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Direct Differentiation of Human Pluripotent Stem Cells into Advanced Spermatogenic Cells: In Search of an In Vitro System to Model Male Factor Infertility

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Abstract

Differentiation of stem cells into spermatogenic lineages in vitro provides a unique window into the biological mechanisms responsible for driving pluripotent stem cells into essential progeny—haploid spermatids and viable sperm—as well as provides an innovative approach for determining novel root causes for male infertility. Our recent work outlined a novel approach for differentiating human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) into advanced spermatogenic lineages including haploid spermatids with correct parent-of-origin genomic imprints on two loci. The work described here in this chapter provides a foundation for building a true in vitro model for human spermatogenesis with which to model, diagnose and potentially treat male factor infertility.

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References

  1. Brinster, R. L., & Avarbock, M. R. (1994). Germline transmission of donor haplotype following spermatogonial transplantation. Proceedings of the National Academy of Sciences of the United States of America, 91(24), 11303–11307.

    Article  Google Scholar 

  2. Buaas, F. W., Kirsh, A. L., Sharma, M., McLean, D. J., Morris, J. L., Griswold, M. D., et al. (2004). Plzf is required in adult male germ cells for stem cell self-renewal. Nature Genetics, 36(6), 647–652.

    Article  Google Scholar 

  3. Bucay, N., Yebra, M., Cirulli, V., Afrikanova, I., Kaido, T., Hayek, A., et al. (2009). A novel approach for the derivation of putative primordial germ cells and sertoli cells from human embryonic stem cells. Stem Cells, 27(1), 68–77.

    Article  Google Scholar 

  4. Carrell, D. T., Emery, B. R., & Hammoud, S. (2007). Altered protamine expression and diminished spermatogenesis: What is the link? Human Reproduction Update, 13(3), 313–327.

    Article  Google Scholar 

  5. Castrillon, D. H., Quade, B. J., Wang, T. Y., Quigley, C., & Crum, C. P. (2000). The human VASA gene is specifically expressed in the germ cell lineage. Proceedings of the National Academy of Sciences of the United States of America, 97(17), 9585–9590.

    Article  Google Scholar 

  6. Chuma, S., Kanatsu-Shinohara, M., Inoue, K., Ogonuki, N., Miki, H., Toyokuni, S., et al. (2005). Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis. Development, 132(1), 117–122.

    Article  Google Scholar 

  7. Cibelli, J. B., Campbell, K. H., Seidel, G. E., West, M. D., & Lanza, R. P. (2002). The health profile of cloned animals. Nature Biotechnology, 20(1), 13–14.

    Article  Google Scholar 

  8. Conrad, S., Renninger, M., Hennenlotter, J., Wiesner, T., Just, L., Bonin, M., et al. (2008). Generation of pluripotent stem cells from adult human testis. Nature, 456(7220), 344–349.

    Article  Google Scholar 

  9. Costoya, J. A., Hobbs, R. M., Barna, M., Cattoretti, G., Manova, K., Sukhwani, M., et al. (2004). Essential role of Plzf in maintenance of spermatogonial stem cells. Nature Genetics, 36(6), 653–659.

    Article  Google Scholar 

  10. Daley, G. Q. (2007). Gametes from embryonic stem cells: A cup half empty or half full? Science, 316(5823), 409–410.

    Article  Google Scholar 

  11. Deng, W., & Lin, H. (2002). Miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Developmental Cell, 2(6), 819–830.

    Article  Google Scholar 

  12. Easley, C. A., Phillips, B., McGuire, M., Barringer, J., Valli, H., Hermann, B. P., et al. (2012). Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Reports, 2(3), 440–446.

    Article  Google Scholar 

  13. Easley, C. A., Phillips, B. T., Wu, G., Schatten, G. P., & Simerly, C. R. (2012). Clinical implications of human spermatogenesis initiation in vitro. Journal of Medical Sciences, 32(6), 257–263.

    Google Scholar 

  14. Easley, C. A., 4th, Simerly, C. R., & Schatten, G. (2013). Stem cell therapeutic possibilities: Future therapeutic options for male-factor and female-factor infertility? Reproductive Biomedicine Online, 27(1), 75–80.

    Article  Google Scholar 

  15. Eguizabal, C., Montserrat, N., Vassena, R., Barragan, M., Garreta, E., Garcia-Quevedo, L., et al. (2011). Complete meiosis from human induced pluripotent stem cells. Stem Cells, 29(8), 1186–1195.

    Article  Google Scholar 

  16. Feng, L. X., Chen, Y., Dettin, L., Pera, R. A., Herr, J. C., Goldberg, E., et al. (2002). Generation and in vitro differentiation of a spermatogonial cell line. Science, 297(5580), 392–395.

    Article  Google Scholar 

  17. Fukunaga, N., Teramura, T., Onodera, Y., Takehara, T., Fukuda, K., & Hosoi, Y. (2010). Leukemia inhibitory factor (LIF) enhances germ cell differentiation from primate embryonic stem cells. Cellular Reprogramming, 12(4), 369–376.

    Article  Google Scholar 

  18. Geijsen, N., Horoschak, M., Kim, K., Gribnau, J., Eggan, K., & Daley, G. Q. (2004). Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature, 427(6970), 148–154.

    Article  Google Scholar 

  19. Ginsberg, J. P., Carlson, C. A., Lin, K., Hobbie, W. L., Wigo, E., Wu, X., et al. (2010). An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: A report of acceptability and safety. Human Reproduction, 25(1), 37–41.

    Article  Google Scholar 

  20. 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, 1–14.

    Article  Google Scholar 

  21. Hermann, B. P., Sukhwani, M., Lin, C. C., Sheng, Y., Tomko, J., Rodriguez, M., et al. (2007). Characterization, cryopreservation, and ablation of spermatogonial stem cells in adult rhesus macaques. Stem Cells, 25(9), 2330–2338.

    Article  Google Scholar 

  22. Hermann, B. P., Sukhwani, M., Winkler, F., Pascarella, J. N., Peters, K. A., Sheng, Y., et al. (2012). Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm. Cell Stem Cell, 11(5), 715–726.

    Article  Google Scholar 

  23. Hobbs, R. M., Seandel, M., Falciatori, I., Rafii, S., & Pandolfi, P. P. (2010). Plzf regulates germline progenitor self-renewal by opposing mTORC1. Cell, 142(3), 468–479.

    Article  Google Scholar 

  24. Houk, C. P., Rogol, A., & Lee, P. A. (2010). Fertility in men with Klinefleter syndrome. Pediatric Endocrinology Reviews, 8(Suppl 1), 182–186.

    Google Scholar 

  25. Hwang, K., & Lamb, D. J. (2010). New advances on the expansion and storage of human spermatogonial stem cells. Current Opinion in Urology, 20(6), 510–514.

    Article  Google Scholar 

  26. Jahnukainen, K., Ehmcke, J., Hou, M., & Schlatt, S. (2011). Testicular function and fertility preservation in male cancer patients. Best Practice & Research. Clinical Endocrinology & Metabolism, 25(2), 287–302.

    Article  Google Scholar 

  27. Jahnukainen, K., Ehmcke, J., Quader, M. A., Saiful Huq, M., Epperly, M. W., Hergenrother, S., et al. (2011). Testicular recovery after irradiation differs in prepubertal and pubertal non-human primates, and can be enhanced by autologous germ cell transplantation. Human Reproduction, 26(8), 1945–1954.

    Article  Google Scholar 

  28. Kanatsu-Shinohara, M., Ogonuki, N., Inoue, K., Miki, H., Ogura, A., Toyokuni, S., et al. (2003). Long-term proliferation in culture and germline transmission of mouse male germline stem cells. Biology of Reproduction, 69(2), 612–616.

    Article  Google Scholar 

  29. Kee, K., Angeles, V. T., Flores, M., Nguyen, H. N., & Reijo Pera, R. A. (2009). Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature, 462(7270), 222–225.

    Article  Google Scholar 

  30. Keros, V., Hultenby, K., Borgstrom, B., Fridstrom, M., Jahnukainen, K., & Hovatta, O. (2007). Methods of cryopreservation of testicular tissue with viable spermatogonia in pre-pubertal boys undergoing gonadotoxic cancer treatment. Human Reproduction, 22(5), 1384–1395.

    Article  Google Scholar 

  31. Ko, K., Huebner, K., Mueller-Keuker, J., & Schoeler, H. R. (2010). In vitro derivation of germ cells from embryonic stem cells. Frontiers in Bioscience (Landmark Edition), 15, 46–56.

    Article  Google Scholar 

  32. Ko, K., Tapia, N., Wu, G., Kim, J. B., Bravo, M. J., Sasse, P., et al. (2009). Induction of pluripotency in adult unipotent germline stem cells. Cell Stem Cell, 5(1), 87–96.

    Article  Google Scholar 

  33. Kossack, N., Meneses, J., Shefi, S., Nguyen, H. N., Chavez, S., Nicholas, C., et al. (2009). Isolation and characterization of pluripotent human spermatogonial stem cell-derived cells. Stem Cells, 27(1), 138–149.

    Article  Google Scholar 

  34. Levine, J., Canada, A., & Stern, C. J. (2010). Fertility preservation in adolescents and young adults with cancer. Journal of Clinical Oncology, 28(32), 4831–4841.

    Article  Google Scholar 

  35. Lokman, M., & Moore, H. (2010). An artificial sperm – next year or never? Human Fertility (Cambridge, England), 13(4), 272–276.

    Article  Google Scholar 

  36. Lucifero, D., Mertineit, C., Clarke, H. J., Bestor, T. H., & Trasler, J. M. (2002). Methylation dynamics of imprinted genes in mouse germ cells. Genomics, 79(4), 530–538.

    Article  Google Scholar 

  37. Lucifero, D., & Reik, W. (2006). Artificial sperm and epigenetic reprogramming. Nature Biotechnology, 24(9), 1097–1098.

    Article  Google Scholar 

  38. Marques-Mari, A. I., Lacham-Kaplan, O., Medrano, J. V., Pellicer, A., & Simon, C. (2009). Differentiation of germ cells and gametes from stem cells. Human Reproduction Update, 15(3), 379–390.

    Article  Google Scholar 

  39. Mathews, D. J., Donovan, P. J., Harris, J., Lovell-Badge, R., Savulescu, J., & Faden, R. (2009). Pluripotent stem cell-derived gametes: Truth and (potential) consequences. Cell Stem Cell, 5(1), 11–14.

    Article  Google Scholar 

  40. Moreno, R. D., Palomino, J., & Schatten, G. (2006). Assembly of spermatid acrosome depends on microtubule organization during mammalian spermiogenesis. Developmental Biology, 293(1), 218–227.

    Article  Google Scholar 

  41. Nayernia, K., Nolte, J., Michelmann, H. W., Lee, J. H., Rathsack, K., Drusenheimer, N., et al. (2006). In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Developmental Cell, 11(1), 125–132.

    Article  Google Scholar 

  42. Nolte, J., Michelmann, H. W., Wolf, M., Wulf, G., Nayernia, K., Meinhardt, A., et al. (2010). PSCDGs of mouse multipotent adult germline stem cells can enter and progress through meiosis to form haploid male germ cells in vitro. Differentiation, 80(4–5), 184–194.

    Article  Google Scholar 

  43. Orwig, K. E., & Schlatt, S. (2005). Cryopreservation and transplantation of spermatogonia and testicular tissue for preservation of male fertility. Journal of the National Cancer Institute. Monographs, 34, 51–56.

    Article  Google Scholar 

  44. Panula, S., Medrano, J. V., Kee, K., Bergstrom, R., Nguyen, H. N., Byers, B., et al. (2011). Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells. Human Molecular Genetics, 20(4), 752–762.

    Article  Google Scholar 

  45. Park, T. S., Galic, Z., Conway, A. E., Lindgren, A., van Handel, B. J., Magnusson, M., 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(4), 783–795.

    Article  Google Scholar 

  46. Pick, M., Stelzer, Y., Bar-Nur, O., Mayshar, Y., Eden, A., & Benvenisty, N. (2009). Clone- and gene-specific aberrations of parental imprinting in human induced pluripotent stem cells. Stem Cells, 27(11), 2686–2690.

    Article  Google Scholar 

  47. Ramalho-Santos, J., Schatten, G., & Moreno, R. D. (2002). Control of membrane fusion during spermiogenesis and the acrosome reaction. Biology of Reproduction, 67(4), 1043–1051.

    Article  Google Scholar 

  48. Sadri-Ardekani, H., Akhondi, M. A., van der Veen, F., Repping, S., & van Pelt, A. M. (2011). In vitro propagation of human prepubertal spermatogonial stem cells. JAMA, 305(23), 2416–2418.

    Article  Google Scholar 

  49. Schatten, G. (1994). The centrosome and its mode of inheritance: The reduction of the centrosome during gametogenesis and its restoration during fertilization. Developmental Biology, 165(2), 299–335.

    Article  Google Scholar 

  50. Schlatt, S., Ehmcke, J., & Jahnukainen, K. (2009). Testicular stem cells for fertility preservation: Preclinical studies on male germ cell transplantation and testicular grafting. Pediatric Blood & Cancer, 53(2), 274–280.

    Article  Google Scholar 

  51. Schlegel, P. N. (2009). Evaluation of male infertility. Minerva Ginecologica, 61(4), 261–283.

    MathSciNet  Google Scholar 

  52. Silber, S. J. (2010). Sperm retrieval for azoospermia and intracytoplasmic sperm injection success rates–a personal overview. Human Fertility (Cambridge, England), 13(4), 247–256.

    Article  MathSciNet  Google Scholar 

  53. Stanford, P. K. (2005). August Weismann’s theory of the germ-plasm and the problem of unconceived alternatives. History and Philosophy of the Life Sciences, 27(2), 163–199.

    Google Scholar 

  54. Strome, S., & Lehmann, R. (2007). Germ versus soma decisions: Lessons from flies and worms. Science, 316(5823), 392–393.

    Article  Google Scholar 

  55. Teramura, T., Takehara, T., Kawata, N., Fujinami, N., Mitani, T., Takenoshita, M., et al. (2007). Primate embryonic stem cells proceed to early gametogenesis in vitro. Cloning and Stem Cells, 9(2), 144–156.

    Article  Google Scholar 

  56. Tilgner, K., Atkinson, S. P., Golebiewska, A., Stojkovic, M., Lako, M., & Armstrong, L. (2008). Isolation of primordial germ cells from differentiating human embryonic stem cells. Stem Cells, 26(12), 3075–3085.

    Article  Google Scholar 

  57. Wallace, W. H. (2011). Oncofertility and preservation of reproductive capacity in children and young adults. Cancer, 117(10 Suppl), 2301–2310.

    Article  Google Scholar 

  58. White, Y. A., Woods, D. C., Takai, Y., Ishihara, O., Seki, H., & Tilly, J. L. (2012). Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nature Medicine, 18(3), 413–421.

    Article  Google Scholar 

  59. Woodruff, T. K. (2010). The Oncofertility Consortium – addressing fertility in young people with cancer. Nature Reviews. Clinical Oncology, 7(8), 466–475.

    Article  Google Scholar 

  60. Wyns, C., Curaba, M., Petit, S., Vanabelle, B., Laurent, P., Wese, J. F., et al. (2011). Management of fertility preservation in prepubertal patients: 5 years’ experience at the Catholic University of Louvain. Human Reproduction, 26(4), 737–747.

    Article  Google Scholar 

  61. Wyns, C., Curaba, M., Vanabelle, B., Van Langendonckt, A., & Donnez, J. (2010). Options for fertility preservation in prepubertal boys. Human Reproduction Update, 16(3), 312–328.

    Article  Google Scholar 

  62. Yamauchi, K., Hasegawa, K., Chuma, S., Nakatsuji, N., & Suemori, H. (2009). In vitro germ cell differentiation from cynomolgus monkey embryonic stem cells. PLoS One, 4(4), e5338.

    Article  Google Scholar 

  63. Yao, L., Yu, X., Hui, N., & Liu, S. (2011). Application of iPS in assisted reproductive technology: Sperm from somatic cells? Stem Cell Reviews, 7(3), 714–721.

    Article  Google Scholar 

  64. Zhao, X. Y., Li, W., Lv, Z., Liu, L., Tong, M., Hai, T., et al. (2010). Viable fertile mice generated from fully pluripotent iPS cells derived from adult somatic cells. Stem Cell Reviews, 6(3), 390–397.

    Article  Google Scholar 

  65. Zou, K., Yuan, Z., Yang, Z., Luo, H., Sun, K., Zhou, L., et al. (2009). Production of offspring from a germline stem cell line derived from neonatal ovaries. Nature Cell Biology, 11(5), 631–636.

    Article  Google Scholar 

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Correspondence to Charles A. Easley IV .

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Easley, C.A., Simerly, C.R., Schatten, G. (2014). Direct Differentiation of Human Pluripotent Stem Cells into Advanced Spermatogenic Cells: In Search of an In Vitro System to Model Male Factor Infertility. In: Toni, B. (eds) New Frontiers of Multidisciplinary Research in STEAM-H (Science, Technology, Engineering, Agriculture, Mathematics, and Health). Springer Proceedings in Mathematics & Statistics, vol 90. Springer, Cham. https://doi.org/10.1007/978-3-319-07755-0_12

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