Skip to main content
SpringerLink
Log in

Heterogeneity of Spermatogonial Stem Cells

  • Chapter
  • First Online:
Stem Cells Heterogeneity in Different Organs

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1169))

Abstract

Germ cells transfer genetic materials from one generation to the next, which ensures the continuation of the species. Spermatogenesis, the process of male germ cell production, is one of the most productive systems in adult tissues. This high productivity depends on the well-coordinated differentiation cascade in spermatogonia, occurring via their synchronized cell division and proliferation. Spermatogonial stem cells (SSCs) are responsible for maintaining the spermatogonial population via self-renewal and the continuous generation of committed progenitor cells that differentiate into spermatozoa. Like other stem cells in the body, SSCs are defined by their self-renewal and differentiation abilities. A functional transplantation assay, in which these biological properties of SSCs can be quantitatively evaluated, was developed using mice, and the cell surface characteristics and intracellular marker gene expression of murine SSCs were successfully determined. Another approach to elucidate SSC identity is a cell lineage-tracing experiment using transgenic mice, which can track the SSC behavior in the testes. Recent studies using both these experimental approaches have revealed that the SSC identity changed depending upon the developmental, homeostatic, and regenerative circumstances. In addition, single-cell transcriptomic analyses have further indicated the instability of marker gene expression in SSCs. More studies are needed to unify the results of the determination of SSC identity based on the functional properties and accumulating transcriptomic data of SSCs, to elucidate the functional interaction between SSC behavior and gene products and illustrate the conserved features of SSCs amidst their heterogeneity. Furthermore, the deterministic roles of distinct SSC niches under different physiological conditions in the SSC heterogeneity and its causal regulators must also be clarified in future studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Amann RP (1981) A critical review of methods for evaluation of spermatogenesis from seminal characteristics. J Androl 2:37–58

    Article  Google Scholar 

  2. Russell LD, Ettlin RA, Sinha Hikim AP, Clegg ED (1990) Histological and histopathological evaluation of the testis. Cache River Press, Clearwater

    Google Scholar 

  3. Fijak M, Meinhardt A (2006) The testis in immune privilege. Immunol Rev 213:66–81

    Article  CAS  PubMed  Google Scholar 

  4. Meistrich ML, van Beek MEAB (1993) Spermatogonial stem cells. In: Desjardins C, Ewing LL (eds) Cell and molecular biology of the testis. Oxford University Press, New York, pp 266–295

    Google Scholar 

  5. Kubota H, Brinster RL (2006) Technology insight: in vitro culture of spermatogonial stem cells and their potential therapeutic uses. Nat Clin Pract Endocrinol Metab 2:99–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kubota H, Brinster RL (2017) Transplantation and culture of spermatogonial stem cells. In: Oatley J, Griswold M (eds) The biology of mammalian spermatogonia. Springer New York, New York, pp 271–300

    Chapter  Google Scholar 

  7. Fayomi AP, Orwig KE (2018) Spermatogonial stem cells and spermatogenesis in mice, monkeys and men. Stem Cell Res 29:207–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kubota H, Brinster RL (2018) Spermatogonial stem cells. Biol Reprod 99:52–74

    Article  PubMed  PubMed Central  Google Scholar 

  9. de Rooij DG, Russell LD (2000) All you wanted to know about spermatogonia but were afraid to ask. J Androl 21:776–798

    PubMed  Google Scholar 

  10. Greenbaum MP, Iwamori T, Buchold GM, Matzuk MM (2011) Germ cell intercellular bridges. Cold Spring Harb Perspect Biol 3:a005850

    Article  PubMed  PubMed Central  Google Scholar 

  11. Russell LD, Chiarini-Garcia H, Korsmeyer SJ, Knudson CM (2002) Bax-dependent spermatogonia apoptosis is required for testicular development and spermatogenesis1. Biol Reprod 66:950–958

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Oakberg EF (1971) Spermatogonial stem-cell renewal in the mouse. Anat Rec 169:515–531

    Article  CAS  PubMed  Google Scholar 

  14. Nakagawa T, Sharma M, Nabeshima Y, Braun RE, Yoshida S (2010) Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science 328:62–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hara K, Nakagawa T, Enomoto H, Suzuki M, Yamamoto M, Simons BD, Yoshida S (2014) Mouse spermatogenic stem cells continually interconvert between equipotent singly isolated and syncytial states. Cell Stem Cell 14:658–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lagasse E, Shizuru JA, Uchida N, Tsukamoto A, Weissman IL (2001) Toward regenerative medicine. Immunity 14:425–436

    Article  CAS  PubMed  Google Scholar 

  17. Brinster RL, Zimmermann JW (1994) Spermatogenesis following male germ-cell transplantation. Proc Natl Acad Sci U S A 91:11298–11302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Brinster RL, Avarbock MR (1994) Germline transmission of donor haplotype following spermatogonial transplantation. Proc Natl Acad Sci U S A 91:11303–11307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang X, Ebata KT, Nagano MC (2003) Genetic analysis of the clonal origin of regenerating mouse spermatogenesis following transplantation. Biol Reprod 69:1872–1878

    Article  CAS  PubMed  Google Scholar 

  20. Kanatsu-Shinohara M, Inoue K, Miki H, Ogonuki N, Takehashi M, Morimoto T, Ogura A, Shinohara T (2006) Clonal origin of germ cell colonies after spermatogonial transplantation in mice. Biol Reprod 75:68–74

    Article  CAS  PubMed  Google Scholar 

  21. Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222

    Article  CAS  PubMed  Google Scholar 

  22. Shinohara T, Avarbock MR, Brinster RL (1999) beta1- and alpha6-integrin are surface markers on mouse spermatogonial stem cells. Proc Natl Acad Sci U S A 96:5504–5509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tokuda M, Kadokawa Y, Kurahashi H, Marunouchi T (2007) CDH1 is a specific marker for undifferentiated spermatogonia in mouse testes. Biol Reprod 76:130–141

    Article  CAS  PubMed  Google Scholar 

  24. Shinohara T, Orwig KE, Avarbock MR, Brinster RL (2000) Spermatogonial stem cell enrichment by multiparameter selection of mouse testis cells. Proc Natl Acad Sci U S A 97:8346–8351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kubota H, Avarbock MR, Brinster RL (2003) Spermatogonial stem cells share some, but not all, phenotypic and functional characteristics with other stem cells. Proc Natl Acad Sci U S A 100:6487–6492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kanatsu-Shinohara M, Toyokuni S, Shinohara T (2004) CD9 is a surface marker on mouse and rat male germline stem cells. Biol Reprod 70:70–75

    Article  CAS  PubMed  Google Scholar 

  27. Kanatsu-Shinohara M, Morimoto H, Shinohara T (2012) Enrichment of mouse spermatogonial stem cells by melanoma cell adhesion molecule expression. Biol Reprod 87:139

    Article  PubMed  Google Scholar 

  28. Buageaw A, Sukhwani M, Ben-Yehudah A, Ehmcke J, Rawe VY, Pholpramool C, Orwig KE, Schlatt S (2005) GDNF family receptor alpha1 phenotype of spermatogonial stem cells in immature mouse testes1. Biol Reprod 73:1011–1016

    Article  CAS  PubMed  Google Scholar 

  29. Yoshinaga K, Nishikawa S, Ogawa M, Hayashi S, Kunisada T, Fujimoto T (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

    CAS  PubMed  Google Scholar 

  30. Kubota H, Avarbock MR, Brinster RL (2004) Culture conditions and single growth factors affect fate determination of mouse spermatogonial stem cells. Biol Reprod 71:722–731

    Article  CAS  PubMed  Google Scholar 

  31. Ohbo K, Yoshida S, Ohmura M, Ohneda O, Ogawa T, Tsuchiya H, Kuwana T, Kehler J, Abe K, Scholer HR, Suda T (2003) Identification and characterization of stem cells in prepubertal spermatogenesis in mice. Dev Biol 258:209–225

    Article  CAS  PubMed  Google Scholar 

  32. Arnold K, Sarkar A, Yram Mary A, Polo Jose M, Bronson R, Sengupta S, Seandel M, Geijsen N, Hochedlinger K (2011) sox2+ adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9:317–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pech MF, Garbuzov A, Hasegawa K, Sukhwani M, Zhang RJ, Benayoun BA, Brockman SA, Lin S, Brunet A, Orwig KE, Artandi SE (2015) High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells. Genes Dev 29:2420–2434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chan F, Oatley MJ, Kaucher AV, Yang QE, Bieberich CJ, Shashikant CS, Oatley JM (2014) Functional and molecular features of the Id4+ germline stem cell population in mouse testes. Genes Dev 28:1351–1362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Oatley MJ, Kaucher AV, Racicot KE, Oatley JM (2011) Inhibitor of DNA binding 4 is expressed selectively by single spermatogonia in the male germline and regulates the self-renewal of spermatogonial stem cells in mice. Biol Reprod 85:347–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Costoya JA, Hobbs RM, Barna M, Cattoretti G, Manova K, Sukhwani M, Orwig KE, Wolgemuth DJ, Pandolfi PP (2004) Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36:653–659

    Article  CAS  PubMed  Google Scholar 

  37. Buaas FW, Kirsh AL, Sharma M, McLean DJ, Morris JL, Griswold MD, de Rooij DG, Braun RE (2004) Plzf is required in adult male germ cells for stem cell self-renewal. Nat Genet 36:647–652

    Article  CAS  PubMed  Google Scholar 

  38. La HM, Mäkelä J-A, Chan A-L, Rossello FJ, Nefzger CM, Legrand JMD, De Seram M, Polo JM, Hobbs RM (2018) Identification of dynamic undifferentiated cell states within the male germline. Nat Commun 9:2819

    Article  PubMed  PubMed Central  Google Scholar 

  39. Best SA, Hutt KJ, Fu NY, Vaillant F, Liew SH, Hartley L, Scott CL, Lindeman GJ, Visvader JE (2014) Dual roles for Id4 in the regulation of estrogen signaling in the mammary gland and ovary. Development 141:3159–3164

    Article  CAS  PubMed  Google Scholar 

  40. Helsel AR, Yang QE, Oatley MJ, Lord T, Sablitzky F, Oatley JM (2017) ID4 levels dictate the stem cell state in mouse spermatogonia. Development 144:624–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kanatsu-Shinohara M, Inoue K, Lee J, Yoshimoto M, Ogonuki N, Miki H, Baba S, Kato T, Kazuki Y, Toyokuni S, Toyoshima M, Niwa O et al (2004) Generation of pluripotent stem cells from neonatal mouse testis. Cell 119:1001–1012

    Article  CAS  PubMed  Google Scholar 

  42. Guan K, Nayernia K, Maier LS, Wagner S, Dressel R, Lee JH, Nolte J, Wolf F, Li M, Engel W, Hasenfuss G (2006) Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440:1199–1203

    Article  CAS  PubMed  Google Scholar 

  43. Seandel M, James D, Shmelkov SV, Falciatori I, Kim J, Chavala S, Scherr DS, Zhang F, Torres R, Gale NW, Yancopoulos GD, Murphy A et al (2007) Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature 449:346–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ko K, Tapia N, Wu G, Kim JB, Bravo MJ, Sasse P, Glaser T, Ruau D, Han DW, Greber B, Hausdorfer K, Sebastiano V et al (2009) Induction of pluripotency in adult unipotent germline stem cells. Cell Stem Cell 5:87–96

    Article  CAS  PubMed  Google Scholar 

  45. Szabó PE, Hübner K, Schöler H, Mann JR (2002) Allele-specific expression of imprinted genes in mouse migratory primordial germ cells. Mech Dev 115:157–160

    Article  PubMed  Google Scholar 

  46. Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Ohbo K, Gross M, Hubner K, Scholer HR (1996) Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122:881–894

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Hao L-Y, Armanios M, Strong MA, Karim B, Feldser DM, Huso D, Greider CW (2005) Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123:1121–1131

    Article  CAS  PubMed  Google Scholar 

  49. Garbuzov A, Pech MF, Hasegawa K, Sukhwani M, Zhang RJ, Orwig KE, Artandi SE (2018) Purification of GFRα1+ and GFRα1– spermatogonial stem cells reveals a niche-dependent mechanism for fate determination. Stem Cell Reports 10:553–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Nagano MC (2003) Homing efficiency and proliferation kinetics of male germ line stem cells following transplantation in mice. Biol Reprod 69:701–707

    Article  CAS  PubMed  Google Scholar 

  52. Kretzschmar K, Watt FM (2012) Lineage tracing. Cell 148:33–45

    Article  CAS  PubMed  Google Scholar 

  53. Feil R, Wagner J, Metzger D, Chambon P (1997) Regulation of cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun 237:752–757

    Article  CAS  PubMed  Google Scholar 

  54. Sada A, Suzuki A, Suzuki H, Saga Y (2009) The RNA-binding protein NANOS2 is required to maintain murine spermatogonial stem cells. Science 325:1394–1398

    Article  CAS  PubMed  Google Scholar 

  55. Sun F, Xu Q, Zhao D, Degui CC (2015) Id4 marks spermatogonial stem cells in the mouse testis. Sci Rep 5:17594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Komai Y, Tanaka T, Tokuyama Y, Yanai H, Ohe S, Omachi T, Atsumi N, Yoshida N, Kumano K, Hisha H, Matsuda T, Ueno H (2014) Bmi1 expression in long-term germ stem cells. Sci Rep 4:6175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Aloisio GM, Nakada Y, Saatcioglu HD, Peña CG, Baker MD, Tarnawa ED, Mukherjee J, Manjunath H, Bugde A, Sengupta AL, Amatruda JF, Cuevas I et al (2014) PAX7 expression defines germline stem cells in the adult testis. J Clin Invest 124:3929–3944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Takase HM, Nusse R (2016) Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis. Proc Natl Acad Sci 113:E1489–E1497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. de Rooij DG, Lok D, Weenk D (1985) Feedback regulation of the proliferation of the undifferentiated spermatogonia in the Chinese hamster by the differentiating spermatogonia. Cell Tissue Kinet 18:71–81

    PubMed  Google Scholar 

  60. Carrieri C, Comazzetto S, Grover A, Morgan M, Buness A, Nerlov C, O’Carroll D (2017) A transit-amplifying population underpins the efficient regenerative capacity of the testis. J Exp Med 214:1631–1641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Barroca V, Lassalle B, Coureuil M, Louis JP, Le Page F, Testart J, Allemand I, Riou L, Fouchet P (2009) Mouse differentiating spermatogonia can generate germinal stem cells in vivo. Nat Cell Biol 11:190–196

    Article  CAS  PubMed  Google Scholar 

  62. Meng X, Lindahl M, Hyvonen ME, Parvinen M, de Rooij DG, Hess MW, Raatikainen-Ahokas A, Sainio K, Rauvala H, Lakso M, Pichel JG, Westphal H et al (2000) Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287:1489–1493

    Article  CAS  PubMed  Google Scholar 

  63. Kubota H, Avarbock MR, Brinster RL (2004) Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells. Proc Natl Acad Sci U S A 101:16489–16494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Oatley JM, Avarbock MR, Telaranta AI, Fearon DT, Brinster RL (2006) Identifying genes important for spermatogonial stem cell self-renewal and survival. Proc Natl Acad Sci U S A 103:9524–9529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu X, Goodyear SM, Tobias JW, Avarbock MR, Brinster RL (2011) Spermatogonial stem cell self-renewal requires ETV5-mediated downstream activation of Brachyury in mice. Biol Reprod 85:1114–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sada A, Hasegawa K, Pin PH, Saga Y (2012) NANOS2 acts downstream of glial cell line-derived neurotrophic factor signaling to suppress differentiation of spermatogonial stem cells. Stem Cells 30:280–291

    Article  CAS  PubMed  Google Scholar 

  67. Hermann BP, Mutoji KN, Velte EK, Ko D, Oatley JM, Geyer CB, McCarrey JR (2015) Transcriptional and translational heterogeneity among neonatal mouse spermatogonia. Biol Reprod 92:54

    Article  PubMed  PubMed Central  Google Scholar 

  68. Wang M, Liu X, Chang G, Chen Y, An G, Yan L, Gao S, Xu Y, Cui Y, Dong J, Chen Y, Fan X et al (2018) Single-cell RNA sequencing analysis reveals sequential cell fate transition during human spermatogenesis. Cell Stem Cell 23:599–614.e594

    Article  CAS  PubMed  Google Scholar 

  69. Hermann BP, Cheng K, Singh A, Roa-De La Cruz L, Mutoji KN, Chen IC, Gildersleeve H, Lehle JD, Mayo M, Westernströer B, Law NC, Oatley MJ et al (2018) The mammalian spermatogenesis single-cell transcriptome, from spermatogonial stem cells to spermatids. Cell Rep 25:1650–1667.e1658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Green CD, Ma Q, Manske GL, Shami AN, Zheng X, Marini S, Moritz L, Sultan C, Gurczynski SJ, Moore BB, Tallquist MD, Li JZ et al (2018) A comprehensive roadmap of murine spermatogenesis defined by single-cell RNA-seq. Dev Cell 46:651–667.e610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks Dr. K. Kakiuchi for having continual discussions that have helped improve this manuscript. This work was partially supported by the Grant-in-Aid for Scientific Research (No. 23380168) of the Japan Society for the Promotion of Science.

Author information

Authors and Affiliations

  1. Laboratory of Cell and Molecular Biology, Department of Animal Science, School of Veterinary Medicine, Kitasato University, Towada, Aomori, 034-8628, Japan

    Hiroshi Kubota

Authors
  1. Hiroshi Kubota
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Kubota .

Editor information

Editors and Affiliations

  1. Department of Pathology, Federal University of Minas Gerais, Department of Radiology, Columbia University Medical Center, New York, NY, USA, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kubota, H. (2019). Heterogeneity of Spermatogonial Stem Cells. In: Birbrair, A. (eds) Stem Cells Heterogeneity in Different Organs. Advances in Experimental Medicine and Biology, vol 1169. Springer, Cham. https://doi.org/10.1007/978-3-030-24108-7_12

Download citation

Publish with us

Policies and ethics

Search

Navigation