar 

  80. Childs AJ, Kinnell HL, Collins CS, Hogg K, Bayne RA, Green SJ, McNeilly AS, Anderson RA (2010) BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis. Stem Cells 28:1368–1378

    Article  PubMed  CAS  Google Scholar 

  81. Wagner TU (2007) Bone morphogenetic protein signaling in stem cells—one signal, many consequences. FEBS J 274:2968–2976

    Article  PubMed  CAS  Google Scholar 

  82. Dudley BM, Runyan C, Takeuchi Y, Schaible K, Molyneaux K (2007) BMP signaling regulates PGC numbers and motility in organ culture. Mech Dev 124:68–77

    Article  PubMed  CAS  Google Scholar 

  83. Chu LF, Surani MA, Jaenisch R, Zwaka TP (2011) Blimp1 expression predicts embryonic stem cell development in vitro. Curr Biol 21:1759–1765

    Article  PubMed  CAS  Google Scholar 

  84. Wei W, Qing TT, Ye X, Liu HS, Zhang DH, Yang WF, Deng HK (2008) Primordial germ cell specification from embryonic stem cells. Plos One 3(12):e4013

    Article  PubMed  Google Scholar 

  85. Guo G, Yang J, Nichols J, Hall JS, Eyres I, Mansfield W, Smith A (2009) Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136:1063–1069

    Article  PubMed  CAS  Google Scholar 

  86. Imamura M, Aoi T, Tokumasu A, Mise N, Abe K, Yamanaka S, Noce T (2010) Induction of primordial germ cells from mouse induced pluripotent stem cells derived from adult hepatocytes. Mol Reprod Dev 77:802–811

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077, Goettingen, Germany

    Mehdi Pirouz, Alexander Klimke & Michael Kessel

Authors
  1. Mehdi Pirouz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Klimke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Kessel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Kessel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pirouz, M., Klimke, A. & Kessel, M. The reciprocal relationship between primordial germ cells and pluripotent stem cells. J Mol Med 90, 753–761 (2012). https://doi.org/10.1007/s00109-012-0912-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-012-0912-1

Keywords

Search

Navigation