Abstract
The germline is the only cell type that is inherited by the next generation in many multicellular animals. For the purposes of successful reproduction, animals need to produce enough gametes for a sufficient duration of time. It is also crucial to adjust the production of gametes according to the reproduction strategy that each species uniquely develops. In many animals, these features of germ cells are provided by the function of stem cells. Stem cells by definition continually produce differentiating cells (e.g., spermatozoa) while maintaining their own population, viz. the stem cell pool. Mammalian spermatogenic stem cells (also termed spermatogonial stem cells or SSCs) represent the most studied stem cell types, and have been providing important insights into not only the biology of reproduction but also for stem cell research in general. This chapter describes the current position of mammalian (mostly mouse) spermatogenic stem cell research, as well as its future directions. First, in contrast to a general thought that stem cell division always gives rise to one self-renewing and one differentiating daughter cell, the spermatogenic stem cell of each mouse follows a variable fate. Their self-renewal and differentiation is balanced at the level of population; such stem cell dynamics are designated as “population asymmetry.” Second, the current knowledge regarding the identity of “actual” stem cells (cells that support homeostatic spermatogenesis) and their in vivo dynamics will be discussed. Third, our focus will move on to the flexible change of the stem cell behavior depending on tissue contexts; some spermatogonia act as “potential” stem cells which differentiate under homeostasis but contribute to post-insult regeneration or post-transplantation colony formation. Finally, our current knowledge and upcoming questions about the “facultative” or “open” stem cell niche for mouse spermatogenesis will be discussed.
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Aloisio GM, Nakada Y, Saatcioglu HD, Pena CG, Baker MD, Tarnawa ED, Mukherjee J, Manjunath H, Bugde A, Sengupta AL, Amatruda JF, Cuevas I, Hamra FK, Castrillon DH (2014) PAX7 expression defines germline stem cells in the adult testis. J Clin Invest 124(9):3929–3944. https://doi.org/10.1172/JCI75943
Barker N (2014) Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol 15(1):19–33. https://doi.org/10.1038/nrm3721
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(2):190–196. https://doi.org/10.1038/ncb1826. doi:ncb1826 [pii]
Bloom W, Fawcett DW (1975) Textbook of histology, 10th edn. Saunders, Philadelphia
Brawley C, Matunis E (2004) Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304(5675):1331–1334
Brinster RL (2007) Male germline stem cells: from mice to men. Science 316(5823):404–405. https://doi.org/10.1126/science.1137741. doi:316/5823/404 [pii]
Brinster RL, Avarbock MR (1994) Germline transmission of donor haplotype following spermatogonial transplantation. Proc Natl Acad Sci U S A 91(24):11303–11307
Brinster RL, Zimmermann JW (1994) Spermatogenesis following male germ-cell transplantation. Proc Natl Acad Sci U S A 91(24):11298–11302
Brown S, Greco V (2014) Stem cells in the wild: understanding the world of stem cells through intravital imaging. Cell Stem Cell 15(6):683–686. https://doi.org/10.1016/j.stem.2014.11.006
Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner SM, Reth M, Hofer T, Rodewald HR (2015) Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 518(7540):542–546. https://doi.org/10.1038/nature14242
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(12):1351–1362. https://doi.org/10.1101/gad.240465.114
Chen LY, Brown PR, Willis WB, Eddy EM (2014) Peritubular myoid cells participate in male mouse spermatogonial stem cell maintenance. Endocrinology 155(12):4964–4974. https://doi.org/10.1210/en.2014-1406
Chen LY, Willis WD, Eddy EM (2016) Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development. Proc Natl Acad Sci U S A 113(7):1829–1834. https://doi.org/10.1073/pnas.1517994113
Chiarini-Garcia H, Hornick JR, Griswold MD, Russell LD (2001) Distribution of type A spermatogonia in the mouse is not random. Biol Reprod 65(4):1179–1185
Chiarini-Garcia H, Raymer AM, Russell LD (2003) Non-random distribution of spermatogonia in rats: evidence of niches in the seminiferous tubules. Reproduction 126(5):669–680
de Rooij DG, Russell LD (2000) All you wanted to know about spermatogonia but were afraid to ask. J Androl 21(6):776–798
DeFalco T, Potter SJ, Williams AV, Waller B, Kan MJ, Capel B (2015) Macrophages contribute to the spermatogonial niche in the adult testis. Cell Rep 12(7):1107–1119. https://doi.org/10.1016/j.celrep.2015.07.015
Fuller MT, Spradling AC (2007) Male and female drosophila germline stem cells: two versions of immortality. Science 316(5823):402–404
Garcia TX, Farmaha JK, Kow S, Hofmann MC (2014) RBPJ in mouse sertoli cells is required for proper regulation of the testis stem cell niche. Development 141(23):4468–4478. https://doi.org/10.1242/dev.113969
Gely-Pernot A, Raverdeau M, Celebi C, Dennefeld C, Feret B, Klopfenstein M, Yoshida S, Ghyselinck NB, Mark M (2012) Spermatogonia differentiation requires retinoic acid receptor gamma. Endocrinology 153(1):438–449. https://doi.org/10.1210/en.2011-1102
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(5):658–672. https://doi.org/10.1016/j.stem.2014.01.019
Hasegawa K, Saga Y (2014) FGF8-FGFR1 signaling acts as a niche factor for maintaining undifferentiated spermatogonia in the mouse. Biol Reprod 91(6):145. https://doi.org/10.1095/biolreprod.114.121012
Hayashi S, McMahon AP (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244(2):305–318
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(2):54. https://doi.org/10.1095/biolreprod.114.125757
Hess R, Franca L (2005) Structure of the sertoli cells. In: Skinner M, Griswold M (eds) Sertoli cell biology. Elsevier Academic Press, San Diego, pp 19–40
Hofmann MC (2008) Gdnf signaling pathways within the mammalian spermatogonial stem cell niche. Mol Cell Endocrinol 288(1-2):95–103. https://doi.org/10.1016/j.mce.2008.04.012. doi:S0303-7207(08)00153-6 [pii]
Hofmann MC, Braydich-Stolle L, Dym M (2005) Isolation of male germ-line stem cells; influence of GDNF. Dev Biol 279(1):114–124
Hogarth CA, Griswold MD (2010) The key role of vitamin A in spermatogenesis. J Clin Invest 120(4):956–962. https://doi.org/10.1172/JCI41303. doi:41303 [pii]
Hogarth CA, Arnold S, Kent T, Mitchell D, Isoherranen N, Griswold MD (2015) Processive pulses of retinoic acid propel asynchronous and continuous murine sperm production. Biol Reprod 92(2):37. https://doi.org/10.1095/biolreprod.114.126326
Huckins C (1971) The spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation. Anat Rec 169(3):533–557. https://doi.org/10.1002/ar.1091690306
Ikami K, Tokue M, Sugimoto R, Noda C, Kobayashi S, Hara K, Yoshida S (2015) Hierarchical differentiation competence in response to retinoic acid ensures stem cell maintenance during mouse spermatogenesis. Development 142(9):1582–1592. https://doi.org/10.1242/dev.118695
Kai T, Spradling A (2004) Differentiating germ cells can revert into functional stem cells in drosophila melanogaster ovaries. Nature 428(6982):564–569
Kanatsu-Shinohara M, Ogonuki N, Inoue K, Miki H, Ogura A, Toyokuni S, Shinohara T (2003) Long-term proliferation in culture and germline transmission of mouse male germline stem cells. Biol Reprod 69(2):612–616
Kitadate Y, Kobayashi S (2010) Notch and Egfr signaling act antagonistically to regulate germ-line stem cell niche formation in Drosophila male embryonic gonads. Proc Natl Acad Sci U S A 107(32):14241–14246. https://doi.org/10.1073/pnas.1003462107
Kitadate Y, Shigenobu S, Arita K, Kobayashi S (2007) Boss/Sev signaling from germline to soma restricts germline-stem-cell-niche formation in the anterior region of Drosophila male gonads. Dev Cell 13(1):151–159. https://doi.org/10.1016/j.devcel.2007.05.001. doi:S1534-5807(07)00196-7 [pii]
Klein AM, Simons BD (2011) Universal patterns of stem cell fate in cycling adult tissues. Development (Cambridge, England) 138(15):3103–3111. https://doi.org/10.1242/dev.060103. doi:138/15/3103 [pii]
Klein AM, Nakagawa T, Ichikawa R, Yoshida S, Simons BD (2010) Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell 7(2):214–224. https://doi.org/10.1016/j.stem.2010.05.017. doi:S1934-5909(10)00227-4 [pii]
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. https://doi.org/10.1038/srep06175
Krieger T, Simons BD (2015) Dynamic stem cell heterogeneity. Development (Cambridge, England) 142(8):1396–1406. https://doi.org/10.1242/dev.101063
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(47):16489–16494
Leblond CP, Clermont Y (1952) Definition of the stages of the cycle of the seminiferous epithelium in the rat. Ann N Y Acad Sci 55(4):548–573
Lombardi J (1998) Gametes and their production. In: Comparative vertebrate reproduction. Springer Science+Business Media New York, New York, pp 109–153
Losick VP, Morris LX, Fox DT, Spradling A (2011) Drosophila stem cell niches: a decade of discovery suggests a unified view of stem cell regulation. Dev Cell 21(1):159–171. https://doi.org/10.1016/j.devcel.2011.06.018. doi:S1534-5807(11)00252-8 [pii]
Meistrich ML, van Beek ME (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
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, Saarma M, Sariola H (2000) Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287(5457):1489–1493
Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132(4):598–611. https://doi.org/10.1016/j.cell.2008.01.038. doi:S0092-8674(08)00139-6 [pii]
Nakagawa T, Nabeshima Y, Yoshida S (2007) Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev Cell 12(2):195–206
Nakagawa T, Sharma M, Nabeshima Y, Braun RE, Yoshida S (2010) Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science 328(5974):62–67. https://doi.org/10.1126/science.1182868. doi:science.1182868 [pii]
Naughton CK, Jain S, Strickland AM, Gupta A, Milbrandt J (2006) Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Biol Reprod 74(2):314–321
Oakberg EF (1956) Duration of spermatogenesis in the mouse and timing of stages of the cycle of the seminiferous epithelium. Am J Anat 99(3):507–516. https://doi.org/10.1002/aja.1000990307
Oakberg EF (1971) Spermatogonial stem-cell renewal in the mouse. Anat Rec 169(3):515–531
Oatley JM, Brinster RL (2008) Regulation of spermatogonial stem cell self-renewal in mammals. Annu Rev Cell Dev Biol 24:263–286. https://doi.org/10.1146/annurev.cellbio.24.110707.175355
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(2):347–356. https://doi.org/10.1095/biolreprod.111.091330
Oatley MJ, Racicot KE, Oatley JM (2011b) Sertoli cells dictate spermatogonial stem cell niches in the mouse testis. Biol Reprod 84(4):639–645. https://doi.org/10.1095/biolreprod.110.087320
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(1):209–225
Potten CS, Loeffler M (1990) Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110(4):1001–1020
Russell L, Ettlin R, Sinha Hikim A, Clegg E (1990) Histological and histopathological evaluation of the testis. Cache River Press, Clearwater
Sada A, Suzuki A, Suzuki H, Saga Y (2009) The RNA-binding protein NANOS2 is required to maintain murine spermatogonial stem cells. Science 325(5946):1394–1398. https://doi.org/10.1126/science.1172645. doi:325/5946/1394 [pii]
Sato T, Aiyama Y, Ishii-Inagaki M, Hara K, Tsunekawa N, Harikae K, Uemura-Kamata M, Shinomura M, Zhu XB, Maeda S, Kuwahara-Otani S, Kudo A, Kawakami H, Kanai-Azuma M, Fujiwara M, Miyamae Y, Yoshida S, Seki M, Kurohmaru M, Kanai Y (2011) Cyclical and patch-like GDNF distribution along the basal surface of sertoli cells in mouse and hamster testes. PLoS One 6(12):e28367. https://doi.org/10.1371/journal.pone.0028367
Shirakawa T, Yaman-Deveci R, Tomizawa S, Kamizato Y, Nakajima K, Sone H, Sato Y, Sharif J, Yamashita A, Takada-Horisawa Y, Yoshida S, Ura K, Muto M, Koseki H, Suda T, Ohbo K (2013) An epigenetic switch is crucial for spermatogonia to exit the undifferentiated state toward a Kit-positive identity. Development 140(17):3565–3576. https://doi.org/10.1242/dev.094045
Skinner MK, Griswold MD ed. (2005) Sertoli cell biology. Elsevier-Academic Press, San Diego
Smith BE, Braun RE (2012) Germ cell migration across sertoli cell tight junctions. Science 338(6108):798–802. https://doi.org/10.1126/science.1219969
Song HW, Wilkinson MF (2014) Transcriptional control of spermatogonial maintenance and differentiation. Semin Cell Dev Biol 30:14–26. https://doi.org/10.1016/j.semcdb.2014.02.005
Spradling A, Fuller MT, Braun RE, Yoshida S (2011) Germline stem cells. Cold Spring Harb Perspect Biol 3:a002642. https://doi.org/10.1101/cshperspect.a002642. doi:cshperspect.a002642 [pii]
Stine RR, Matunis EL (2013) Stem cell competition: finding balance in the niche. Trends Cell Biol 23(8):357–364. https://doi.org/10.1016/j.tcb.2013.03.001
Sugimoto R, Nabeshima Y, Yoshida S (2012) Retinoic acid metabolism links the periodical differentiation of germ cells with the cycle of sertoli cells in mouse seminiferous epithelium. Mech Dev 128(11-12):610–624. https://doi.org/10.1016/j.mod.2011.12.003
Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, Klein A, Hofmann O, Camargo FD (2014) Clonal dynamics of native haematopoiesis. Nature 514(7522):322–327. https://doi.org/10.1038/nature13824
Sun F, Xu Q, Zhao D, Degui Chen C (2015) Id4 marks spermatogonial stem cells in the mouse testis. Sci Rep 5:17594. https://doi.org/10.1038/srep17594
Suzuki H, Sada A, Yoshida S, Saga Y (2009) The heterogeneity of spermatogonia is revealed by their topology and expression of marker proteins including the germ cell-specific proteins Nanos2 and Nanos3. Dev Biol 336(2):222–231. https://doi.org/10.1016/j.ydbio.2009.10.002. doi:S0012-1606(09)01245-7 [pii]
van Es JH, Sato T, van de Wetering M, Lyubimova A, Nee AN, Gregorieff A, Sasaki N, Zeinstra L, van den Born M, Korving J, Martens AC, Barker N, van Oudenaarden A, Clevers H (2012) Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14(10):1099–1104. https://doi.org/10.1038/ncb2581
Vernet N, Dennefeld C, Rochette-Egly C, Oulad-Abdelghani M, Chambon P, Ghyselinck NB, Mark M (2006) Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis. Endocrinology 147(1):96–110. https://doi.org/10.1210/en.2005-0953. doi:en.2005-0953 [pii]
Yoshida S (2010) Stem cells in mammalian spermatogenesis. Develop Growth Differ 52(3):311–317. https://doi.org/10.1111/j.1440-169X.2010.01174.x. doi:DGD1174 [pii]
Yoshida S (2012) Elucidating the identity and behavior of spermatogenic stem cells in the mouse testis. Reproduction 144(3):293–302. https://doi.org/10.1530/REP-11-0320
Yoshida S (2016) From cyst to tubule: innovations in vertebrate spermatogenesis. Wiley interdisciplinary reviews. Dev Biol 5(1):119–131. https://doi.org/10.1002/wdev.204
Yoshida S, Takakura A, Ohbo K, Abe K, Wakabayashi J, Yamamoto M, Suda T, Nabeshima Y (2004) Neurogenin3 delineates the earliest stages of spermatogenesis in the mouse testis. Dev Biol 269(2):447–458
Yoshida S, Nabeshima Y, Nakagawa T (2007) Stem cell heterogeneity: actual and potential stem cell compartments in mouse spermatogenesis. Ann N Y Acad Sci 1120:47–58
Yoshida S, Sukeno M, Nabeshima Y (2007b) A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317(5845):1722–1726
Acknowledgements
The author thanks Kazuya Kobayashi for providing this invaluable opportunity to contribute to this chapter. I also express my deep appreciation to my laboratory members, collaborators, and all the colleagues, for continual and passionate interplay. Funding by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, by the Japan Society for the Promotion of Science (JSPS), and by Precursory Research for Embryonic Science and Technology (PRESTO) from Japan Science and Technology Agency (JST), as well as institutional support from the National Institute for Basic Biology (NIBB) are also appreciated.
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Yoshida, S. (2018). Regulatory Mechanism of Spermatogenic Stem Cells in Mice: Their Dynamic and Context-Dependent Behavior. In: Kobayashi, K., Kitano, T., Iwao, Y., Kondo, M. (eds) Reproductive and Developmental Strategies. Diversity and Commonality in Animals. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56609-0_4
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