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Stem Cell Therapies for Male Infertility: Where Are We Now and Where Are We Going?

  • Chapter
Biennial Review of Infertility

Abstract

Chemotherapy and radiation treatments for cancer and other conditions can cause permanent infertility. Adult men have the option to cryopreserve a semen sample with sperm prior to treatment and use their sample in the future to have biological children using the established assisted reproductive technologies, in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). This option is not available to prepubertal boys who are not yet producing mature sperm. However, these boys do have spermatogonial stem cells in their testes that are poised to initiate sperm production at puberty. Centers in the United States and abroad are actively cryopreserving testicular tissue for prepubertal cancer patients, bone marrow transplant patients, and others in anticipation that stem cell therapies will be available for them in the future. This chapter reviews progress in the development of spermatogonial stem cell transplantation, testicular tissue grafting and xenografting, testicular tissue organ culture, de novo testicular morphogenesis, and pluripotent stem cell-derived gametogenesis. The prepubertal cancer patient is used throughout this chapter as a model for discussion, which intended to stimulate thinking about other applications of stem cell technologies for preserving and treating male infertility.

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References

  1. Sharpe RM. Regulation of spermatogenesis. In: Knobil E, Neill JD, editors. The physiology of reproduction. New York, NY: Raven Press; 1994. p. 1363–434.

    Google Scholar 

  2. Tegelenbosch RA, de Rooij DG. A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F1 hybrid mouse. Mutat Res. 1993;290(2):193–200.

    CAS  PubMed  Google Scholar 

  3. de Rooij DG, Grootegoed JA. Spermatogonial stem cells. Curr Opin Cell Biol. 1998;10(6):694–701.

    PubMed  Google Scholar 

  4. Phillips BT, Gassei K, Orwig KE. Spermatogonial stem cell regulation and spermatogenesis. Philos Trans R Soc Lond B Biol Sci. 2010;365(1546):1663–78.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Valli H, Phillips BT, Gassei K, Nagano MC, Orwig KE. Spermatogonial stem cells and spermatogenesis. In: Plant TM, Zeleznik AJ, editors. Knobil and Neill’s physiology of reproduction. 4th ed. San Diego, CA: Elsevier; 2015. p. 595–635.

    Google Scholar 

  6. Regaud C. Étude sur la structure des tubes séminifères et sur la spermatogénèse chez les mamminféres. Arch D’anat Microscopique. 1901;4:101–56.

    Google Scholar 

  7. Aeckerle N, Eildermann K, Drummer C, Ehmcke J, Schweyer S, Lerchl A, Bergmann M, Kliesch S, Gromoll J, Schlatt S, Behr R. The pluripotency factor LIN28 in monkey and human testes: a marker for spermatogonial stem cells? Mol Hum Reprod. 2012;18(10):477–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Kanatsu-Shinohara M, Toyokuni S, Morimoto T, Matsui S, Honjo T, Shinohara T. Functional assessment of self-renewal activity of male germline stem cells following cytotoxic damage and serial transplantation. Biol Reprod. 2003;68(5):1801–7.

    CAS  PubMed  Google Scholar 

  9. Abuelhija M, Weng CC, Shetty G, Meistrich ML. Rat models of post-irradiation recovery of spermatogenesis: interstrain differences. Andrology. 2013;1(2):206–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Hermann BP, Sukhwani M, Lin CC, Sheng Y, Tomko J, Rodriguez M, Shuttleworth JJ, McFarland D, Hobbs RM, Pandolfi PP, Schatten GP, Orwig KE. Characterization, cryopreservation, and ablation of spermatogonial stem cells in adult rhesus macaques. Stem Cells. 2007;25(9):2330–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Clermont Y, Antar M. Duration of the cycle of the seminiferous epithelium and the spermatogonial renewal in the monkey Macaca arctoides. Am J Anat. 1973;136(2):153–65.

    CAS  PubMed  Google Scholar 

  12. van Alphen MM, van de Kant HJ, de Rooij DG. Repopulation of the seminiferous epithelium of the rhesus monkey after X irradiation. Radiat Res. 1988;113(3):487–500.

    PubMed  Google Scholar 

  13. Clifton DK, Bremner WJ. The effect of testicular x-irradiation on spermatogenesis in man. A comparison with the mouse. J Androl. 1983;4(6):387–92.

    CAS  PubMed  Google Scholar 

  14. Oakberg EF. Mammalian gametogenesis and species comparisons in radiation response of the gonads. In: Effects of radiation on meiotic systems. Vienna: International Atomic Energy Agency; 1968. p. 3–15.

    Google Scholar 

  15. Oakberg EF. Effects of radiation on the testis. In: Hamilton DW, Greep RO, editors. Handbook of physiology. Washington, DC: American Physiological Society; 1975 (Section 7).

    Google Scholar 

  16. Hamada AJ, Montgomery B, Agarwal A. Male infertility: a critical review of pharmacologic management. Expert Opin Pharmacother. 2012;13(17):2511–31.

    CAS  PubMed  Google Scholar 

  17. Schlegel PN. Evaluation of male infertility. Minerva Ginecol. 2009;61(4):261–83.

    CAS  PubMed  Google Scholar 

  18. Chandra A, Copen CE, Stephen EH. Infertility and impaired fecundity in the United States, 1982–2010: data from the National Survey of Family Growth. Natl Health Stat Report. 2013;67:1–18.

    PubMed  Google Scholar 

  19. Louis JF, Thoma ME, Sorensen DN, McLain AC, King RB, Sundaram R, Keiding N, Buck Louis GM. The prevalence of couple infertility in the United States from a male perspective: evidence from a nationally representative sample. Andrology. 2013;1(5):741–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Bak CW, Seok HH, Song SH, Kim ES, Her YS, Yoon TK. Hormonal imbalances and psychological scars left behind in infertile men. J Androl. 2012;33(2):181–9.

    CAS  PubMed  Google Scholar 

  21. Slade P, O’Neill C, Simpson AJ, Lashen H. The relationship between perceived stigma, disclosure patterns, support and distress in new attendees at an infertility clinic. Hum Reprod. 2007;22(8):2309–17.

    CAS  PubMed  Google Scholar 

  22. Wu AK, Elliott P, Katz PP, Smith JF. Time costs of fertility care: the hidden hardship of building a family. Fertil Steril. 2013;99(7):2025–30.

    PubMed Central  PubMed  Google Scholar 

  23. Jensen TK, Jacobsen R, Christensen K, Nielsen NC, Bostofte E. Good semen quality and life expectancy: a cohort study of 43,277 men. Am J Epidemiol. 2009;170(5):559–65.

    PubMed  Google Scholar 

  24. Wallace WH, Anderson RA, Irvine DS. Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncol. 2005;6(4):209–18.

    PubMed  Google Scholar 

  25. Meistrich ML. Male gonadal toxicity. Pediatr Blood Cancer. 2009;53(2):261–6.

    PubMed Central  PubMed  Google Scholar 

  26. Levine J, Canada A, Stern CJ. Fertility preservation in adolescents and young adults with cancer. J Clin Oncol. 2010;28(32):4831–41.

    PubMed  Google Scholar 

  27. Green DM, Kawashima T, Stovall M, Leisenring W, Sklar CA, Mertens AC, Donaldson SS, Byrne J, Robison LL. Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2010;28(2):332–9.

    PubMed Central  PubMed  Google Scholar 

  28. Meistrich ML, Vassilopoulou-Sellin R, Lipshultz LI. Adverse effects of treatment: gonadal dysfunction. In: DeVita VT, Hellman S, Rosenberg SA, editors. Principles and practice of oncology. 7th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2004. p. 2560–74.

    Google Scholar 

  29. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK. SEER Cancer Statistic Review 1975–2008. Bethesda, MD: National Cancer Institute; 2010. [cited 2011], Available from: http://seer.cancer.gov/csr/1975_2008/.

    Google Scholar 

  30. Valli H, Phillips BT, Shetty G, Byrne JA, Clark AT, Meistrich ML, Orwig KE. Germline stem cells: toward the regeneration of spermatogenesis. Fertil Steril. 2014;101(1):3–13.

    PubMed  Google Scholar 

  31. Schover LR. Patient attitudes toward fertility preservation. Pediatr Blood Cancer. 2009;53(2):281–4.

    PubMed  Google Scholar 

  32. Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, Beck LN, Brennan LV, Oktay K. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006;24(18):2917–31.

    PubMed  Google Scholar 

  33. Loren AW, Mangu PB, Beck LN, Brennan L, Magdalinski AJ, Partridge AH, Quinn G, Wallace WH, Oktay K. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500–10.

    PubMed  Google Scholar 

  34. Ethics Committee of the American Society for Reproductive Medicine. Fertility preservation and reproduction in cancer patients. Fertil Steril. 2005;83(6):1622–8.

    Google Scholar 

  35. Practice Committee of American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. 2013;100(5):1214–23.

    Google Scholar 

  36. Schover LR, Brey K, Lichtin A, Lipshultz LI, Jeha S. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol. 2002;20(7):1880–9.

    PubMed  Google Scholar 

  37. Hsiao W, Stahl PJ, Osterberg EC, Nejat E, Palermo GD, Rosenwaks Z, Schlegel PN. Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: the Weill Cornell experience. J Clin Oncol. 2011;29(12):1607–11.

    PubMed  Google Scholar 

  38. Paniagua R, Nistal M. Morphological and histometric study of human spermatogonia from birth to the onset of puberty. J Anat. 1984;139(Pt 3):535–52.

    PubMed Central  PubMed  Google Scholar 

  39. Orwig KE, Shaw PH, Sanfilippo JS, Kauma SW, Nayak S, Cannon GM. Fertility preservation program of Magee-Womens hospital in Pittsburgh. http://www.mwrif.org/220.

  40. Wyns C, Curaba M, Petit S, Vanabelle B, Laurent P, Wese JF, Donnez J. Management of fertility preservation in prepubertal patients: 5 years’ experience at the Catholic University of Louvain. Hum Reprod. 2011;26(4):737–47.

    CAS  PubMed  Google Scholar 

  41. Ginsberg JP, Carlson CA, Lin K, Hobbie WL, Wigo E, Wu X, Brinster RL, Kolon TF. An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Hum Reprod. 2010;25(1):37–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Sadri-Ardekani H, Mizrak SC, van Daalen SK, Korver CM, Roepers-Gajadien HL, Koruji M, Hovingh S, de Reijke TM, de la Rosette JJ, van der Veen F, de Rooij DG, Repping S, van Pelt AM. Propagation of human spermatogonial stem cells in vitro. JAMA. 2009;302(19):2127–34.

    CAS  PubMed  Google Scholar 

  43. Sadri-Ardekani H, Akhondi MA, van der Veen F, Repping S, van Pelt AM. In vitro propagation of human prepubertal spermatogonial stem cells. JAMA. 2011;305(23):2416–8.

    CAS  PubMed  Google Scholar 

  44. Keros V, Hultenby K, Borgstrom B, Fridstrom M, Jahnukainen K, Hovatta O. Methods of cryopreservation of testicular tissue with viable spermatogonia in pre-pubertal boys undergoing gonadotoxic cancer treatment. Hum Reprod. 2007;22(5):1384–95.

    CAS  PubMed  Google Scholar 

  45. Goossens E, Van Saen D, Tournaye H. Spermatogonial stem cell preservation and transplantation: from research to clinic. Hum Reprod. 2013;28(4):897–907.

    CAS  PubMed  Google Scholar 

  46. Ginsberg JP. New advances in fertility preservation for pediatric cancer patients. Curr Opin Pediatr. 2011;23(1):9–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Brinster RL, Zimmermann JW. Spermatogenesis following male germ-cell transplantation. Proc Natl Acad Sci U S A. 1994;91(24):11298–302.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Brinster RL, Avarbock MR. Germline transmission of donor haplotype following spermatogonial transplantation. Proc Natl Acad Sci U S A. 1994;91(24):11303–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Ogawa T, Dobrinski I, Avarbock MR, Brinster RL. Transplantation of male germ line stem cells restores fertility in infertile mice. Nat Med. 2000;6(1):29–34.

    CAS  PubMed  Google Scholar 

  50. Shinohara T, Orwig KE, Avarbock MR, Brinster RL. Remodeling of the postnatal mouse testis is accompanied by dramatic changes in stem cell number and niche accessibility. Proc Natl Acad Sci U S A. 2001;98(11):6186–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Nagano M, Brinster CJ, Orwig KE, Ryu BY, Avarbock MR, Brinster RL. Transgenic mice produced by retroviral transduction of male germ-line stem cells. Proc Natl Acad Sci U S A. 2001;98(23):13090–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Brinster CJ, Ryu BY, Avarbock MR, Karagenc L, Brinster RL, Orwig KE. Restoration of fertility by germ cell transplantation requires effective recipient preparation. Biol Reprod. 2003;69(2):412–20.

    CAS  PubMed  Google Scholar 

  53. Honaramooz A, Behboodi E, Megee SO, Overton SA, Galantino-Homer H, Echelard Y, Dobrinski I. Fertility and germline transmission of donor haplotype following germ cell transplantation in immunocompetent goats. Biol Reprod. 2003;69(4):1260–4.

    CAS  PubMed  Google Scholar 

  54. Izadyar F, Den Ouden K, Creemers LB, Posthuma G, Parvinen M, De Rooij DG. Proliferation and differentiation of bovine type A spermatogonia during long-term culture. Biol Reprod. 2003;68(1):272–81.

    CAS  PubMed  Google Scholar 

  55. Mikkola M, Sironen A, Kopp C, Taponen J, Sukura A, Vilkki J, Katila T, Andersson M. Transplantation of normal boar testicular cells resulted in complete focal spermatogenesis in a boar affected by the immotile short-tail sperm defect. Reprod Domest Anim. 2006;41(2):124–8.

    CAS  PubMed  Google Scholar 

  56. Kim Y, Turner D, Nelson J, Dobrinski I, McEntee M, Travis AJ. Production of donor-derived sperm after spermatogonial stem cell transplantation in the dog. Reproduction. 2008;136(6):823–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Herrid M, Olejnik J, Jackson M, Suchowerska N, Stockwell S, Davey R, Hutton K, Hope S, Hill JR. Irradiation enhances the efficiency of testicular germ cell transplantation in sheep. Biol Reprod. 2009;81(5):898–905.

    CAS  PubMed  Google Scholar 

  58. Hermann BP, Sukhwani M, Winkler F, Pascarella JN, Peters KA, Sheng Y, Valli H, Rodriguez M, Ezzelarab M, Dargo G, Peterson K, Masterson K, Ramsey C, Ward T, Lienesch M, Volk A, Cooper DK, Thomson AW, Kiss JE, Penedo MC, Schatten GP, Mitalipov S, Orwig KE. Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm. Cell Stem Cell. 2012;11(5):715–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Izadyar F, Den Ouden K, Stout TA, Stout J, Coret J, Lankveld DP, Spoormakers TJ, Colenbrander B, Oldenbroek JK, Van der Ploeg KD, Woelders H, Kal HB, De Rooij DG. Autologous and homologous transplantation of bovine spermatogonial stem cells. Reproduction. 2003;126(6):765–74.

    CAS  PubMed  Google Scholar 

  60. Schlatt S, Foppiani L, Rolf C, Weinbauer GF, Nieschlag E. Germ cell transplantation into X-irradiated monkey testes. Hum Reprod. 2002;17(1):55–62.

    CAS  PubMed  Google Scholar 

  61. Jahnukainen K, Ehmcke J, Quader MA, Saiful Huq M, Epperly MW, Hergenrother S, Nurmio M, Schlatt S. Testicular recovery after irradiation differs in prepubertal and pubertal non-human primates, and can be enhanced by autologous germ cell transplantation. Hum Reprod. 2011;26(8):1945–54.

    PubMed Central  PubMed  Google Scholar 

  62. Ryu BY, Orwig KE, Avarbock MR, Brinster RL. Stem cell and niche development in the postnatal rat testis. Dev Biol. 2003;263(2):253–63.

    CAS  PubMed  Google Scholar 

  63. Dobrinski I, Avarbock MR, Brinster RL. Transplantation of germ cells from rabbits and dogs into mouse testes. Biol Reprod. 1999;61(5):1331–9.

    CAS  PubMed  Google Scholar 

  64. Dobrinski I, Avarbock MR, Brinster RL. Germ cell transplantation from large domestic animals into mouse testes. Mol Reprod Dev. 2000;57(3):270–9.

    CAS  PubMed  Google Scholar 

  65. Abu Elhija M, Lunenfeld E, Schlatt S, Huleihel M. Differentiation of murine male germ cells to spermatozoa in a soft agar culture system. Asian J Androl. 2011;14:285–93.

    PubMed Central  PubMed  Google Scholar 

  66. Shetty G, Uthamanthil RK, Zhou W, Shao SH, Weng CC, Tailor RC, Hermann BP, Orwig KE, Meistrich ML. Hormone suppression with GnRH antagonist promotes spermatogenic recovery from transplanted spermatogonial stem cells in irradiated cynomolgus monkeys. Andrology. 2013;1(6):886–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Radford JA, Shalet SM, Lieberman BA. Fertility after treatment for cancer. BMJ. 1999;319(7215):935–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Radford J. Restoration of fertility after treatment for cancer. Horm Res. 2003;59 Suppl 1:21–3.

    CAS  PubMed  Google Scholar 

  69. Brougham MF, Kelnar CJ, Sharpe RM, Wallace WH. Male fertility following childhood cancer: current concepts and future therapies. Asian J Androl. 2003;5(4):325–37.

    PubMed  Google Scholar 

  70. Mitchell RT, Saunders PT, Sharpe RM, Kelnar CJ, Wallace WH. Male fertility and strategies for fertility preservation following childhood cancer treatment. Endocr Dev. 2009;15:101–34.

    CAS  PubMed  Google Scholar 

  71. Wallace WH. Oncofertility and preservation of reproductive capacity in children and young adults. Cancer. 2011;117(10 Suppl):2301–10.

    PubMed  Google Scholar 

  72. Schlatt S, Ehmcke J, Jahnukainen K. Testicular stem cells for fertility preservation: preclinical studies on male germ cell transplantation and testicular grafting. Pediatr Blood Cancer. 2009;53(2):274–80.

    PubMed  Google Scholar 

  73. Ginsberg JP, Li Y, Carlson CA, Gracia CR, Hobbie WL, Miller VA, Mulhall J, Shnorhavorian M, Brinster RL, Kolon TF. Testicular tissue cryopreservation in prepubertal male children: an analysis of parental decision-making. Pediatr Blood Cancer. 2014;61(9):1673–8.

    PubMed  Google Scholar 

  74. Valli H, Sukhwani M, Dovey SL, Peters KA, Donohue J, Castro CA, Chu T, Marshall GR, Orwig KE. Fluorescence- and magnetic-activated cell sorting strategies to isolate and enrich human spermatogonial stem cells. Fertil Steril. 2014;102(2):566–80.

    PubMed  Google Scholar 

  75. Nagano M, Avarbock MR, Leonida EB, Brinster CJ, Brinster RL. Culture of mouse spermatogonial stem cells. Tissue Cell. 1998;30(4):389–97.

    CAS  PubMed  Google Scholar 

  76. Nagano M, Shinohara T, Avarbock MR, Brinster RL. Retrovirus-mediated gene delivery into male germ line stem cells. FEBS Lett. 2000;475(1):7–10.

    CAS  PubMed  Google Scholar 

  77. Nagano M, Watson DJ, Ryu BY, Wolfe JH, Brinster RL. Lentiviral vector transduction of male germ line stem cells in mice. FEBS Lett. 2002;524(1–3):111–5.

    CAS  PubMed  Google Scholar 

  78. Nagano M, Ryu BY, Brinster CJ, Avarbock MR, Brinster RL. Maintenance of mouse male germ line stem cells in vitro. Biol Reprod. 2003;68(6):2207–14.

    CAS  PubMed  Google Scholar 

  79. Orwig KE, Avarbock MR, Brinster RL. Retrovirus-mediated modification of male germline stem cells in rats. Biol Reprod. 2002;67(3):874–9.

    CAS  PubMed  Google Scholar 

  80. Kanatsu-Shinohara M, Ogonuki N, Inoue K, Miki H, Ogura A, Toyokuni S, Shinohara T. Long-term proliferation in culture and germline transmission of mouse male germline stem cells. Biol Reprod. 2003;69(2):612–6.

    CAS  PubMed  Google Scholar 

  81. Kubota H, Avarbock MR, Brinster RL. Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells. Proc Natl Acad Sci U S A. 2004;101(47):16489–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Oatley JM, Brinster RL. Spermatogonial stem cells. Methods Enzymol. 2006;419:259–82.

    CAS  PubMed  Google Scholar 

  83. Kubota H, Avarbock MR, Brinster RL. Culture conditions and single growth factors affect fate determination of mouse spermatogonial stem cells. Biol Reprod. 2004;71(3):722–31.

    CAS  PubMed  Google Scholar 

  84. Kanatsu-Shinohara M, Miki H, Inoue K, Ogonuki N, Toyokuni S, Ogura A, Shinohara T. Long-term culture of mouse male germline stem cells under serum-or feeder-free conditions. Biol Reprod. 2005;72(4):985–91.

    CAS  PubMed  Google Scholar 

  85. Kanatsu-Shinohara M, Ogonuki N, Matoba S, Morimoto H, Ogura A, Shinohara T. Improved serum- and feeder-free culture of mouse germline stem cells. Biol Reprod. 2014;91(4):88.

    PubMed  Google Scholar 

  86. Hamra FK, Chapman KM, Nguyen DM, Williams-Stephens AA, Hammer RE, Garbers DL. Self renewal, expansion, and transfection of rat spermatogonial stem cells in culture. Proc Natl Acad Sci U S A. 2005;102(48):17430–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Ryu BY, Kubota H, Avarbock MR, Brinster RL. Conservation of spermatogonial stem cell self-renewal signaling between mouse and rat. Proc Natl Acad Sci U S A. 2005;102(40):14302–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Kanatsu-Shinohara M, Muneto T, Lee J, Takenaka M, Chuma S, Nakatsuji N, Horiuchi T, Shinohara T. Long-term culture of male germline stem cells from hamster testes. Biol Reprod. 2008;78(4):611–7.

    CAS  PubMed  Google Scholar 

  89. Richardson TE, Chapman KM, Tenenhaus Dann C, Hammer RE, Hamra FK. Sterile testis complementation with spermatogonial lines restores fertility to DAZL-deficient rats and maximizes donor germline transmission. PLoS One. 2009;4(7):e6308.

    PubMed Central  PubMed  Google Scholar 

  90. Kala S, Kaushik R, Singh KP, Kadam PH, Singh MK, Manik RS, Singla SK, Palta P, Chauhan MS. In vitro culture and morphological characterization of prepubertal buffalo (Bubalus bubalis) putative spermatogonial stem cell. J Assist Reprod Genet. 2012;29(12):1335–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Luo J, Megee S, Rathi R, Dobrinski I. Protein gene product 9.5 is a spermatogonia-specific marker in the pig testis: application to enrichment and culture of porcine spermatogonia. Mol Reprod Dev. 2006;73(12):1531–40.

    CAS  PubMed  Google Scholar 

  92. Kuijk EW, Colenbrander B, Roelen BA. The effects of growth factors on in vitro-cultured porcine testicular cells. Reproduction. 2009;138(4):721–31.

    CAS  PubMed  Google Scholar 

  93. Eildermann K, Gromoll J, Behr R. Misleading and reliable markers to differentiate between primate testis-derived multipotent stromal cells and spermatogonia in culture. Hum Reprod. 2012;27(6):1754–67.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Langenstroth D, Kossack N, Westernströer B, Wistuba J, Behr R, Gromoll J, et al. Separation of somatic and germ cells is required to establish primate spermatogonial cultures. Hum Reprod. 2014;29(9):2018–31.

    PubMed  Google Scholar 

  95. Wu X, Schmidt JA, Avarbock MR, Tobias JW, Carlson CA, Kolon TF, Ginsberg JP, Brinster RL. Prepubertal human spermatogonia and mouse gonocytes share conserved gene expression of germline stem cell regulatory molecules. Proc Natl Acad Sci U S A. 2009;106(51):21672–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. He Z, Kokkinaki M, Jiang J, Dobrinski I, Dym M. Isolation, characterization, and culture of human spermatogonia. Biol Reprod. 2010;82(2):363–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Mirzapour T, Movahedin M, Tengku Ibrahim TA, Koruji M, Haron AW, Nowroozi MR, Rafieian SH. Effects of basic fibroblast growth factor and leukaemia inhibitory factor on proliferation and short-term culture of human spermatogonial stem cells. Andrologia. 2012;44:41–55.

    PubMed  Google Scholar 

  98. Chen B, Wang YB, Zhang ZL, Xia WL, Wang HX, Xiang ZQ, Hu K, Han YF, Wang YX, Huang YR, Wang Z. Xeno-free culture of human spermatogonial stem cells supported by human embryonic stem cell-derived fibroblast-like cells. Asian J Androl. 2009;11(5):557–65.

    PubMed Central  PubMed  Google Scholar 

  99. Kokkinaki M, Djourabtchi A, Golestaneh N. Long-term culture of human SSEA-4 positive spermatogonial stem cells (SSCs). J Stem Cell Res Ther. 2011;S2:003.

    Google Scholar 

  100. Liu S, Tang Z, Xiong T, Tang W. Isolation and characterization of human spermatogonial stem cells. Reprod Biol Endocrinol. 2011;9:141.

    PubMed Central  PubMed  Google Scholar 

  101. Smith JF, Yango P, Altman E, Choudhry S, Poelzl A, Zamah AM, Rosen M, Klatsky PC, Tran ND. Testicular niche required for human spermatogonial stem cell expansion. Stem Cells Transl Med. 2014;3(9):1043–54.

    CAS  PubMed  Google Scholar 

  102. Nowroozi MR, Ahmadi H, Rafiian S, Mirzapour T, Movahedin M. In vitro colonization of human spermatogonia stem cells: effect of patient’s clinical characteristics and testicular histologic findings. Urology. 2011;78(5):1075–81.

    PubMed  Google Scholar 

  103. von Kopylow K, Staege H, Spiess AN, Schulze W, Will H, Primig M, Kirchhoff C. Differential marker protein expression specifies rarefaction zone-containing human Adark spermatogonia. Reproduction. 2012;143(1):45–57.

    Google Scholar 

  104. Lim J, Goriely A, Turner GD, Ewen KA, Jacobsen GK, Graem N, Wilkie AO, Rajpert-De ME. OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia. J Pathol. 2011;224(4):473–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. von Kopylow K, Staege H, Schulze W, Will H, Kirchhoff C. Fibroblast growth factor receptor 3 is highly expressed in rarely dividing human type A spermatogonia. Histochem Cell Biol. 2012;138(5):759–72.

    CAS  Google Scholar 

  106. Kusz KM, Tomczyk L, Sajek M, Spik A, Latos-Bielenska A, Jedrzejczak P, Pawelczyk L, Jaruzelska J. The highly conserved NANOS2 protein: testis-specific expression and significance for the human male reproduction. Mol Hum Reprod. 2009;15(3):165–71.

    CAS  PubMed  Google Scholar 

  107. Dovey SL, Valli H, Hermann BP, Sukhwani M, Donohue J, Castro CA, Chu T, Sanfilippo JS, Orwig KE. Eliminating malignant contamination from therapeutic human spermatogonial stem cells. J Clin Invest. 2013;123(4):1833–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Zohni K, Zhang X, Tan SL, Chan P, Nagano M. CD9 is expressed on human male germ cells that have a long-term repopulation potential after transplantation into mouse testes. Biol Reprod. 2012;87(2):27.

    PubMed  Google Scholar 

  109. Izadyar F, Wong J, Maki C, Pacchiarotti J, Ramos T, Howerton K, Yuen C, Greilach S, Zhao HH, Chow M, Chow YC, Rao J, Barritt J, Bar-Chama N, Copperman A. Identification and characterization of repopulating spermatogonial stem cells from the adult human testis. Hum Reprod. 2011;26(6):1296–306.

    PubMed  Google Scholar 

  110. Kim TH, Hargreaves HK, Brynes RK, Hawkins HK, Lui VK, Woodard J, Ragab AH. Pretreatment testicular biopsy in childhood acute lymphocytic leukaemia. Lancet. 1981;2(8248):657–8.

    CAS  PubMed  Google Scholar 

  111. Jahnukainen K, Hou M, Petersen C, Setchell B, Soder O. Intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia. Cancer Res. 2001;61(2):706–10.

    CAS  PubMed  Google Scholar 

  112. Shinohara T, Orwig KE, Avarbock MR, Brinster RL. Spermatogonial stem cell enrichment by multiparameter selection of mouse testis cells. Proc Natl Acad Sci U S A. 2000;97(15):8346–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Fujita K, Ohta H, Tsujimura A, Takao T, Miyagawa Y, Takada S, Matsumiya K, Wakayama T, Okuyama A. Transplantation of spermatogonial stem cells isolated from leukemic mice restores fertility without inducing leukemia. J Clin Invest. 2005;115(7):1855–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Fujita K, Tsujimura A, Miyagawa Y, Kiuchi H, Matsuoka Y, Takao T, Takada S, Nonomura N, Okuyama A. Isolation of germ cells from leukemia and lymphoma cells in a human in vitro model: potential clinical application for restoring human fertility after anticancer therapy. Cancer Res. 2006;66(23):11166–71.

    CAS  PubMed  Google Scholar 

  115. Hermann BP, Sukhwani M, Salati J, Sheng Y, Chu T, Orwig KE. Separating spermatogonia from cancer cells in contaminated prepubertal primate testis cell suspensions. Hum Reprod. 2011;26(12):3222–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Hou M, Andersson M, Zheng C, Sundblad A, Soder O, Jahnukainen K. Decontamination of leukemic cells and enrichment of germ cells from testicular samples from rats with Roser’s T-cell leukemia by flow cytometric sorting. Reproduction. 2007;134(6):767–79.

    CAS  PubMed  Google Scholar 

  117. Geens M, Van de Velde H, De Block G, Goossens E, Van Steirteghem A, Tournaye H. The efficiency of magnetic-activated cell sorting and fluorescence-activated cell sorting in the decontamination of testicular cell suspensions in cancer patients. Hum Reprod. 2007;22(3):733–42.

    CAS  PubMed  Google Scholar 

  118. Dolmans MM, Marinescu C, Saussoy P, Van Langendonckt A, Amorim C, Donnez J. Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood. 2010;116(16):2908–14.

    CAS  PubMed  Google Scholar 

  119. Rosendahl M, Andersen MT, Ralfkiaer E, Kjeldsen L, Andersen MK, Andersen CY. Evidence of residual disease in cryopreserved ovarian cortex from female patients with leukemia. Fertil Steril. 2010;94(6):2186–90.

    PubMed  Google Scholar 

  120. Honaramooz A, Snedaker A, Boiani M, Scholer H, Dobrinski I, Schlatt S. Sperm from neonatal mammalian testes grafted in mice. Nature. 2002;418(6899):778–81.

    CAS  PubMed  Google Scholar 

  121. Schlatt S, Honaramooz A, Boiani M, Scholer HR, Dobrinski I. Progeny from sperm obtained after ectopic grafting of neonatal mouse testes. Biol Reprod. 2003;68(6):2331–5.

    CAS  PubMed  Google Scholar 

  122. Honaramooz A, Li MW, Penedo MCT, Meyers S, Dobrinski I. Accelerated maturation of primate testis by xenografting into mice. Biol Reprod. 2004;70(5):1500–3.

    CAS  PubMed  Google Scholar 

  123. Jamieson SW, Madani MM. The choice of valve protheses*. J Am Coll Cardiol. 2004;44(2):389–90.

    PubMed  Google Scholar 

  124. Andreas M, Wallner S, Ruetzler K, Wiedemann D, Ehrlich M, Heinze G, Binder T, Moritz A, Hiesmayr MJ, Kocher A, Laufer G. Comparable long-term results for porcine and pericardial prostheses after isolated aortic valve replacement. Eur J Cardiothorac Surg. 2014;18:2014.

    Google Scholar 

  125. Cozzi E, White DJ. The generation of transgenic pigs as potential organ donors for humans. Nat Med. 1995;1(9):964–6.

    CAS  PubMed  Google Scholar 

  126. Kimsa MC, Strzalka-Mrozik B, Kimsa MW, Gola J, Nicholson P, Lopata K, Mazurek U. Porcine endogenous retroviruses in xenotransplantation–molecular aspects. Viruses. 2014;6(5):2062–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Weiss RA. The discovery of endogenous retroviruses. Retrovirology. 2006;3:67.

    PubMed Central  PubMed  Google Scholar 

  128. Geens M, De Block G, Goossens E, Frederickx V, Van Steirteghem A, Tournaye H. Spermatogonial survival after grafting human testicular tissue to immunodeficient mice. Hum Reprod. 2006;21(2):390–6.

    PubMed  Google Scholar 

  129. Goossens E, Geens M, De Block G, Tournaye H. Spermatogonial survival in long-term human prepubertal xenografts. Fertil Steril. 2008;90(5):2019–22.

    PubMed  Google Scholar 

  130. Van Saen D, Goossens E, Bourgain C, Ferster A, Tournaye H. Meiotic activity in orthotopic xenografts derived from human postpubertal testicular tissue. Hum Reprod. 2011;26(2):282–93.

    PubMed  Google Scholar 

  131. Schlatt S, Honaramooz A, Ehmcke J, Goebell PJ, Rubben H, Dhir R, Dobrinski I, Patrizio P. Limited survival of adult human testicular tissue as ectopic xenograft. Hum Reprod. 2006;21(2):384–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Sato Y, Nozawa S, Yoshiike M, Arai M, Sasaki C, Iwamoto T. Xenografting of testicular tissue from an infant human donor results in accelerated testicular maturation. Hum Reprod. 2010;25(5):1113–22.

    CAS  PubMed  Google Scholar 

  133. Wyns C, Van Langendonckt A, Wese FX, Donnez J, Curaba M. Long-term spermatogonial survival in cryopreserved and xenografted immature human testicular tissue. Hum Reprod. 2008;23(11):2402–14.

    PubMed  Google Scholar 

  134. Luetjens CM, Stukenborg J-B, Nieschlag E, Simoni M, Wistuba J. Complete spermatogenesis in orthotopic but not in ectopic transplants of autologously grafted marmoset testicular tissue. Endocrinology. 2008;149(4):1736–47.

    CAS  PubMed  Google Scholar 

  135. Pacchiarotti J, Ramos T, Howerton K, Greilach S, Zaragoza K, Olmstead M, Izadyar F. Developing a clinical-grade cryopreservation protocol for human testicular tissue and cells. BioMed Res Int. 2013;2013:10.

    Google Scholar 

  136. Poels J, Van Langendonckt A, Many MC, Wese FX, Wyns C. Vitrification preserves proliferation capacity in human spermatogonia. Hum Reprod. 2013;28(3):578–89.

    CAS  PubMed  Google Scholar 

  137. Keros V, Rosenlund B, Hultenby K, Aghajanova L, Levkov L, Hovatta O. Optimizing cryopreservation of human testicular tissue: comparison of protocols with glycerol, propanediol and dimethylsulphoxide as cryoprotectants. Hum Reprod. 2005;20(6):1676–87.

    CAS  PubMed  Google Scholar 

  138. Curaba M, Poels J, van Langendonckt A, Donnez J, Wyns C. Can prepubertal human testicular tissue be cryopreserved by vitrification? Fertil Steril. 2011;95(6):2123.e9–12.

    Google Scholar 

  139. Kvist K, Thorup J, Byskov AG, Hoyer PE, Mollgard K, Yding Andersen C. Cryopreservation of intact testicular tissue from boys with cryptorchidism. Hum Reprod. 2006;21(2):484–91.

    CAS  PubMed  Google Scholar 

  140. Unni S, Kasiviswanathan S, D’Souza S, Khavale S, Mukherjee S, Patwardhan S, Bhartiya D. Efficient cryopreservation of testicular tissue: effect of age, sample state, and concentration of cryoprotectant. Fertil Steril. 2012;97(1):200–8. 1.

    CAS  PubMed  Google Scholar 

  141. Baert Y, Van Saen D, Haentjens P, In’t Veld P, Tournaye H, Goossens E. What is the best cryopreservation protocol for human testicular tissue banking? Hum Reprod. 2013;28(7):1816–26.

    CAS  PubMed  Google Scholar 

  142. Yango P, Altman E, Smith JF, Klatsky PC, Tran ND. Optimizing cryopreservation of human spermatogonial stem cells: comparing the effectiveness of testicular tissue and single cell suspension cryopreservation. Fertil Steril. 2014;102(5):1491–8. 5.

    CAS  PubMed  Google Scholar 

  143. Sa R, Cremades N, Malheiro I, Sousa M. Cryopreservation of human testicular diploid germ cell suspensions. Andrologia. 2012;44(6):366–72.

    CAS  PubMed  Google Scholar 

  144. Brook PF, Radford JA, Shalet SM, Joyce AD, Gosden RG. Isolation of germ cells from human testicular tissue for low temperature storage and autotransplantation. Fertil Steril. 2001;75(2):269–74.

    CAS  PubMed  Google Scholar 

  145. Kanatsu-Shinohara M, Ogonuki N, Inoue K, Ogura A, Toyokuni S, Shinohara T. Restoration of fertility in infertile mice by transplantation of cryopreserved male germline stem cells. Hum Reprod. 2003;18(12):2660–7.

    CAS  PubMed  Google Scholar 

  146. Hermann BP, Sukhwani M, Simorangkir DR, Chu T, Plant TM, Orwig KE. Molecular dissection of the male germ cell lineage identifies putative spermatogonial stem cells in rhesus macaques. Hum Reprod. 2009;24(7):1704–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Dufour JM, Rajotte RV, Korbutt GS. Development of an in vivo model to study testicular morphogenesis. J Androl. 2002;23(5):635–44.

    PubMed  Google Scholar 

  148. Gassei K, Schlatt S, Ehmcke J. De novo morphogenesis of seminiferous tubules from dissociated immature rat testicular cells in xenografts. J Androl. 2006;27(4):611–8.

    PubMed  Google Scholar 

  149. Kita K, Watanabe T, Ohsaka K, Hayashi H, Kubota Y, Nagashima Y, Aoki I, Taniguchi H, Noce T, Inoue K, Miki H, Ogonuki N, Tanaka H, Ogura A, Ogawa T. Production of functional spermatids from mouse germline stem cells in ectopically reconstituted seminiferous tubules. Biol Reprod. 2007;76(2):211–7.

    CAS  PubMed  Google Scholar 

  150. Honaramooz A, Megee SO, Rathi R, Dobrinski I. Building a testis: formation of functional testis tissue after transplantation of isolated porcine (Sus scrofa) testis cells. Biol Reprod. 2007;76(1):43–7.

    CAS  PubMed  Google Scholar 

  151. Arregui L, Rathi R, Megee SO, Honaramooz A, Gomendio M, Roldan ER, Dobrinski I. Xenografting of sheep testis tissue and isolated cells as a model for preservation of genetic material from endangered ungulates. Reproduction. 2008;136(1):85–93.

    CAS  PubMed  Google Scholar 

  152. Baert Y, Stukenborg JB, Landreh M, De Kock J, Jornvall H, Soder O, Goossens E. Derivation and characterization of a cytocompatible scaffold from human testis. Hum Reprod. 2015;30(2):256–67.

    CAS  PubMed  Google Scholar 

  153. Sato T, Katagiri K, Gohbara A, Inoue K, Ogonuki N, Ogura A, Kubota Y, Ogawa T. In vitro production of functional sperm in cultured neonatal mouse testes. Nature. 2011;471(7339):504–7.

    CAS  PubMed  Google Scholar 

  154. Sato T, Katagiri K, Kubota Y, Ogawa T. In vitro sperm production from mouse spermatogonial stem cell lines using an organ culture method. Nat Protoc. 2013;8(11):2098–104.

    CAS  PubMed  Google Scholar 

  155. Trowell OA. The culture of mature organs in a synthetic medium. Exp Cell Res. 1959;16(1):118–47.

    CAS  PubMed  Google Scholar 

  156. Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell. 2011;146(4):519–32.

    CAS  PubMed  Google Scholar 

  157. Teramura T, Takehara T, Kawata N, Fujinami N, Mitani T, Takenoshita M, Matsumoto K, Saeki K, Iritani A, Sagawa N, Hosoi Y. Primate embryonic stem cells proceed to early gametogenesis in vitro. Cloning Stem Cells. 2007;9(2):144–56.

    CAS  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  159. Park TS, Galic Z, Conway AE, Lindgren A, van Handel BJ, Magnusson M, Richter L, Teitell MA, Mikkola HK, Lowry WE, Plath K, Clark AT. 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. 2009;27(4):783–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Easley IV CA, Phillips BT, McGuire MM, Barringer JM, Valli H, Hermann BP, Simerly CR, Rajkovic A, Miki T, Orwig KE, Schatten GP. Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep. 2012;2(3):440–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Easley IV CA, Simerly CR, Schatten G. Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility? Reprod Biomed Online. 2013;27(1):75–80.

    PubMed Central  PubMed  Google Scholar 

  162. Kee K, Gonsalves JM, Clark AT, Pera RA. Bone morphogenetic proteins induce germ cell differentiation from human embryonic stem cells. Stem Cells Dev. 2006;15(6):831–7.

    CAS  PubMed  Google Scholar 

  163. Kee K, Angeles VT, Flores M, Nguyen HN, Reijo Pera RA. Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature. 2009;462(7270):222–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Panula S, Medrano JV, Kee K, Bergstrom R, Nguyen HN, Byers B, Wilson KD, Wu JC, Simon C, Hovatta O, Reijo Pera RA. Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells. Hum Mol Genet. 2011;20(4):752–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Durruthy Durruthy J, Ramathal C, Sukhwani M, Fang F, Cui J, Orwig KE, Reijo Pera RA. Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules. Hum Mol Genet. 2014;23(12):3071–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Ramathal C, Durruthy-Durruthy J, Sukhwani M, Arakaki JE, Turek PJ, Orwig KE, Reijo Pera RA. Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. Cell Rep. 2014;7(4):1284–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Dominguez AA, Chiang HR, Sukhwani M, Orwig KE, Reijo Pera RA. Human germ cell formation in xenotransplants of induced pluripotent stem cells carrying X chromosome aneuploidies. Sci Rep. 2014;4:6432.

    PubMed Central  PubMed  Google Scholar 

  168. Gkountela S, Li Z, Vincent JJ, Zhang KX, Chen A, Pellegrini M, Clark AT. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat Cell Biol. 2013;15(1):113–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978;2(8085):366.

    CAS  PubMed  Google Scholar 

  170. Snedaker AK, Honaramooz A, Dobrinski I. A game of cat and mouse: xenografting of testis tissue from domestic kittens results in complete cat spermatogenesis in a mouse host. J Androl. 2004;25(6):926–30.

    PubMed  Google Scholar 

  171. Rathi R, Honaramooz A, Zeng W, Schlatt S, Dobrinski I. Germ cell fate and seminiferous tubule development in bovine testis xenografts. Reproduction. 2005;130(6):923–9.

    CAS  PubMed  Google Scholar 

  172. Oatley JM, de Avila DM, Reeves JJ, McLean DJ. Spermatogenesis and germ cell transgene expression in xenografted bovine testicular tissue. Biol Reprod. 2004;71(2):494–501.

    CAS  PubMed  Google Scholar 

  173. Wistuba J, Luetjens CM, Wesselmann R, Nieschlag E, Simoni M, Schlatt S. Meiosis in autologous ectopic transplants of immature testicular tissue grafted to Callithrix jacchus. Biol Reprod. 2006;74(4):706–13.

    CAS  PubMed  Google Scholar 

  174. Feng LX, Chen Y, Dettin L, Pera RA, Herr JC, Goldberg E, Dym M. Generation and in vitro differentiation of a spermatogonial cell line. Science. 2002;297(5580):392–5.

    CAS  PubMed  Google Scholar 

  175. Stukenborg JB, Wistuba J, Luetjens CM, Elhija MA, Huleihel M, Lunenfeld E, Gromoll J, Nieschlag E, Schlatt S. Coculture of spermatogonia with somatic cells in a novel three-dimensional soft-agar-culture-system. J Androl. 2008;29(3):312–29.

    CAS  PubMed  Google Scholar 

  176. Hermann BP, Orwig KE. Translating spermatogonial stem cell transplantation to the clinic. In: Orwig KE, Hermann BP, editors. Male germline stem cells: developmental and regenerative potential. New York, NY: Springer; 2011. p. 227–53.

    Google Scholar 

  177. Agarwal A, Allamaneni SR. Artificial insemination. In: Falcone T, Hurd W, editors. Clinical Reproductive Medicine and Surgery. Philadelphia: Elsevier; 2007. p. 539–48.

    Google Scholar 

  178. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978;2(8085):366.

    Google Scholar 

  179. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;340(8810):17–8.

    Google Scholar 

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Acknowledgments

The authors would like to thank the Scaife Foundation, the Richard King Mellon Foundation, the Magee-Womens Research Institute and Foundation, and the University of Pittsburgh Departments of Obstetrics, Gynecology and Reproductive Sciences and Urology who have generously provided funds to support the Fertility Preservation Program in Pittsburgh. It is in this context that we have had the opportunity to meet the infertile patients that fuel our passion for fertility research. The Orwig Lab is supported by the Magee-Womens Research Institute and Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development grants HD075795 and HD076412, the US-Israel Binational Science Foundation, and gift funds from Montana State University, Sylvia Bernassoli, and Julie and Michael McMullen.

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Valli, H., Gassei, K., Orwig, K.E. (2015). Stem Cell Therapies for Male Infertility: Where Are We Now and Where Are We Going?. In: Carrell, D., Schlegel, P., Racowsky, C., Gianaroli, L. (eds) Biennial Review of Infertility. Springer, Cham. https://doi.org/10.1007/978-3-319-17849-3_3

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