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

Spermatogonial stem cells: unlimited potential

M. Dym A B , Z. He A , J. Jiang A , D. Pant A and M. Kokkinaki A
+ Author Affiliations
- Author Affiliations

A Georgetown University Medical Center, Department of Biochemistry and Molecular and Cellular Biology, 3900 Reservoir Road, NW, Washington, DC 20057, USA.

B Corresponding author. Email: dymm@georgetown.edu

Reproduction, Fertility and Development 21(1) 15-21 https://doi.org/10.1071/RD08221
Published: 9 December 2008

Abstract

Recent reports have demonstrated that adult cells can be reprogrammed to pluripotency, but mostly with genes delivered using retroviruses. Some of the genes are cancer causing; thus, these adult-derived embryonic stem (ES)-like cells cannot be used for therapy to cure human diseases. Remarkably, it has also been demonstrated recently by several groups that, in mice, spermatogonial stem cells (SSCs) can be reprogrammed to ES-like cells without the necessity of exogenously added genes. SSCs constitute one of the most important stem cell systems in the body, not only because they produce spermatozoa that transmit genetic information from generation to generation, but also because of the recent studies showing their remarkable plasticity. Very little is known about SSCs in humans, except for the earlier work of Clermont and colleagues who demonstrated that there are Adark and Apale spermatogonia, with the Adark referred to as the reserve stem cells and the Apale being the renewing stem cells. We now demonstrate that G protein-coupled receptor 125 (GPR125) may be a marker for human SSCs. Putative human SSCs can also be reprogrammed to pluripotency. We were able to achieve this result without the addition of genes, suggesting that human SSCs have considerable potential for cell-based, autologous organ regeneration therapy for various diseases.

Additional keywords: differentiation, embryonic stem cells, GFRA1, GPR125, pluripotency, renewal.


References

Aoi, T. , Yae, K. , Nakagawa, M. , Ichisaka, T. , Okita, K. , Takahashi, K. , Chiba, T. , and Yamanaka, S. (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321, 699–702.
CrossRef | PubMed | CAS |

Brawley, C. , and Matunis, E. (2004). Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304, 1331–1334.
CrossRef | PubMed | CAS |

Brinster, R. L. , and Avarbock, M. R. (1994). Germ line transmission of donor haplotype following spermatogonial transplantation. Proc. Natl Acad. Sci. USA 91, 11 303–11 307.
CrossRef | PubMed | CAS |

Brinster, R. L. , and Zimmerman, J. W. (1994). Spermatogenesis following male germ cell transplantation. Proc. Natl Acad. Sci. USA 91, 11 298–11 302.
CrossRef | PubMed | CAS |

Buaas, F. W. , Kirsh, A. L. , Sharma, M. , McLean, D. J. , Morris, J. L. , Griswold, M. D. , de Rooij, D. G. , and Braun, R. E. (2004). Plzf is required in adult male germ cells for stem cell self-renewal. Nat. Genet. 36, 647–652.
CrossRef | PubMed | CAS |

Buageaw, A. , Sukhwani, M. , Ben-Yehudah, A. , Ehmcke, J. , Rawe, V. Y. , Pholpramool, C. , Orwig, K. E. , and Schlatt, S. (2005). GDNF family receptor alpha1 phenotype of spermatogonial stem cells in immature mouse testes. Biol. Reprod. 73, 1011–1016.
CrossRef | PubMed | CAS |

Clermont, Y. (1963). The cycle of the seminiferous epithelium in man. Am. J. Anat. 112, 35–51.
CrossRef | PubMed | CAS |

Clermont, Y. (1966a). Renewal of spermatogonia in man. Am. J. Anat. 118, 509–524.
CrossRef | PubMed | CAS |

Clermont, Y. (1966b). Spermatogenesis in man. A study of the spermatogonial population. Fertil. Steril. 17, 705–721.
PubMed | |  CAS |

Clermont, Y. (1972). Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Physiol. Rev. 52, 198–236.
PubMed | |  CAS |

Clermont, Y. , and Bustos-Obregon, E. (1968). Re-examination of spermatogonial renewal in the rat by means of seminiferous tubules mounted ‘in toto’. Am. J. Anat. 122, 237–247.
CrossRef | PubMed | CAS |

Conrad S., Renninger M., Hennenlotter J., Wiesner T., Just L., et al. (2008). Generation of pluripotent stem cells from adult human testis. Nature, in press. doi:10.1038/NATURE07404

Costoya, J. A. , Hobbs, R. M. , Barna, M. , Cattoretti, G. , Manova, K. , Sukhwani, M. , Orwig, K. E. , Wolgemuth, D. J. , and Pandolfi, P. P. (2004). Essential role of Plzf in maintenance of spermatogonial stem cells. Nat. Genet. 36, 653–659.
CrossRef | PubMed | CAS |

Dann C. T., Alvarado A. L., Molyneux L. A., Denard B. S., Garbers D. L., and Porteus M. H. (2008). Spermatogonial stem cell self renewal requires OCT4, a factor down-regulated during retinoic acid induced differentiation. Stem Cells, in press.

de Rooij, D. G. , and Grootegoed, J. A. (1998). Spermatogonial stem cells. Curr. Opin. Cell Biol. 10, 694–701.
CrossRef | PubMed | CAS |

de Rooij, D. G. , and Russell, L. D. (2000). All you wanted to know about spermatogonia but were afraid to ask. J. Androl. 21, 776–798.
PubMed | |  CAS |

Dobrinski, I. , Avarbock, M. R. , and Brinster, R. L. (1999). Transplantation of germ cells from rabbits and dogs into mouse testes. Biol. Reprod. 61, 1331–1339.
CrossRef | PubMed | CAS |

Dobrinski, I. , Avarbock, M. R. , and Brinster, R. L. (2000). Germ cell transplantation from large domestic animals into mouse testes. Mol. Reprod. Dev. 57, 270–279.
CrossRef | PubMed | CAS |

Dym, M. (1994). Spermatogonial stem cells of the testis. Proc. Natl Acad. Sci. USA 91, 11 287–11 289.
CrossRef | PubMed | CAS |

Dym, M. , and Clermont, Y. (1970). Role of spermatogonia in the repair of the seminiferous epithelium following X-irradiation of the rat testis. Am. J. Anat. 128, 265–282.
CrossRef | PubMed | CAS |

Dym, M. , and Fawcett, D. W. (1971). Further observations on the numbers of spermatogonia, spermatocytes, and spermatids connected by intercellular bridges in the mammalian testis. Biol. Reprod. 4, 195–215.
PubMed | |  CAS |

Ehmcke, J. , and Schlatt, S. (2006). A revised model for spermatogonial expansion in man: lessons from non-human primates. Reproduction 132, 673–680.
CrossRef | PubMed | CAS |

Golestaneh N., Kokkinaki M., Jiang J., DeStefano D., Fernandez-Bueno C., Gallicano Y., and Dym M. (2007). Human sperm stem cells can ‘de-differentiate’ into pluripotency. In ‘Proceedings of the American Society of Cell Biology, Annual Meeting’.

Greenbaum, M. P. , Yan, W. , Wu, M. H. , Lin, Y. N. , Agno, J. E. , Sharma, M. , Braun, R. E. , Rajkovic, A. , and Matzuk, M. M. (2006). TEX14 is essential for intercellular bridges and fertility in male mice. Proc. Natl Acad. Sci. USA 103, 4982–4987.
CrossRef | PubMed | CAS |

Guan, K. , Nayernia, K. , Maier, L. S. , Wagner, S. , and Dressel, R. , et al. (2006). Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440, 1199–1203.
CrossRef | PubMed | CAS |

Hanna, J. , Wernig, M. , Markoulaki, S. , Sun, C. W. , and Meissner, A. , et al. (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920–1923.
CrossRef | PubMed | CAS |

He Z., Jiang J., Hofmann M. C., and Dym M. (2007). Gfra1 silencing in mouse spermatogonial stem cells results in their differentiation via the inactivation of RET tyrosine kinase. Biol. Reprod. 77, 723–733.

Hermann, B. P. , Sukhwani, M. , Lin, C. C. , Sheng, Y. , and Tomko, J. , et al. (2007). Characterization, cryopreservation, and ablation of spermatogonial stem cells in adult rhesus macaques. Stem Cells 25, 2330–2338.
CrossRef | PubMed | CAS |

Hofmann, M. C. , Braydich-Stolle, L. , Dettin, L. , Johnson, E. , and Dym, M. (2005a). Immortalization of mouse germ line stem cells. Stem Cells 23, 200–210.
CrossRef | PubMed |

Hofmann, M. C. , Braydich-Stolle, L. , and Dym, M. (2005b). Isolation of male germ-line stem cells; influence of GDNF. Dev. Biol. 279, 114–124.
CrossRef | PubMed | CAS |

Huckins, C. (1971). The spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation. Anat. Rec. 169, 533–557.
CrossRef | PubMed | CAS |

Kanatsu-Shinohara, M. , Inoue, K. , Lee, J. , Yoshimoto, M. , and Ogonuki, N. , et al. (2004). Generation of pluripotent stem cells from neonatal mouse testis. Cell 119, 1001–1012.
CrossRef | PubMed | CAS |

Kim, K. , Lerou, P. , Yabuuchi, A. , Lengerke, C. , Ng, K. , West, J. , Kirby, A. , Daly, M. J. , and Daley, G. Q. (2007). Histocompatible embryonic stem cells by parthenogenesis. Science 315, 482–486.
CrossRef | PubMed | CAS |

Kim, J. B. , Zaehres, H. , Wu, G. , Gentile, L. , and Ko, K. , et al. (2008). Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454, 646–650.
CrossRef | PubMed | CAS |

Kim, N. W. , Piatyszek, M. A. , Prowse, K. R. , Harley, C. B. , West, M. D. , Ho, P. L. , Coviello, G. M. , Wright, W. E. , Weinrich, S. L. , and Shay, J. W. (1994). Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015.
CrossRef | PubMed | CAS |

Meissner, A. , Wernig, M. , and Jaenisch, R. (2007). Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat. Biotechnol. 25, 1177–1181.
CrossRef | PubMed | CAS |

Meng, X. , Lindahl, M. , Hyvonen, M. E. , Parvinen, M. , and de Rooij, D. G. , et al. (2000). Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489–1493.
CrossRef | PubMed | CAS |

Nagano, M. , McCarrey, J. R. , and Brinster, R. L. (2001). Primate spermatogonial stem cells colonize mouse testes. Biol. Reprod. 64, 1409–1416.
CrossRef | PubMed | CAS |

Nagano, M. , Patrizio, P. , and Brinster, R. L. (2002). Long-term survival of human spermatogonial stem cells in mouse testes. Fertil. Steril. 78, 1225–1233.
CrossRef | PubMed |

Naughton, C. K. , Jain, S. , Strickland, A. M. , Gupta, A. , and Milbrandt, J. (2006). Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Biol. Reprod. 74, 314–321.
CrossRef | PubMed | CAS |

Oakberg, E. F. (1971). Spermatogonial stem-cell renewal in the mouse. Anat. Rec. 169, 515–531.
CrossRef | PubMed | CAS |

Ohbo, K. , Yoshida, S. , Ohmura, M. , Ohneda, O. , and Ogawa, T. , et al. (2003). Identification and characterization of stem cells in prepubertal spermatogenesis in mice small star, filled. Dev. Biol. 258, 209–225.
CrossRef | PubMed | CAS |

Ohmura, M. , Yoshida, S. , Ide, Y. , Nagamatsu, G. , Suda, T. , and Ohbo, K. (2004). Spatial analysis of germ stem cell development in Oct-4/EGFP transgenic mice. Arch. Histol. Cytol. 67, 285–296.
CrossRef | PubMed | CAS |

Okita, K. , Ichisaka, T. , and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317.
CrossRef | PubMed | CAS |

Orwig, K. E. , Shinohara, T. , Avarbock, M. R. , and Brinster, R. L. (2002). Functional analysis of stem cells in the adult rat testis. Biol. Reprod. 66, 944–949.
CrossRef | CAS | PubMed |

Ramalho-Santos, M. , and Willenbring, H. (2007). On the origin of the term ‘stem cell’. Cell Stem Cell 1, 35–38.
CrossRef | PubMed | CAS |

Regaud, C. (1901). Études sur la structure des tubes séminiféres et sur la spermatogénèse chez les mammifères. Archives d’Anatomie Microscopiques et de Morphologie Expérimentale 4, 101–156.


Sanchez-Pernaute, R. , Lee, H. , Patterson, M. , Reske-Nielsen, C. , Yoshizaki, T. , Sonntag, K. C. , Studer, L. , and Isacson, O. (2008). Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson’s disease. Brain 131, 2127–2139.
CrossRef | PubMed |

Seandel, M. , James, D. , Shmelkov, S. V. , Falciatori, I. , and Kim, J. , et al. (2007). Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature 449, 346–350.
CrossRef | PubMed | CAS |

Stadtfeld M., Nagaya M., Utikal J., Weir G., and Hochedlinger K. (2008). Induced pluripotent stem cells generated without viral integration. ScienceXpress, in press.

Takahashi, K. , and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676.
CrossRef | PubMed | CAS |

Takahashi, K. , Tanabe, K. , Ohnuki, M. , Narita, M. , Ichisaka, T. , Tomoda, K. , and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872.
CrossRef | PubMed | CAS |

Wernig, M. , Meissner, A. , Foreman, R. , Brambrink, T. , Ku, M. , Hochedlinger, K. , Bernstein, B. E. , and Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324.
CrossRef | PubMed | CAS |

Yoshida, S. , Nabeshima, Y. , and Nakagawa, T. (2008). Stem cell heterogeneity: actual and potential stem cell compartments in mouse spermatogenesis. Ann. N. Y. Acad. Sci. 1120, 47–58.
CrossRef |

Yoshinaga, K. , Nishikawa, S. , Ogawa, M. , Hayashi, S. , Kunisada, T. , Fujimoto, T. , and Nishikawa, S. (1991). Role of c-kit in mouse spermatogenesis: identification of spermatogonia as a specific site of c-kit expression and function. Development 113, 689–699.
PubMed | |  CAS |



Rent Article (via Deepdyve) Export Citation Cited By (20)

View Altmetrics