Germline stem cells: toward the regeneration of spermatogenesis
2013; Elsevier BV; Volume: 101; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2013.10.052
ISSN1556-5653
AutoresHanna Valli, Bart Phillips, Gunapala Shetty, James Byrne, Amander T. Clark, Marvin L. Meistrich, Kyle E. Orwig,
Tópico(s)Pluripotent Stem Cells Research
ResumoImproved therapies for cancer and other conditions have resulted in a growing population of long-term survivors. Infertility is an unfortunate side effect of some cancer therapies that impacts the quality of life of survivors who are in their reproductive or prereproductive years. Some of these patients have the opportunity to preserve their fertility using standard technologies that include sperm, egg, or embryo banking, followed by IVF and/or ET. However, these options are not available to all patients, especially the prepubertal patients who are not yet producing mature gametes. For these patients, there are several stem cell technologies in the research pipeline that may give rise to new fertility options and allow infertile patients to have their own biological children. We will review the role of stem cells in normal spermatogenesis as well as experimental stem cell–based techniques that may have potential to generate or regenerate spermatogenesis and sperm. We will present these technologies in the context of the fertility preservation paradigm, but we anticipate that they will have broad implications for the assisted reproduction field. Improved therapies for cancer and other conditions have resulted in a growing population of long-term survivors. Infertility is an unfortunate side effect of some cancer therapies that impacts the quality of life of survivors who are in their reproductive or prereproductive years. Some of these patients have the opportunity to preserve their fertility using standard technologies that include sperm, egg, or embryo banking, followed by IVF and/or ET. However, these options are not available to all patients, especially the prepubertal patients who are not yet producing mature gametes. For these patients, there are several stem cell technologies in the research pipeline that may give rise to new fertility options and allow infertile patients to have their own biological children. We will review the role of stem cells in normal spermatogenesis as well as experimental stem cell–based techniques that may have potential to generate or regenerate spermatogenesis and sperm. We will present these technologies in the context of the fertility preservation paradigm, but we anticipate that they will have broad implications for the assisted reproduction field. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/vallih-germline-stem-cells-spermatogenesis/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/vallih-germline-stem-cells-spermatogenesis/ High-dose chemotherapy, whole-body radiation, or radiation to the gonads can cause permanent infertility (1Meistrich M.L. Male gonadal toxicity.Pediatr Blood Cancer. 2009; 53: 261-266Crossref PubMed Scopus (25) Google Scholar). This is a significant human health concern because over 75,000 people under the age of 40 in the United States are diagnosed with cancer each year and most are cured (2Howlader N. Noone A.M. Krapcho M. Neyman N. Aminou R. Waldron W. et al.SEER Cancer Stat Rev 1975–2008. National Cancer Institute, Bethesda, MD2010Google Scholar). Thus, cancer patients can look beyond their diagnosis and treatment to quality of life after cancer. Parenthood is important to cancer survivors, and distress over infertility can have long-term psychological and relationship implications (3Schover L.R. Patient attitudes toward fertility preservation.Pediatr Blood Cancer. 2009; 53: 281-284Crossref PubMed Scopus (38) Google Scholar). Therefore, the American Society for Clinical Oncology (ASCO) (4Lee S.J. Schover L.R. Partridge A.H. Patrizio P. Wallace W.H. Hagerty K. et al.American Society of Clinical Oncology recommendations on fertility preservation in cancer patients.J Clin Oncol. 2006; 24: 2917-2931Crossref PubMed Scopus (735) Google Scholar) and the American Society for Reproductive Medicine Ethics Committee (5Fertility preservation and reproduction in cancer patients.Fertil Steril. 2005; 83: 1622-1628Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar) recommend that the reproductive risks of gonadotoxic therapies and options for preserving fertility be discussed with patients before initiating treatment. While adoption and third-party reproduction provide alternative family-building options, the available data indicate that most cancer survivors prefer to have their own biological children (4Lee S.J. Schover L.R. Partridge A.H. Patrizio P. Wallace W.H. Hagerty K. et al.American Society of Clinical Oncology recommendations on fertility preservation in cancer patients.J Clin Oncol. 2006; 24: 2917-2931Crossref PubMed Scopus (735) Google Scholar). Postpubertal adolescent and adult males have the option to cryopreserve sperm before oncological treatment (Fig. 1, top). This is a simple and established method for preserving fertility potential and allows men to father their own genetic children. Nearly 17,000 men between the ages of 15 and 44 are diagnosed with cancer each year in the United States, and nearly 2,385 survivors will receive a treatment that puts them at high risk of azoospermia (2Howlader N. Noone A.M. Krapcho M. Neyman N. Aminou R. Waldron W. et al.SEER Cancer Stat Rev 1975–2008. National Cancer Institute, Bethesda, MD2010Google Scholar, 6Meistrich M.L. Vassilopoulou-Sellin R. Lipshultz L.I. Adverse effects of treatment: gonadal dysfunction.in: DeVita V.T. Hellman S. Rosenberg S.A. Principles and practice of oncology. 7th ed. Lippincott Williams & Wilkins, Philadelphia2004: 2560-2574Google Scholar). Unfortunately, only about 24% of men in this age range cryopreserve semen before their oncological treatment (7Schover L.R. Brey K. Lichtin A. Lipshultz L.I. Jeha S. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors.J Clin Oncol. 2002; 20: 1880-1889Crossref PubMed Scopus (220) Google Scholar). Therefore, we calculate that each year in the United States, over 1,800 adult cancer survivors will be infertile with azoospermia and have limited options to have their own biological children because they did not save a semen sample. In some cases, sperm can be recovered surgically from small focal areas of spermatogenesis in the testes using the testicular sperm extraction method and can be used to fertilize oocytes by intracytoplasmic sperm injection (ICSI) (8Hsiao W. Stahl P.J. Osterberg E.C. Nejat E. Palermo G.D. Rosenwaks Z. et al.Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: the Weill Cornell Experience.J Clin Oncol. 2011; 29: 1607-1611Crossref PubMed Scopus (24) Google Scholar). There are no options to preserve the fertility of prepubertal boys, who are not yet making sperm. This is a significant problem because about 5,131 boys under the age of 15 in the United States are expected to develop cancer each year and 83% are expected to survive (2Howlader N. Noone A.M. Krapcho M. Neyman N. Aminou R. Waldron W. et al.SEER Cancer Stat Rev 1975–2008. National Cancer Institute, Bethesda, MD2010Google Scholar). A report from the Childhood Cancer Survivor Study indicates that the cytotoxic therapies for cancer reduce the number of young men subsequently able to have children by 44% (6Meistrich M.L. Vassilopoulou-Sellin R. Lipshultz L.I. Adverse effects of treatment: gonadal dysfunction.in: DeVita V.T. Hellman S. Rosenberg S.A. Principles and practice of oncology. 7th ed. Lippincott Williams & Wilkins, Philadelphia2004: 2560-2574Google Scholar, 9Green D.M. Kawashima T. Stovall M. Leisenring W. Sklar C.A. Mertens A.C. et al.Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.J Clin Oncol. 2010; 28: 332-339Crossref PubMed Scopus (59) Google Scholar). Based on these statistics, we calculate that each year in the United States, 1,874 young male cancer patients will become sterile owing to their treatment. In addition to cancer survivors, over 500 patients under the age of 20 receive hematopoietic stem cell transplants each year in the United States for nonmalignant conditions (e.g., bone marrow failure, blood and immune deficiencies, autoimmune disorders) (10Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides. http://www.cibmtr.org; 2012.Google Scholar). Myeloablative conditioning therapy before bone marrow transplantation is associated with a high risk of infertility (4Lee S.J. Schover L.R. Partridge A.H. Patrizio P. Wallace W.H. Hagerty K. et al.American Society of Clinical Oncology recommendations on fertility preservation in cancer patients.J Clin Oncol. 2006; 24: 2917-2931Crossref PubMed Scopus (735) Google Scholar, 9Green D.M. Kawashima T. Stovall M. Leisenring W. Sklar C.A. Mertens A.C. et al.Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.J Clin Oncol. 2010; 28: 332-339Crossref PubMed Scopus (59) Google Scholar, 11Wallace W.H. Anderson R.A. Irvine D.S. Fertility preservation for young patients with cancer: who is at risk and what can be offered?.Lancet Oncol. 2005; 6: 209-218Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 12Mitchell R.T. Saunders P.T. Sharpe R.M. Kelnar C.J. Wallace W.H. Male fertility and strategies for fertility preservation following childhood cancer treatment.Endocr Dev. 2009; 15: 101-134Crossref PubMed Scopus (21) Google Scholar). The ASCO report notes that “Impaired future fertility is difficult for children to understand, but potentially traumatic to them as adults” (4Lee S.J. Schover L.R. Partridge A.H. Patrizio P. Wallace W.H. Hagerty K. et al.American Society of Clinical Oncology recommendations on fertility preservation in cancer patients.J Clin Oncol. 2006; 24: 2917-2931Crossref PubMed Scopus (735) Google Scholar). The available data indicate that greater than 80% of parents consented to fertility preservation procedures on behalf of their children before initiation of gonadotoxic therapies (13Wyns C. Curaba M. Petit S. Vanabelle B. Laurent P. Wese J.F. et al.Management of fertility preservation in prepubertal patients: 5 years' experience at the Catholic University of Louvain.Humanit Rep. 2011; 26: 737-747Crossref Scopus (28) Google Scholar, 14Ginsberg J.P. New advances in fertility preservation for pediatric cancer patients.Curr Opin Pediatr. 2011; 23: 9-13Crossref PubMed Scopus (6) Google Scholar). The summed incidence of chemotherapy or radiation-induced male factor infertility that cannot be treated with existing reproductive therapies is approximately 4,000 individuals each year in the United States. Therefore, responsible development of novel therapies to help these patients have biological children has a significant potential impact. Promising results in animal models and human cell lines (Fig. 1, bottom) have generated enthusiasm that stem cells might be used or manipulated to preserve and/or restore the fertility of patients who are not producing sperm and have no other options to protect their future fertility before receiving gonadotoxic chemotherapy or radiation treatments (14Ginsberg J.P. New advances in fertility preservation for pediatric cancer patients.Curr Opin Pediatr. 2011; 23: 9-13Crossref PubMed Scopus (6) Google Scholar, 15Meistrich M.L. Shetty G. Hormonal suppression for fertility preservation in males and females.Reproduction. 2008; 136: 691-701Crossref PubMed Scopus (29) Google Scholar, 16Ginsberg J.P. Carlson C.A. Lin K. Hobbie W.L. Wigo E. Wu X. et al.An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety.Hum Reprod. 2010; 25: 37-41Crossref PubMed Scopus (45) Google Scholar, 17Ginsberg J.P. 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In vitro germ cell differentiation from cynomolgus monkey embryonic stem cells.PLoS ONE. 2009; 4: e5338Crossref PubMed Scopus (21) Google Scholar, 34Clark A.T. Phillips B.T. Orwig K.E. Fruitful progress to fertility: male fertility in the test tube.Nat Med. 2011; 17: 1564-1565Crossref PubMed Scopus (5) Google Scholar). We will review the methods of spermatogonial stem cell (SSC) transplantation (Fig. 1, blue boxes), testicular tissue grafting, testicular tissue organ culture (Fig. 1, orange boxes), and induced pluripotent stem cell differentiation into gametes or transplantable male germ line stem cells (Fig. 1, red boxes). Table 1 summarizes published reports detailing the progress of each method. Enthusiasm for these experimental stem cell technologies is tempered by concerns about feasibility and safety, particularly for the vulnerable prepubertal patient population (14Ginsberg J.P. New advances in fertility preservation for pediatric cancer patients.Curr Opin Pediatr. 2011; 23: 9-13Crossref PubMed Scopus (6) Google Scholar, 35Holoch P. Wald M. Current options for preservation of fertility in the male.Fertil Steril. 2011; 96: 286-290Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 36Wallace W.H. Oncofertility and preservation of reproductive capacity in children and young adults.Cancer. 2011; 117: 2301-2310Crossref PubMed Scopus (30) Google Scholar, 37Lamar C.A. DeCherney A.H. Fertility preservation: state of the science and future research directions.Fertil Steril. 2009; 91: 316-319Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Questions about feasibility stem from the early stage of technology development, uncertainty about optimal freezing conditions, concerns that a small testicular biopsy will contain few stem cells, and the lack of culture conditions to expand human germ line stem cells. Questions about safety are associated with the risks of surgery to obtain testicular tissue and the potential for malignant contamination in transplanted cells or tissue. Nonetheless, academic centers around the world are already cryopreserving testicular tissues for prepubertal boys and men in anticipation that stem cells in that tissue can be used safely and effectively to restore future fertility (13Wyns C. Curaba M. Petit S. Vanabelle B. Laurent P. Wese J.F. et al.Management of fertility preservation in prepubertal patients: 5 years' experience at the Catholic University of Louvain.Humanit Rep. 2011; 26: 737-747Crossref Scopus (28) Google Scholar, 16Ginsberg J.P. Carlson C.A. Lin K. Hobbie W.L. Wigo E. Wu X. et al.An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety.Hum Reprod. 2010; 25: 37-41Crossref PubMed Scopus (45) Google Scholar, 21Sadri-Ardekani H. Mizrak S.C. van Daalen S.K. Korver C.M. Roepers-Gajadien H.L. Koruji M. et al.Propagation of human spermatogonial stem cells in vitro.J Am Med Assoc. 2009; 302: 2127-2134Crossref Scopus (77) Google Scholar, 38Sadri-Ardekani H. Akhondi M.A. van der Veen F. Repping S. van Pelt A.M. In vitro propagation of human prepubertal spermatogonial stem cells.JAMA. 2011; 305: 2416-2418Crossref PubMed Scopus (33) Google Scholar, 39Keros 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: 1384-1395Crossref PubMed Scopus (98) Google Scholar, 40Orwig KE, Shaw PH, Sanfilippo JS. Fertility preservation in Pittsburgh. http://www.mwrif.org/220.Google Scholar, 41Goossens E. Van Saen D. Tournaye H. Spermatogonial stem cell preservation and transplantation: from research to clinic.Hum Reprod. 2013; 28: 897-907Crossref PubMed Scopus (5) Google Scholar).Table 1Literature reporting progress in stem cell technology development.Stem cell technologies(q)Real time polymerase chain reactionHistologyImmunocytochemistryImmunohistochemistryFlow/flow cytometry/ magnetic cell sortingXenotransplantationHomologous transplantationAutologous transplantationSpermaSperm and spermatogenesis.FertilizationProgenySSC transplant Rodents30Brinster R.L. Zimmermann J.W. Spermatogenesis following male germ-cell transplantation.Proc Natl Acad Sci U S A. 1994; 91: 11298-11302Crossref PubMed Scopus (736) Google Scholar, 31Brinster R.L. Avarbock M.R. Germline transmission of donor haplotype following spermatogonial transplantation.Proc Natl Acad Sci U S A. 1994; 91: 11303-11307Crossref PubMed Scopus (547) Google Scholar, 48Ogawa T. Dobrinski I. Avarbock M.R. Brinster R.L. Transplantation of male germ line stem cells restores fertility in infertile mice.Nat Med. 2000; 6: 29-34Crossref PubMed Scopus (194) Google Scholar, 49Shinohara T. Orwig K.E. Avarbock M.R. Brinster R.L. 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: 6186-6191Crossref PubMed Scopus (142) Google Scholar, 50Nagano M. Brinster C.J. Orwig K.E. Ryu B.Y. Avarbock M.R. Brinster R.L. Transgenic mice produced by retroviral transduction of male germ-line stem cells.Proc Natl Acad Sci U S A. 2001; 98: 13090-13095Crossref PubMed Scopus (185) Google Scholar, 51Brinster C.J. Ryu B.Y. Avarbock M.R. Karagenc L. Brinster R.L. Orwig K.E. Restoration of fertility by germ cell transplantation requires effective recipient preparation.Biol Reprod. 2003; 69: 412-420Crossref PubMed Scopus (72) Google Scholar, 57Richardson T.E. Chapman K.M. Tenenhaus Dann C. Hammer R.E. Hamra F.K. Sterile testis complementation with spermatogonial lines restores fertility to DAZL-deficient rats and maximizes donor germline transmission.PLoS ONE. 2009; 4: e6308Crossref PubMed Scopus (11) Google Scholar, 58Kanatsu-Shinohara M. Ogonuki N. Inoue K. Miki H. Ogura A. Toyokuni S. et al.Long-term proliferation in culture and germline transmission of mouse male germline stem cells.Biol Reprod. 2003; 69: 612-616Crossref PubMed Scopus (340) Google Scholar, 118Clouthier D.E. Avarbock M.R. Maika S.D. Hammer R.E. Brinster R.L. Rat spermatogenesis in mouse testis.Nature. 1996; 381: 418-421Crossref PubMed Scopus (253) Google Scholar, 119Ogawa T. Dobrinski I. Avarbock M.R. Brinster R.L. Xenogeneic spermatogenesis following transplantation of hamster germ cells to mouse testes.Biol Reprod. 1999; 60: 515-521Crossref PubMed Scopus (145) Google Scholar71Ryu B.Y. Kubota H. Avarbock M.R. Brinster R.L. Conservation of spermatogonial stem cell self-renewal signaling between mouse and rat.Proc Natl Acad Sci U S A. 2005; 102: 14302-14307Crossref PubMed Scopus (119) Google Scholar, 120Shinohara T. Kato M. Takehashi M. Lee J. Chuma S. Nakatsuji N. et al.Rats produced by interspecies spermatogonial transplantation in mice and in vitro microinsemination.Proc Natl Acad Sci U S A. 2006; 103: 13624-13628Crossref PubMed Scopus (47) Google Scholar71Ryu B.Y. Kubota H. Avarbock M.R. Brinster R.L. Conservation of spermatogonial stem cell self-renewal signaling between mouse and rat.Proc Natl Acad Sci U S A. 2005; 102: 14302-14307Crossref PubMed Scopus (119) Google Scholar, 118Clouthier D.E. Avarbock M.R. Maika S.D. Hammer R.E. Brinster R.L. Rat spermatogenesis in mouse testis.Nature. 1996; 381: 418-421Crossref PubMed Scopus (253) Google Scholar, 119Ogawa T. Dobrinski I. Avarbock M.R. Brinster R.L. Xenogeneic spermatogenesis following transplantation of hamster germ cells to mouse testes.Biol Reprod. 1999; 60: 515-521Crossref PubMed Scopus (145) Google Scholar, 120Shinohara T. Kato M. Takehashi M. Lee J. Chuma S. Nakatsuji N. et al.Rats produced by interspecies spermatogonial transplantation in mice and in vitro microinsemination.Proc Natl Acad Sci U S A. 2006; 103: 13624-13628Crossref PubMed Scopus (47) Google Scholar30Brinster R.L. Zimmermann J.W. Spermatogenesis following male germ-cell transplantation.Proc Natl Acad Sci U S A. 1994; 91: 11298-11302Crossref PubMed Scopus (736) Google Scholar, 31Brinster R.L. Avarbock M.R. Germline transmission of donor haplotype following spermatogonial transplantation.Proc Natl Acad Sci U S A. 1994; 91: 11303-11307Crossref PubMed Scopus (547) Google Scholar, 48Ogawa T. Dobrinski I. Avarbock M.R. Brinster R.L. Transplantation of male germ line stem cells restores fertility in infertile mice.Nat Med. 2000; 6: 29-34Crossref PubMed Scopus (194) Google Scholar, 49Shinohara T. Orwig K.E. Avarbock M.R. Brinster R.L. 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: 6186-6191Crossref PubMed Scopus (142) Google Scholar, 50Nagano M. Brinster C.J. Orwig K.E. Ryu B.Y. Avarbock M.R. Brinster R.L. Transgenic mice produced by retroviral transduction of male germ-line stem cells.Proc Natl Acad Sci U S A. 2001; 98: 13090-13095Crossref PubMed Scopus (185) Google Scholar, 51Brinster C.J. Ryu B.Y. Avarbock M.R. Karagenc L. Brinster R.L. Orwig K.E. Restoration of fertility by germ cell transplantation requires effective recipient preparation.Biol Reprod. 2003; 69: 412-420Crossref PubMed Scopus (72) Google Scholar, 57Richardson T.E. Chapman K.M. Tenenhaus Dann C. Hammer R.E. Hamra F.K. Sterile testis complementation with spermatogonial lines restores fertility to DAZL-deficient rats and maximizes donor germline transmission.PLoS ONE. 2009; 4: e6308Crossref PubMed Scopus (11) Google Scholar, 58Kanatsu-Shinohara M. Ogonuki N. Inoue K. Miki H. Ogura A. Toyokuni S. et al.Long-term proliferation in culture and germline transmission of mouse male germline stem cells.Biol Reprod. 2003; 69: 612-616Crossref PubMed Scopus (340) Google Scholar, 70Kubota H. Avarbock M.R. Brinster R.L. Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells.Proc Natl Acad Sci U S A. 2004; 101: 16489-16494Crossref PubMed Scopus (346) Google Scholar, 121Kubota H. Avarbock M.R. Brinster R.L. Culture conditions and single growth factors affect fate determination of mouse spermatogonial stem cells.Biol Reprod. 2004; 71: 722-731Crossref PubMed Scopus (130) Google Scholar30Brinster R.L. Zimmermann J.W. Spermatogenesis following male germ-cell transplantation.Proc Natl Acad Sci U S A. 1994; 91: 11298-11302Crossref PubMed Scopus (736) Google Scholar, 31Brinster R.L. Avarbock M.R. Germline transmission of donor haplotype following spermatogonial transplantation.Proc Natl Acad Sci U S A. 1994; 91: 11303-11307Crossref PubMed Scopus (547) Google Scholar, 48Ogawa T. Dobrinski I. Avarbock M.R. Brinster R.L. Transplantation of male germ line stem cells restores fertility in infertile mice.Nat Med. 2000; 6: 29-34Crossref PubMed Scopus (194) Google Scholar, 50Nagano M. Brinster C.J. Orwig K.E. Ryu B.Y. Avarbock M.R. Brinster R.L. Transgenic mice produced by retroviral transduction of male germ-line stem cells.Proc Natl Acad Sci U S A. 2001; 98: 13090-13095Crossref PubMed Scopus (185) Google Scholar, 51Brinster C.J. Ryu B.Y. Avarbock M.R. Karagenc L. Brinster R.L. Orwig K.E. Restoration of fertility by germ cell transplantation requires effective recipient preparation.Biol Reprod. 2003; 69: 412-420Crossref PubMed Scopus (72) Google Scholar, 57Richardson T.E. Chapman K.M. Tenenhaus Dann C. Hammer R.E. Hamra F.K. Sterile testis complementation with spermatogonial lines restores fertility to DAZL-deficient rats and maximizes donor germline transmission.PLoS ONE. 2009; 4: e6308Crossref PubMed Scopus (11) Google Scholar, 58Kanatsu-Shinohara M. Ogonuki N. Inoue K. Miki H. Ogura A. Toyokuni S. et al.Long-term proliferation in culture and germline transmission of mouse male germline stem cells.Biol Reprod. 2003; 69: 612-616Crossref PubMed Scopus (340) Google Scholar, 71Ryu B.Y. Kubota H. Avarbock M.R. Brinster R.L. Conservation of spermatogonial stem cell self-renewal signaling between mouse and rat.Proc Natl Acad Sci U S A. 2005; 102: 14302-14307Crossref PubMed Scopus (119) Google Scholar, 118Clouthier D.E. Avarbock M.R. Maika S.D. Hammer R.E. Brinster R.L. 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