Skip to main content

Stem Cells in the Mammalian Gonads

  • Chapter
  • First Online:
Book cover Stem Cells

Abstract

Besides spermatogonial stem cells (SSCs) and ovarian stem cells (OSCs), a novel population of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) has been reported in both adult mouse and human testes and ovaries. VSELs and SSCs/OSCs are developmentally linked to each other. VSELs are relatively quiescent, small-sized stem cells that undergo asymmetrical cell divisions (ACDs) whereby they self-renew and give rise to the slightly bigger SSCs/OSCs which in turn undergo symmetrical cell divisions (SCDs) and clonal expansion to form germ cell chains/nests before further differentiation into gametes. Comparison of VSELs and SSCs/OSCs for their potential to differentiate into sperm/oocytes is irrelevant since VSELs only undergo ACD to give rise to SSCs/OSCs that further differentiate into gametes. Being relatively quiescent, VSELs survive oncotherapy and can be manipulated to regenerate nonfunctional gonads of cancer survivors, and thus there is possibly no need to bank testicular/ovarian tissue prior to oncotherapy. Being developmentally linked to the primordial germ cells (PGCs) which are the natural precursors to the gametes, VSELs differentiate into haploid sperm/oocyte-like structures in vitro when cultured on appropriate feeder support, in the absence of a cocktail of growth factors. VSELs express receptors for pituitary and sex hormones (FSHR, ER) and thus get directly stimulated/affected by their circulating levels. Excessive self-renewal of VSELs in the gonads may initiate testicular and ovarian cancers. To conclude, VSELs can be targeted to regenerate the gonads of patients with gonadal insufficiency including cancer survivors and are excellent candidates to differentiate into gametes in vitro.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
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. Guo J, Cairns BR (2019) Isolation and enrichment of spermatogonial stem cells from human testis tissues. Curr Protoc Stem Cell Biol https://doi.org/10.1002/cpsc.77

    Article  PubMed  CAS  Google Scholar 

  2. Martin JJ, Woods DC, Tilly JL (2019) Implications and current limitations of oogenesis from female germline or oogonial stem cells in adult mammalian ovaries. Cells 8(2):93

    Article  CAS  PubMed Central  Google Scholar 

  3. Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327(5965):542–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. De Rosa L, De Luca M (2012) Cell biology: Dormant and restless skin stem cells. Nature 489(7415):215–217

    Article  PubMed  CAS  Google Scholar 

  5. Clevers H, Watt FM (2018) Defining adult stem cells by function, not by phenotype. Annu Rev Biochem 87:1015–1027

    Article  CAS  PubMed  Google Scholar 

  6. Bhartiya D, Shaikh A, Anand S, Patel H, Kapoor S et al (2016) Endogenous, very small embryonic-like stem cells: critical review, therapeutic potential and a look ahead. Hum Reprod Update 23(1):41–76

    Article  PubMed  CAS  Google Scholar 

  7. Bhartiya D, Patel H, Ganguly R, Shaikh A, Shukla Y et al (2018) Novel insights into adult and cancer stem cell biology. Stem Cells Dev 27(22):1527–1539

    Article  PubMed  Google Scholar 

  8. Bhartiya D (2016) Use of very small embryonic-like stem cells to avoid legal, ethical, and safety issues associated with oncofertility. JAMA Oncol 2(5):689

    Article  PubMed  Google Scholar 

  9. Bhartiya D, Anand S, Patel H, Parte S (2017) Making gametes from alternate sources of stem cells: past, present and future. Reprod Biol Endocrinol 15(1):89

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Shaikh A, Anand S, Kapoor S, Ganguly R, Bhartiya D (2017) Mouse bone marrow VSELs exhibit differentiation into three embryonic germ lineages and germ & hematopoietic cells in culture. Stem Cell Rev 13(2):202–216

    Article  CAS  Google Scholar 

  11. Ghasemzadeh-Hasankolaei M, Eslaminejad MB, Ghasemzadeh-Hasankolaei M (2018) Functional germ cells from non-testicular adult stem cells: a dream or reality? Curr Stem Cell Res Ther 13(1):60–79

    CAS  PubMed  Google Scholar 

  12. Ratajczak MZ, Ratajczak J, Kucia M (2019) Very small embryonic-like stem cells (VSELs). Circ Res 124(2):208–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bhartiya D (2017) Pluripotent stem cells in adult tissues: struggling to be acknowledged over two decades. Stem Cell Rev 13(6):713–724

    Article  CAS  Google Scholar 

  14. Patel H, Bhartiya D (2016) Testicular stem cells express follicle-stimulating hormone receptors and are directly modulated by FSH. Reprod Sci 23(11):1493–1508

    Article  CAS  PubMed  Google Scholar 

  15. Parte S, Bhartiya D, Telang J, Daithankar V, Salvi V et al (2011) Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putative stem cells in adult mammalian ovary. Stem Cells Dev 20(8):1451–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abbott A (2013) Doubt cast over tiny stem cells. Nature 499(7459):390

    Article  CAS  PubMed  Google Scholar 

  17. Danova-Alt R, Heider A, Egger D, Cross M, Alt R (2015) Very small embryonic-like stem cells purified from umbilical cord blood lack stem cell characteristics. Nat Med 21(10):1126–1127

    Article  CAS  Google Scholar 

  18. Miyanishi M, Mori Y, Seita J, Chen JY, Karten S et al (2013) Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? Stem Cell Reports 1(2):198–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Szade K, Bukowska-Strakova K, Nowak WN, Szade A, Kachamakova-Trojanowska N et al (2013) Murine bone marrow LinSca1+CD45 very small embryonic-like (VSEL) cells are heterogeneous population lacking Oct-4A expression. PLoS One 8(5):e63329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Alvarez-Gonzalez C, Duggleby R, Vagaska B, Querol S, Gomez SG et al (2012) Cord blood Lin (−) CD45(−) embryonic-like stem cells are a heterogeneous population that lack self-renewal capacity. PLoS One 7(4):e34899

    Article  CAS  Google Scholar 

  21. Albertini DF, Gleicher N (2015) A detour in the quest for oogonial stem cells: methods matter. Nat Med 21(10):1126–1127

    Article  CAS  PubMed  Google Scholar 

  22. Bhartiya D, Ali Mohammad S, Guha A, Singh P, Sharma D, Kaushik A (2019) Evolving definition of adult stem/progenitor cells. Stem Cell Rev Rep 15(3):456–458

    Article  PubMed  Google Scholar 

  23. Virant-Klun I (2018) Functional testing of primitive oocyte-like cells developed in ovarian surface epithelium cell culture from small VSEL-like stem cells: can they be fertilized one day? Stem Cell Rev Rep 14(5):715–721

    Article  CAS  PubMed  Google Scholar 

  24. Zuba-Surma EK, Kucia M, Wu W, Klich I, Lillard JW Jr et al (2008) Very small embryonic-like stem cells are present in adult murine organs: image stream-based morphological analysis and distribution studies. Cytometry A 73A:1116–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lim JJ, Sung SY, Kim HJ, Song SH, Hong JY et al (2010) Long-term proliferation and characterization of human spermatogonial stem cells obtained from obstructive and non-obstructive azoospermia under exogenous feeder-free culture conditions. Cell Prolif 43:405–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Izadyar F, Wong J, Maki C, Pacchiarotti J, Ramos T et al (2011) Identification and characterization of repopulating spermatogonial stem cells from the adult human testis. Hum Reprod 26:1296–1306

    Article  PubMed  Google Scholar 

  27. Kokkinaki M, Djourabtchi A, Golestaneh N (2011) Long-term culture of human SSEA-4positive spermatogonial stem cells (SSCs). J Stem Cell Res Ther 2(2):2488

    PubMed  PubMed Central  Google Scholar 

  28. Bhartiya D, Kasiviswanathan S, Unni SK, Pethe P, Dhabalia JV et al (2010) Newer insights into premeiotic development of germ cells in adult human testis using Oct-4 as a stem cell marker. J Histochem Cytochem 58(12):1093–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Anand S, Bhartiya D, Sriraman K, Patel H, Manjramkar DD (2014) Very small embryonic-like stem cells survive and restore spermatogenesis after busulphan treatment in mouse testis. J Stem Cell Res Ther 4:216

    Google Scholar 

  30. Anand S, Bhartiya D, Sriraman K, Mallick A (2016) Underlying mechanisms that restore spermatogenesis on transplanting healthy niche cells in busulphan treated mouse testis. Stem Cell Rev 12:682–697

    Article  CAS  Google Scholar 

  31. Kurkure P, Prasad M, Dhamankar V, Bakshi G (2015) Very small embryonic-like stem cells (VSELs) detected in azoospermic testicular biopsies of adult survivors of childhood cancer. Reprod Biol Endocrinol 13:122. https://doi.org/10.1186/s12958-015-0121-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huckins C (1971) The spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation. Anat Rec 169(3):533–557

    Article  CAS  PubMed  Google Scholar 

  33. Hara K, Nakagawa T, Enomoto H, Suzuki M, Yamamoto M et al (2014) Mouse spermatogenic stem cells continually interconvert between equipotent singly isolated and syncytial states. Cell Stem Cell 14(5):658–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Helsel AR, Yang QE, Oatley MJ, Lord T, Sablitzky F et al (2017) ID4 levels dictate the stem cell state in mouse spermatogonia. Development 144(4):624–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. deRooij DG (2017) The nature and dynamics of spermatogonial stem cells. Development 144(17):3022–3030

    Article  CAS  Google Scholar 

  36. Bhartiya D, Parte S, Patel H, Sriraman K, Zaveri K et al (2016b) Novel action of FSH on stem cells in adult mammalian ovary induces postnatal oogenesis and primordial follicle assembly. Stem Cells Int https://doi.org/10.1155/2016/5096596

    Article  CAS  Google Scholar 

  37. Bhartiya D (2017) Letter to the editor: rejuvenate eggs or regenerate ovary? Mol Cell Endocrinol 446:111–113

    Article  CAS  PubMed  Google Scholar 

  38. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL (2004) Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428:145–150

    Article  CAS  PubMed  Google Scholar 

  39. Virant-Klun I, Zech N, Rozman P, Vogler A, Cvjeticanin B et al (2008) Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation 76:843–856

    Article  CAS  PubMed  Google Scholar 

  40. Bhartiya D, Patel H (2018) Ovarian stem cells-resolving controversies. J Assist Reprod Genet 35(3):393–398

    Article  PubMed  Google Scholar 

  41. Patel H, Bhartiya D, Parte S, Gunjal P, Yedurkar S, Bhatt M (2013) Follicle stimulating hormone modulates ovarian stem cells through alternately spliced receptor variant FSH-R3. J Ovarian Res. https://doi.org/10.1186/1757-2215-6-52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lei L, Spradling AC (2013) Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proc Natl Acad Sci U S A 110(21):8585–8590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bhartiya D, Sriraman K, Parte S, Patel H (2013) Ovarian stem cells: absence of evidence is not evidence of absence. J Ovarian Res 6(1):65

    Article  PubMed  PubMed Central  Google Scholar 

  44. Parte S, Bhartiya D, Manjramkar DD, Chauhan A, Joshi A (2013) Stimulation of ovarian stem cells by follicle stimulating hormone and basic fibroblast growth factor during cortical tissue culture. J Ovarian Res 6(1):20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bhartiya D, Sriraman K, Gunjal P, Modak H (2012) Gonadotropin treatment augments postnatal oogenesis and primordial follicle assembly in adult mouse ovaries? J Ovarian Res 5(1):32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bhartiya D, Singh J (2015) FSH-FSHR3-stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer. Reproduction 149(1):R35–R48

    Article  PubMed  CAS  Google Scholar 

  47. Sullivan RR, Faris BR, Eborn D, Grieger DM, Cino-Ozuna AG, Rozell TG (2013) Follicular expression of follicle stimulating hormone receptor variants in the ewe. Reprod Biol Endocrinol 11:113. https://doi.org/10.1186/1477-7827-11-113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Silvestris E, Cafforio P, D'Oronzo S, Felici C, Silvestris F et al (2018) In vitro differentiation of human oocyte-like cells from oogonial stem cells: single-cell isolation and molecular characterization. Hum Reprod 33(3):464–473

    Article  CAS  PubMed  Google Scholar 

  49. Bhartiya D, Patel H, Parte S (2018) Improved understanding of very small embryonic-like stem cells in adult mammalian ovary. Hum Reprod 33(5):978–979

    Article  PubMed  Google Scholar 

  50. Patel H, Bhartiya D, Parte S (2018) Further characterization of adult sheep ovarian stem cells and their involvement in neo-oogenesis and follicle assembly. J Ovarian Res 11(1):3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Parte S, Bhartiya D, Patel H, Daithankar V, Chauhan A et al (2014) Dynamics associated with spontaneous differentiation of ovarian stem cells in vitro. J Ovarian Res 7:25

    Article  PubMed  PubMed Central  Google Scholar 

  52. Simoni M, Weinbauer GF, Gromoll J, Nieschlag E (1999) Role of FSH in male gonadal function. Ann Endocrinol (Paris) 60(2):102–106

    CAS  Google Scholar 

  53. Ding YM, Zhang XJ, Li JP, Chen SS, Zhang RT et al (2015) Treatment of idiopathic oligozoospermia with recombinant human follicle-stimulating hormone: a prospective, randomized, double-blind, placebo-controlled clinical study in Chinese population. Clin Endocrinol 83(6):866–871

    Article  CAS  Google Scholar 

  54. Attia AM, Abou-Setta AM, Al-Inany HG (2013) Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev 8:CD005071

    Google Scholar 

  55. Oduwole OO, Peltoketo H, Huhtaniemi IT (2018) Role of follicle-stimulating hormone in spermatogenesis. Front Endocrinol (Lausanne) 9:763

    Article  Google Scholar 

  56. Huhtaniemi I (2018) Mechanisms in endocrinology: hormonal regulation of spermatogenesis: mutant mice challenging old paradigms. Eur J Endocrinol 179(3):R143–R150

    Article  CAS  PubMed  Google Scholar 

  57. Tisdall DJ, Watanabe K, Hudson NL, Smith P, McNatty KP (1995) FSH receptor gene expression during ovarian follicle development in sheep. J Mol Endocrinol 15(3):273–281

    Article  CAS  PubMed  Google Scholar 

  58. Oktay K, Briggs D, Gosden RG (1997) Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab 82(11):3748–3751

    CAS  PubMed  Google Scholar 

  59. Méduri G, Charnaux N, Driancourt MA, Combettes L, Granet P et al (2002) Follicle-stimulating hormone receptors in oocytes? J Clin Endocrinol Metab 87(5):2266–2276

    Article  PubMed  Google Scholar 

  60. Zheng W, Magid MS, Kramer EE, Chen YT (1996) Follicle-stimulating hormone receptor is expressed in human ovarian surface epithelium and fallopian tube. Am J Pathol 148(1):47–53

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Roy SK, Albee L (2000) Requirement for follicle-stimulating hormone action in the formation of primordial follicles during perinatal ovarian development in the hamster. Endocrinology 141(12):4449–4456

    Article  CAS  PubMed  Google Scholar 

  62. Sriraman K, Bhartiya D, Anand S, Bhutda S (2015) Mouse ovarian very small embryonic-like stem cells resist chemotherapy and retain ability to initiate oocyte-specific differentiation. Reprod Sci 22(7):884–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gong SP, Lee ST, Lee EJ, Kim DY, Lee G et al (2010) Embryonic stem cell-like cells established by culture of adult ovarian cells in mice. Fertil Steril 93(8):2594–2601

    Article  PubMed  PubMed Central  Google Scholar 

  64. Rajpert-De Meyts E, Skakkebaek NE, Toppari J (2018) Testicular cancer pathogenesis, diagnosis and endocrine aspects. In: Endotext [Internet]. South Dartmouth (MA): MDText.com, https://www.ncbi.nlm.nih.gov/pubmed/25905224

  65. Spiller CM, Bowles J (2017) Germ cell neoplasia in situ: the precursor cell for invasive germ cell tumors of the testis. Int J Biochem Cell Biol 86:22–25

    Article  CAS  PubMed  Google Scholar 

  66. Kaushik A, Bhartiya D (2018) Pluripotent very small embryonic-like stem cells in adult testes – an alternate premise to explain testicular germ cell tumors. Stem Cell Rev 14(6):793–800

    Article  CAS  Google Scholar 

  67. Auersperg N (2013) Ovarian surface epithelium as a source of ovarian cancers: unwarranted speculation or evidence-based hypothesis? Gynecol Oncol 130(1):246–251

    Article  PubMed  Google Scholar 

  68. Peng S, Maihle NJ, Huang Y (2010) Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene 29(14):2153–2159

    Article  CAS  PubMed  Google Scholar 

  69. Samardzija C, Quinn M, Findlay JK, Ahmed N (2012) Attributes of Oct4 in stem cell biology: perspectives on cancer stem cells of the ovary. J Ovarian Res 5(1):37

    Article  PubMed  PubMed Central  Google Scholar 

  70. Virant-Klun I, Stimpfel M (2016) Novel population of small tumour-initiating stem cells in the ovaries of women with borderline ovarian cancer. Sci Rep 6:34730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nieto MA, Huang RY, Jackson RA, Thiery JP (2016) EMT: 2016. Cell 166(1):21–45

    Article  CAS  PubMed  Google Scholar 

  72. Ruan Z, Yang X, Cheng W (2018) OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells. Cancer Manag Res 11:389–399

    Article  PubMed  PubMed Central  Google Scholar 

  73. Moravek MB, Appiah LC, Anazodo A, Burns KC, Gomez-Lobo V et al (2019) Development of a pediatric fertility preservation program: a report from the pediatric initiative network of the oncofertility consortium. J Adolesc Health 64(5):563–573

    Article  Google Scholar 

  74. Pinelli S, Basile S (2018) Fertility preservation: current and future perspectives for oncologic patients at risk for iatrogenic premature ovarian insufficiency. Biomed Res Int 1:1–9. 6465903

    Article  Google Scholar 

  75. Burns KC, Hoefgen H, Strine A, Dasgupta R (2018) Fertility preservation options in pediatric and adolescent patients with cancer. Cancer 124(9):1867–1876

    Article  PubMed  Google Scholar 

  76. ACOG Committee Opinion No. 747: Gynecologic Issues in children and adolescent cancer patients and survivors (2018) Obstet Gynecol 132(2):e67–e77

    Article  Google Scholar 

  77. Anazodo A, Laws P, Logan S, Saunders C, Travaglia J et al (2018) How can we improve oncofertility care for patients? A systematic scoping review of current international practice and models of care. Hum Reprod Update. https://doi.org/10.1093/humupd/dmy038

    Article  PubMed Central  Google Scholar 

  78. Virant-Klun I, Stimpfel M, Cvjeticanin B, Vrtacnik-Bokal E, Skutella T (2013) Small SSEA-4-positive cells from human ovarian cell cultures: related to embryonic stem cells and germinal lineage? J Ovarian Res https://doi.org/10.1186/1757-2215-6-24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fazeli Z, Abedindo A, Omrani MD, Ghaderian SMH (2018) Mesenchymal stem cells (MSCs) therapy for recovery of fertility: a systematic review. Stem Cell Rev 14(1):1–12

    Article  CAS  Google Scholar 

  80. Edessy M, Hosni HN, Shady Y, Waf Y, Bakr S, Kamel M (2016) Autologous stem cells therapy, the first baby of idiopathic premature ovarian failure. Acta Med Int 3:19–23

    Article  Google Scholar 

Download references

Acknowledgments

The authors acknowledge ICMR and DBT, Government of India, New Delhi, for financial support over the last decade which has resulted in this advance in the field.

Conflict of Interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Deepa Bhartiya .

Editor information

Editors and Affiliations

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

Bhartiya, D., Anand, S., Kaushik, A., Sharma, D. (2019). Stem Cells in the Mammalian Gonads. In: Ratajczak, M. (eds) Stem Cells. Advances in Experimental Medicine and Biology, vol 1201. Springer, Cham. https://doi.org/10.1007/978-3-030-31206-0_6

Download citation

Publish with us

Policies and ethics