Journal of Molecular Medicine

, Volume 90, Issue 7, pp 753–761 | Cite as

The reciprocal relationship between primordial germ cells and pluripotent stem cells

  • Mehdi Pirouz
  • Alexander Klimke
  • Michael KesselEmail author


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.


Primordial germ cell Pluripotent stem cell Epigenetics Pluripotency Reproductive Medicine 


  1. 1.
    De Felici M, Farini D (2012) The control of cell cycle in mouse primordial germ cells: old and new players. Curr Pharm Des 18:233–244PubMedCrossRefGoogle Scholar
  2. 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 137:571–584PubMedCrossRefGoogle Scholar
  3. 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 221:209–223PubMedCrossRefGoogle Scholar
  4. 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 7:140PubMedCrossRefGoogle Scholar
  5. 5.
    Saga Y (2008) Mouse germ cell development during embryogenesis. Curr Opin Genet Dev 18:337–341PubMedCrossRefGoogle Scholar
  6. 6.
    Saitou M (2009) Germ cell specification in mice. Curr Opin Genet Dev 19:386–395PubMedCrossRefGoogle Scholar
  7. 7.
    Saitou M (2009) Specification of the germ cell lineage in mice. Front Biosci 14:1068–1087PubMedCrossRefGoogle Scholar
  8. 8.
    Saitou M, Kagiwada S, Kurimoto K (2012) Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139:15–31PubMedCrossRefGoogle Scholar
  9. 9.
    McLaren A (2000) Establishment of the germ cell lineage in mammals. J Cell Physiol 182:141–143PubMedCrossRefGoogle Scholar
  10. 10.
    McLaren A, Lawson KA (2005) How is the mouse germ-cell lineage established? Differentiation 73:435–437PubMedCrossRefGoogle Scholar
  11. 11.
    Tam PP, Snow MH (1981) Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morphol 64:133–147PubMedGoogle Scholar
  12. 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 436:207–213PubMedCrossRefGoogle Scholar
  13. 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 40:1016–1022PubMedCrossRefGoogle Scholar
  14. 14.
    Lin Y, Wong K, Calame K (1997) Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science 276:596–599PubMedCrossRefGoogle Scholar
  15. 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 7:3514–3518PubMedCrossRefGoogle Scholar
  16. 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 134:2627–2638PubMedCrossRefGoogle Scholar
  17. 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 278:440–458PubMedCrossRefGoogle Scholar
  18. 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 22:1617–1635PubMedCrossRefGoogle Scholar
  19. 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 125:483–495PubMedCrossRefGoogle Scholar
  20. 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 75:705–716PubMedCrossRefGoogle Scholar
  21. 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 21:1393–1409PubMedCrossRefGoogle Scholar
  22. 22.
    Smallwood A, Esteve PO, Pradhan S, Carey M (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21:1169–1178PubMedCrossRefGoogle Scholar
  23. 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 125:315–326PubMedCrossRefGoogle Scholar
  24. 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 452:877–881PubMedCrossRefGoogle Scholar
  25. 25.
    Hajkova P (2011) Epigenetic reprogramming in the germline: towards the ground state of the epigenome. Philos Trans R Soc Lond B Biol Sci 366:2266–2273PubMedCrossRefGoogle Scholar
  26. 26.
    Hackett JA, Zylicz JJ, Surani MA (2012) Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet 28(4):164–174PubMedCrossRefGoogle Scholar
  27. 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 463:1101–1105PubMedCrossRefGoogle Scholar
  28. 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 329:78–82PubMedCrossRefGoogle Scholar
  29. 29.
    Bartolomei MS, Ferguson-Smith AC (2011) Mammalian genomic imprinting. Cold Spring Harb Perspect Biol 3:a002592Google Scholar
  30. 30.
    Sasaki H, Matsui Y (2008) Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 9:129–140PubMedCrossRefGoogle Scholar
  31. 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 52:517–525PubMedCrossRefGoogle Scholar
  32. 32.
    Resnick JL, Bixler LS, Cheng L, Donovan PJ (1992) Long-term proliferation of mouse primordial germ cells in culture. Nature 359:550–551PubMedCrossRefGoogle Scholar
  33. 33.
    Matsui Y, Zsebo K, Hogan BL (1992) Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70:841–847PubMedCrossRefGoogle Scholar
  34. 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 95:13726–13731PubMedCrossRefGoogle Scholar
  35. 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 24:1441–1449PubMedCrossRefGoogle Scholar
  36. 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 130:1691–1700PubMedCrossRefGoogle Scholar
  37. 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 137:2279–2287PubMedCrossRefGoogle Scholar
  38. 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 17:2630–2638PubMedCrossRefGoogle Scholar
  39. 39.
    Deng W, Xu Y (2009) Genome integrity: linking pluripotency and tumorgenicity. Trends Genet 25:425–427PubMedCrossRefGoogle Scholar
  40. 40.
    Durcova-Hills G, Tang F, Doody G, Tooze R, Surani MA (2008) Reprogramming primordial germ cells into pluripotent stem cells. PLoS One 3:e3531PubMedCrossRefGoogle Scholar
  41. 41.
    Ng HH, Surani MA (2011) The transcriptional and signalling networks of pluripotency. Nat Cell Biol 13:490–496PubMedCrossRefGoogle Scholar
  42. 42.
    Young RA (2011) Control of the embryonic stem cell state. Cell 144:940–954PubMedCrossRefGoogle Scholar
  43. 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 122:947–956PubMedCrossRefGoogle Scholar
  44. 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 24:2772–2777PubMedCrossRefGoogle Scholar
  45. 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 282:1145–1147PubMedCrossRefGoogle Scholar
  46. 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 119:1001–1012PubMedCrossRefGoogle Scholar
  47. 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 78:681–687PubMedCrossRefGoogle Scholar
  48. 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 5:87–96PubMedCrossRefGoogle Scholar
  49. 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 456:344–349PubMedCrossRefGoogle Scholar
  50. 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 449:346–350PubMedCrossRefGoogle Scholar
  51. 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. 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 18:1115–1126PubMedCrossRefGoogle Scholar
  53. 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 27:138–149PubMedCrossRefGoogle Scholar
  54. 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 25:158–167PubMedCrossRefGoogle Scholar
  55. 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 29:1165–1169PubMedCrossRefGoogle Scholar
  56. 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 29:1304–1309PubMedCrossRefGoogle Scholar
  57. 57.
    Zhu S, Wei W, Ding S (2011) Chemical strategies for stem cell biology and regenerative medicine. Annu Rev Biomed Eng 13:73–90PubMedCrossRefGoogle Scholar
  58. 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 366:2208–2221PubMedCrossRefGoogle Scholar
  59. 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 27:783–795PubMedCrossRefGoogle Scholar
  60. 60.
    Daley GQ (2007) Gametes from embryonic stem cells: a cup half empty or half full? Science 316:409–410PubMedCrossRefGoogle Scholar
  61. 61.
    Saitou M, Yamaji M (2010) Germ cell specification in mice: signaling, transcription regulation, and epigenetic consequences. Reproduction 139:931–942PubMedCrossRefGoogle Scholar
  62. 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 11:125–132PubMedCrossRefGoogle Scholar
  63. 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 427:148–154PubMedCrossRefGoogle Scholar
  64. 64.
    Toyooka Y, Tsunekawa N, Akasu R, Noce T (2003) Embryonic stem cells can form germ cells in vitro. Proc Natl Acad Sci USA 100:11457–11462PubMedCrossRefGoogle Scholar
  65. 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 300:1251–1256PubMedCrossRefGoogle Scholar
  66. 66.
    Lewitzky M, Yamanaka S (2007) Reprogramming somatic cells towards pluripotency by defined factors. Curr Opin Biotechnol 18:467–473PubMedCrossRefGoogle Scholar
  67. 67.
    Stadtfeld M, Hochedlinger K (2010) Induced pluripotency: history, mechanisms, and applications. Genes Dev 24:2239–2263PubMedCrossRefGoogle Scholar
  68. 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 462:222–225PubMedCrossRefGoogle Scholar
  69. 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 20:752–762Google Scholar
  70. 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 1:93–103PubMedCrossRefGoogle Scholar
  71. 71.
    Hayashi K, Surani MA (2009) Self-renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development 136:3549–3556PubMedCrossRefGoogle Scholar
  72. 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 146:519–532PubMedCrossRefGoogle Scholar
  73. 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 453:519–523PubMedCrossRefGoogle Scholar
  74. 74.
    Nichols J, Smith A (2011) The origin and identity of embryonic stem cells. Development 138:3–8PubMedCrossRefGoogle Scholar
  75. 75.
    Zwaka TP, Thomson JA (2005) A germ cell origin of embryonic stem cells? Development 132:227–233PubMedCrossRefGoogle Scholar
  76. 76.
    Nichols J, Silva J, Roode M, Smith A (2009) Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136:3215–3222PubMedCrossRefGoogle Scholar
  77. 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:e22413PubMedCrossRefGoogle Scholar
  78. 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 6:468–478PubMedCrossRefGoogle Scholar
  79. 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 343:84–93PubMedCrossRefGoogle Scholar
  80. 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 28:1368–1378PubMedCrossRefGoogle Scholar
  81. 81.
    Wagner TU (2007) Bone morphogenetic protein signaling in stem cells—one signal, many consequences. FEBS J 274:2968–2976PubMedCrossRefGoogle Scholar
  82. 82.
    Dudley BM, Runyan C, Takeuchi Y, Schaible K, Molyneaux K (2007) BMP signaling regulates PGC numbers and motility in organ culture. Mech Dev 124:68–77PubMedCrossRefGoogle Scholar
  83. 83.
    Chu LF, Surani MA, Jaenisch R, Zwaka TP (2011) Blimp1 expression predicts embryonic stem cell development in vitro. Curr Biol 21:1759–1765PubMedCrossRefGoogle Scholar
  84. 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):e4013PubMedCrossRefGoogle Scholar
  85. 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 136:1063–1069PubMedCrossRefGoogle Scholar
  86. 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 77:802–811PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Mehdi Pirouz
    • 1
  • Alexander Klimke
    • 1
  • Michael Kessel
    • 1
    Email author
  1. 1.Department of Molecular Cell BiologyMax Planck Institute for Biophysical ChemistryGoettingenGermany

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