Skip to main content

Advertisement

SpringerLink
Log in

Sertoli cell-only syndrome: advances, challenges, and perspectives in genetics and mechanisms

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Male infertility can be caused by quantitative and/or qualitative abnormalities in spermatogenesis, which affects men’s physical and mental health. Sertoli cell-only syndrome (SCOS) is the most severe histological phenotype of male infertility characterized by the depletion of germ cells with only Sertoli cells remaining in the seminiferous tubules. Most SCOS cases cannot be explained by the already known genetic causes including karyotype abnormalities and microdeletions of the Y chromosome. With the development of sequencing technology, studies on screening new genetic causes for SCOS are growing in recent years. Directly sequencing of target genes in sporadic cases and whole-exome sequencing applied in familial cases have identified several genes associated with SCOS. Analyses of the testicular transcriptome, proteome, and epigenetics in SCOS patients provide explanations regarding the molecular mechanisms of SCOS. In this review, we discuss the possible relationship between defective germline development and SCOS based on mouse models with SCO phenotype. We also summarize the advances and challenges in the exploration of genetic causes and mechanisms of SCOS. Knowing the genetic factors of SCOS offers a better understanding of SCO and human spermatogenesis, and it also has practical significance for improving diagnosis, making appropriate medical decisions, and genetic counseling. For therapeutic implications, SCOS research, along with the achievements in stem cell technologies and gene therapy, build the foundation to develop novel therapies for SCOS patients to produce functional spermatozoa, giving them hope to father children.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

Not applicable.

References

  1. Abofoul-Azab M, Lunenfeld E, Levitas E et al (2019) Identification of premeiotic, meiotic, and postmeiotic cells in testicular biopsies without sperm from Sertoli cell-only syndrome patients. Int J Mol Sci 20:E470. https://doi.org/10.3390/ijms20030470

    Article  CAS  Google Scholar 

  2. Deruyver Y, Vanderschueren D, Van der Aa F (2014) Outcome of microdissection TESE compared with conventional TESE in non-obstructive azoospermia: a systematic review. Andrology 2:20–24. https://doi.org/10.1111/j.2047-2927.2013.00148.x

    Article  CAS  PubMed  Google Scholar 

  3. Berookhim BM, Palermo GD, Zaninovic N et al (2014) Microdissection testicular sperm extraction in men with Sertoli cell-only testicular histology. Fertil Steril 102:1282–1286. https://doi.org/10.1016/j.fertnstert.2014.08.007

    Article  PubMed  PubMed Central  Google Scholar 

  4. Özman O, Tosun S, Bayazıt N et al (2021) Efficacy of the second micro-testicular sperm extraction after failed first micro-testicular sperm extraction in men with nonobstructive azoospermia. Fertil Steril 115:915–921. https://doi.org/10.1016/j.fertnstert.2020.10.005

    Article  PubMed  Google Scholar 

  5. Hadziselimovic F, Verkauskas G, Vincel B et al (2020) Abnormal histology in testis from prepubertal boys with monorchidism. Basic Clin Androl 30:11. https://doi.org/10.1186/s12610-020-00109-1

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gurbuz F, Ceylaner S, Erdogan S et al (2016) Sertoli cell only syndrome with ambiguous genitalia. J Pediatr Endocrinol Metab 29:849–852. https://doi.org/10.1515/jpem-2015-0458

    Article  PubMed  Google Scholar 

  7. Anniballo R, Brehm R, Steger K (2011) Recognising the Sertoli-cell-only (SCO) syndrome: a case study. Andrologia 43:78–83. https://doi.org/10.1111/j.1439-0272.2009.01030.x

    Article  CAS  PubMed  Google Scholar 

  8. Borg CL, Wolski KM, Gibbs GM, O’Bryan MK (2010) Phenotyping male infertility in the mouse: how to get the most out of a “non-performer.” Hum Reprod Update 16:205–224. https://doi.org/10.1093/humupd/dmp032

    Article  PubMed  Google Scholar 

  9. Jamsai D, O’Bryan MK (2011) Mouse models in male fertility research. Asian J Androl 13:139–151. https://doi.org/10.1038/aja.2010.101

    Article  PubMed  Google Scholar 

  10. Tang WWC, Kobayashi T, Irie N et al (2016) Specification and epigenetic programming of the human germ line. Nat Rev Genet 17:585–600. https://doi.org/10.1038/nrg.2016.88

    Article  CAS  PubMed  Google Scholar 

  11. Fang F, Li Z, Zhao Q et al (2018) Human induced pluripotent stem cells and male infertility: an overview of current progress and perspectives. Hum Reprod Oxf Engl 33:188–195. https://doi.org/10.1093/humrep/dex369

    Article  CAS  Google Scholar 

  12. Mäkelä J-A, Koskenniemi JJ, Virtanen HE, Toppari J (2019) Testis development. Endocr Rev 40:857–905. https://doi.org/10.1210/er.2018-00140

    Article  PubMed  Google Scholar 

  13. Saitou M, Yamaji M (2012) Primordial germ cells in mice. Cold Spring Harb Perspect Biol 4:a008375. https://doi.org/10.1101/cshperspect.a008375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yamaji M, Seki Y, Kurimoto K et al (2008) Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet 40:1016–1022. https://doi.org/10.1038/ng.186

    Article  CAS  PubMed  Google Scholar 

  15. Weber S, Eckert D, Nettersheim D et al (2010) Critical function of AP-2 gamma/TCFAP2C in mouse embryonic germ cell maintenance. Biol Reprod 82:214–223. https://doi.org/10.1095/biolreprod.109.078717

    Article  CAS  PubMed  Google Scholar 

  16. Tsuda M (2003) Conserved role of nanos proteins in germ cell development. Science 301:1239–1241. https://doi.org/10.1126/science.1085222

    Article  CAS  PubMed  Google Scholar 

  17. Kehler J, Tolkunova E, Koschorz B et al (2004) Oct4 is required for primordial germ cell survival. EMBO Rep 5:1078–1083. https://doi.org/10.1038/sj.embor.7400279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kato Y, Alavattam KG, Sin H-S et al (2015) FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis. Hum Mol Genet 24:5234–5249. https://doi.org/10.1093/hmg/ddv244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Culty M (2009) Gonocytes, the forgotten cells of the germ cell lineage. Birth Defects Res Part C Embryo Today Rev 87:1–26. https://doi.org/10.1002/bdrc.20142

    Article  CAS  Google Scholar 

  20. Dura M, Teissandier A, Armand M et al (2022) DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis. Nat Genet 54:469–480. https://doi.org/10.1038/s41588-022-01040-z

    Article  CAS  PubMed  Google Scholar 

  21. Lin H, Cheng K, Kubota H et al (2022) Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells. Genes Dev. https://doi.org/10.1101/gad.349550.122

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sharma S, Wistuba J, Pock T et al (2019) Spermatogonial stem cells: updates from specification to clinical relevance. Hum Reprod Update 25:275–297. https://doi.org/10.1093/humupd/dmz006

    Article  CAS  PubMed  Google Scholar 

  23. Fok KL, Bose R, Sheng K et al (2017) Huwe1 regulates the establishment and maintenance of spermatogonia by suppressing DNA damage response. Endocrinology 158:4000–4016. https://doi.org/10.1210/en.2017-00396

    Article  CAS  PubMed  Google Scholar 

  24. 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 mice1. Biol Reprod 85:347–356. https://doi.org/10.1095/biolreprod.111.091330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Diao F, Jiang C, Wang X-X et al (2016) Alteration of protein prenylation promotes spermatogonial differentiation and exhausts spermatogonial stem cells in newborn mice. Sci Rep 6:28917. https://doi.org/10.1038/srep28917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Unhavaithaya Y, Hao Y, Beyret E et al (2009) MILI, a PIWI-interacting RNA-binding protein, is required for germ line stem Cell self-renewal and appears to positively regulate translation. J Biol Chem 284:6507–6519. https://doi.org/10.1074/jbc.M809104200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kuramochi-Miyagawa S (2004) Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131:839–849. https://doi.org/10.1242/dev.00973

    Article  CAS  PubMed  Google Scholar 

  28. Qin J, Huang T, Wang J et al (2022) RAD51 is essential for spermatogenesis and male fertility in mice. Cell Death Discov 8:118. https://doi.org/10.1038/s41420-022-00921-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Paduch DA, Hilz S, Grimson A et al (2019) Aberrant gene expression by Sertoli cells in infertile men with Sertoli cell-only syndrome. PLoS ONE 14:e0216586. https://doi.org/10.1371/journal.pone.0216586

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chen C, Ouyang W, Grigura V et al (2005) ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 436:1030–1034. https://doi.org/10.1038/nature03894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cui W, He X, Zhai X et al (2020) CARF promotes spermatogonial self-renewal and proliferation through Wnt signaling pathway. Cell Discov 6:85. https://doi.org/10.1038/s41421-020-00212-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang XN, Li ZS, Ren Y et al (2013) The wilms tumor gene, Wt1, is critical for mouse spermatogenesis via regulation of Sertoli cell polarity and is associated with non-obstructive azoospermia in humans. PLoS Genet 9:e1003645. https://doi.org/10.1371/journal.pgen.1003645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen L-Y, Willis WD, Eddy EM (2016) Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development. Proc Natl Acad Sci 113:1829–1834. https://doi.org/10.1073/pnas.1517994113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cinà DP, Flannigan R (2020) Failing to mature: somatic cell dysfunction in the spermatogenic niche among patients with Sertoli cell-only and Klinefelter syndromes. Fertil Steril 113:1155–1156. https://doi.org/10.1016/j.fertnstert.2020.03.006

    Article  PubMed  Google Scholar 

  35. Van Saen D, Vloeberghs V, Gies I et al (2020) Characterization of the stem cell niche components within the seminiferous tubules in testicular biopsies of Klinefelter patients. Fertil Steril 113:1183-1195.e3. https://doi.org/10.1016/j.fertnstert.2020.01.018

    Article  CAS  PubMed  Google Scholar 

  36. Lovasco LA, Gustafson EA, Seymour KA et al (2015) TAF4b is required for mouse spermatogonial stem cell development: TAF4b regulation of spermatogonial stem cells. STEM CELLS 33:1267–1276. https://doi.org/10.1002/stem.1914

    Article  CAS  PubMed  Google Scholar 

  37. Xia X, Zhou X, Quan Y et al (2019) Germline deletion of Cdyl causes teratozoospermia and progressive infertility in male mice. Cell Death Dis 10:229. https://doi.org/10.1038/s41419-019-1455-y

    Article  PubMed  PubMed Central  Google Scholar 

  38. Terada T, Hatakeyama S (1991) Morphological evidence for two types of idiopathic “Sertoli-cell-only” syndrome. Int J Androl 14:117–126. https://doi.org/10.1111/j.1365-2605.1991.tb01073.x

    Article  CAS  PubMed  Google Scholar 

  39. Weller O, Yogev L, Yavetz H et al (2005) Differentiating between primary and secondary Sertoli-cell-only syndrome by histologic and hormonal parameters. Fertil Steril 83:1856–1858. https://doi.org/10.1016/j.fertnstert.2004.11.074

    Article  PubMed  Google Scholar 

  40. McLachlan RI, Rajpert-De Meyts E, Hoei-Hansen CE et al (2007) Histological evaluation of the human testis—approaches to optimizing the clinical value of the assessment: mini review. Hum Reprod 22:2–16. https://doi.org/10.1093/humrep/del279

    Article  CAS  PubMed  Google Scholar 

  41. Anniballo R (2000) Criteria predicting the absence of spermatozoa in the Sertoli cell-only syndrome can be used to improve success rates of sperm retrieval. Hum Reprod 15:2269–2277. https://doi.org/10.1093/humrep/15.11.2269

    Article  CAS  PubMed  Google Scholar 

  42. Adamczewska D, Slowikowska-Hilczer J, Marchlewska K, Walczak-Jedrzejowska R (2020) Features of gonadal dysgenesis and Leydig cell impairment in testes with Sertoli cell-only syndrome. Folia Histochem Cytobiol 58:73–82. https://doi.org/10.5603/FHC.a2020.0008

    Article  CAS  PubMed  Google Scholar 

  43. Stouffs K, Gheldof A, Tournaye H et al (2016) Sertoli cell-only syndrome: behind the genetic scenes. BioMed Res Int. https://doi.org/10.1155/2016/6191307

    Article  PubMed  PubMed Central  Google Scholar 

  44. Krausz C, Riera-Escamilla A (2018) Genetics of male infertility. Nat Rev Urol 15:369–384. https://doi.org/10.1038/s41585-018-0003-3

    Article  CAS  PubMed  Google Scholar 

  45. Vogt PH, Bender U, Deibel B et al (2021) Human AZFb deletions cause distinct testicular pathologies depending on their extensions in Yq11 and the Y haplogroup: new cases and review of literature. Cell Biosci 11:60. https://doi.org/10.1186/s13578-021-00551-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Krausz C, Casamonti E (2017) Spermatogenic failure and the Y chromosome. Hum Genet 136:637–655. https://doi.org/10.1007/s00439-017-1793-8

    Article  CAS  PubMed  Google Scholar 

  47. Kamp C (2001) High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome. Mol Hum Reprod 7:987–994. https://doi.org/10.1093/molehr/7.10.987

    Article  CAS  PubMed  Google Scholar 

  48. Akınsal EC, Baydilli N, Dündar M, Ekmekçioğlu O (2018) The frequencies of Y chromosome microdeletions in infertile males. Turk J Urol 44:389–392. https://doi.org/10.5152/tud.2018.73669

    Article  PubMed  PubMed Central  Google Scholar 

  49. Oates RD, Silber S, Brown LG, Page DC (2002) Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod Oxf Engl 17:2813–2824. https://doi.org/10.1093/humrep/17.11.2813

    Article  CAS  Google Scholar 

  50. Lan K-C, Hung-Jen null, Wang T-J T-J et al (2022) Y-chromosome genes associated with Sertoli cell-only syndrome identified by array comparative genome hybridization. Biomed J. https://doi.org/10.1016/j.bj.2022.03.009

    Article  PubMed  Google Scholar 

  51. Witherspoon L, Dergham A, Flannigan R (2021) Y-microdeletions: a review of the genetic basis for this common cause of male infertility. Transl Androl Urol 10:1383–1390. https://doi.org/10.21037/tau-19-599

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yu Q, Gu X, Shang X et al (2016) Discrimination and characterization of Sertoli cell-only syndrome in non-obstructive azoospermia using cell-free seminal DDX4. Reprod Biomed Online 33:189–196. https://doi.org/10.1016/j.rbmo.2016.05.001

    Article  CAS  PubMed  Google Scholar 

  53. Bieniek J, Drabovich A, Lo K (2016) Seminal biomarkers for the evaluation of male infertility. Asian J Androl 18:426. https://doi.org/10.4103/1008-682X.175781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Drabovich AP, Dimitromanolakis A, Saraon P et al (2013) Differential diagnosis of azoospermia with proteomic biomarkers ECM1 and TEX101 quantified in seminal plasma. Sci Transl Med 5:212ra160. https://doi.org/10.1126/scitranslmed.3006260

    Article  CAS  PubMed  Google Scholar 

  55. Korbakis D, Schiza C, Brinc D et al (2017) Preclinical evaluation of a TEX101 protein ELISA test for the differential diagnosis of male infertility. BMC Med 15:60. https://doi.org/10.1186/s12916-017-0817-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Stahl PJ, Mielnik A, Schlegel PN, Paduch DA (2011) Heat shock factor Y chromosome (HSFY) mRNA level predicts the presence of retrievable testicular sperm in men with nonobstructive azoospermia. Fertil Steril 96:303–308. https://doi.org/10.1016/j.fertnstert.2011.05.055

    Article  CAS  PubMed  Google Scholar 

  57. Lei B, Lv D, Zhou X et al (2015) Biochemical hormone parameters in seminal and blood plasma samples correlate with histopathologic properties of testicular biopsy in azoospermic patients. Urology 85:1074–1078. https://doi.org/10.1016/j.urology.2015.02.011

    Article  PubMed  Google Scholar 

  58. Enatsu N, Miyake H, Chiba K, Fujisawa M (2016) Predictive factors of successful sperm retrieval on microdissection testicular sperm extraction in Japanese men. Reprod Med Biol 15:29–33. https://doi.org/10.1007/s12522-015-0212-x

    Article  PubMed  Google Scholar 

  59. Li H, Chen L-P, Yang J et al (2018) Predictive value of FSH, testicular volume, and histopathological findings for the sperm retrieval rate of microdissection TESE in nonobstructive azoospermia: a meta-analysis. Asian J Androl 20:30–36. https://doi.org/10.4103/aja.aja_5_17

    Article  CAS  PubMed  Google Scholar 

  60. Xavier MJ, Salas-Huetos A, Oud MS et al (2020) Disease gene discovery in male infertility: past, present and future. Hum Genet. https://doi.org/10.1007/s00439-020-02202-x

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhang X (2014) Exome sequencing greatly expedites the progressive research of Mendelian diseases. Front Med 8:42–57. https://doi.org/10.1007/s11684-014-0303-9

    Article  CAS  PubMed  Google Scholar 

  62. Ku C-S, Naidoo N, Pawitan Y (2011) Revisiting Mendelian disorders through exome sequencing. Hum Genet 129:351–370. https://doi.org/10.1007/s00439-011-0964-2

    Article  PubMed  Google Scholar 

  63. Oud MS, Volozonoka L, Smits RM et al (2019) A systematic review and standardized clinical validity assessment of male infertility genes. Hum Reprod Oxf Engl 34:932–941. https://doi.org/10.1093/humrep/dez022

    Article  CAS  Google Scholar 

  64. Hasani N, Mohseni Meybodi A, Rafaee A et al (2019) Spermatogenesis disorder is associated with mutations in the ligand-binding domain of an androgen receptor. Andrologia 51:e13376. https://doi.org/10.1111/and.13376

    Article  PubMed  Google Scholar 

  65. Mirfakhraie R, Kalantar S-M, Mirzajani F et al (2011) A novel mutation in the transactivation-regulating domain of the androgen receptor in a patient with azoospermia. J Androl 32:367–370. https://doi.org/10.2164/jandrol.110.010645

    Article  CAS  PubMed  Google Scholar 

  66. Miyamoto T, Iijima M, Shin T et al (2018) CUL4B mutations are uncommon in Japanese patients with Sertoli-cell-only syndrome and azoospermia. J Obstet Gynaecol 38:293–294. https://doi.org/10.1080/01443615.2017.1336755

    Article  CAS  PubMed  Google Scholar 

  67. Jamsai D, Grealy A, Stahl PJ et al (2013) Genetic variants in the human glucocorticoid-induced leucine zipper (GILZ) gene in fertile and infertile men. Andrology 1:451–455. https://doi.org/10.1111/j.2047-2927.2013.00076.x

    Article  CAS  PubMed  Google Scholar 

  68. Liu W, Gao X, Yan L et al (2018) Analysis of CDK2 mutations in Chinese men with non-obstructive azoospermia who underwent testis biopsy. Reprod Biomed Online 36:356–360. https://doi.org/10.1016/j.rbmo.2017.12.017

    Article  CAS  PubMed  Google Scholar 

  69. Tewes A-C, Ledig S, Tüttelmann F et al (2014) DMRT1 mutations are rarely associated with male infertility. Fertil Steril 102:816-820.e3. https://doi.org/10.1016/j.fertnstert.2014.05.022

    Article  CAS  PubMed  Google Scholar 

  70. O’Bryan MK, Grealy A, Stahl PJ et al (2012) Genetic variants in the ETV5 gene in fertile and infertile men with nonobstructive azoospermia associated with Sertoli cell–only syndrome. Fertil Steril 98:827-835.e3. https://doi.org/10.1016/j.fertnstert.2012.06.013

    Article  CAS  PubMed  Google Scholar 

  71. Chung C-L, Lu C-W, Cheng Y-S et al (2013) Association of aberrant expression of sex-determining gene fibroblast growth factor 9 with Sertoli cell-only syndrome. Fertil Steril 100(1547–1554):e1-4. https://doi.org/10.1016/j.fertnstert.2013.08.004

    Article  CAS  Google Scholar 

  72. Miyamoto T, Iijima M, Shin T et al (2018) An association study of the single-nucleotide polymorphism c190C>T (Arg64Cys) in the human testis-specific histone variant, H3t, of Japanese patients with Sertoli cell-only syndrome. Asian J Androl 20:527–528. https://doi.org/10.4103/aja.aja_66_17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Miyamoto T, Koh E, Tsujimura A et al (2014) Single-nucleotide polymorphisms in the LRWD1 gene may be a genetic risk factor for Japanese patients with Sertoli cell-only syndrome. Andrologia 46:273–276. https://doi.org/10.1111/and.12077

    Article  CAS  PubMed  Google Scholar 

  74. Kusz-Zamelczyk K, Sajek M, Spik A et al (2013) Mutations of NANOS1, a human homologue of the Drosophila morphogen, are associated with a lack of germ cells in testes or severe oligo-astheno-teratozoospermia. J Med Genet 50:187–193. https://doi.org/10.1136/jmedgenet-2012-101230

    Article  CAS  PubMed  Google Scholar 

  75. Ferlin A, Rocca MS, Vinanzi C et al (2015) Mutational screening of NR5A1 gene encoding steroidogenic factor 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations. Fertil Steril 104:163-169.e1. https://doi.org/10.1016/j.fertnstert.2015.04.017

    Article  CAS  PubMed  Google Scholar 

  76. Miyamoto T, Shin T, Iijima M et al (2019) The poly(A) polymerase beta gene may not be associated with azoospermia caused by Sertoli-cell-only syndrome in Japanese patients by comparing patients and normal controls. J Obstet Gynaecol 39:434–436. https://doi.org/10.1080/01443615.2018.1504205

    Article  CAS  PubMed  Google Scholar 

  77. Miyamoto T, Bando Y, Koh E et al (2016) A PLK4 mutation causing azoospermia in a man with Sertoli cell-only syndrome. Andrology 4:75–81. https://doi.org/10.1111/andr.12113

    Article  CAS  PubMed  Google Scholar 

  78. Minase G, Miyamoto T, Miyagawa Y et al (2017) Single-nucleotide polymorphisms in the human RAD21L gene may be a genetic risk factor for Japanese patients with azoospermia caused by meiotic arrest and Sertoli cell-only syndrome. Hum Fertil (Camb) 20:217–220. https://doi.org/10.1080/14647273.2017.1292004

    Article  CAS  PubMed  Google Scholar 

  79. Miyakawa H, Miyamoto T, Koh E et al (2012) Single-nucleotide polymorphisms in the SEPTIN12 gene may be a genetic risk factor for Japanese patients with Sertoli cell-only syndrome. J Androl 33:483–487. https://doi.org/10.2164/jandrol.110.012146

    Article  CAS  PubMed  Google Scholar 

  80. Miyamoto T, Koh E, Tsujimura A et al (2015) SIN3A mutations are rare in men with azoospermia. Andrologia 47:1083–1085. https://doi.org/10.1111/and.12379

    Article  CAS  PubMed  Google Scholar 

  81. Kasak L, Punab M, Nagirnaja L et al (2018) Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia. Am J Human Genet 103:200–212. https://doi.org/10.1016/j.ajhg.2018.07.005

    Article  CAS  Google Scholar 

  82. Fakhro KA, Elbardisi H, Arafa M et al (2018) Point-of-care whole-exome sequencing of idiopathic male infertility. Genet Med 20:1365–1373. https://doi.org/10.1038/gim.2018.10

    Article  CAS  PubMed  Google Scholar 

  83. Krausz C, Riera-Escamilla A, Chianese C et al (2019) From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia. Genet Med 21:189–194. https://doi.org/10.1038/s41436-018-0037-1

    Article  CAS  PubMed  Google Scholar 

  84. Araujo TF, Friedrich C, Grangeiro CHP et al (2020) Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes. Andrologia 8:434–441. https://doi.org/10.1111/andr.12704

    Article  CAS  Google Scholar 

  85. Arafat M, Zeadna A, Levitas E et al (2020) Novel mutation in USP26 associated with azoospermia in a Sertoli cell-only syndrome patient. Mol Genet Genomic Med. https://doi.org/10.1002/mgg3.1258

    Article  PubMed  PubMed Central  Google Scholar 

  86. Murtaza G, Yang L, Khan I et al (2021) Identification and functional investigation of novel heterozygous HELQ mutations in patients with Sertoli cell-only syndrome. Genet Test Mol Biomark 25:654–659. https://doi.org/10.1089/gtmb.2021.0104

    Article  CAS  Google Scholar 

  87. Koc G, Ozdemir AA, Girgin G et al (2019) Male infertility in Sertoli cell-only syndrome: an investigation of autosomal gene defects. Int J Urol 26:292–298. https://doi.org/10.1111/iju.13863

    Article  CAS  PubMed  Google Scholar 

  88. Sharma A, Jain M, Halder A, Kaushal S (2021) Identification of genomic imbalances (CNVs as well as LOH) in sertoli cell only syndrome cases through cytoscan microarray. Gene 801:145851. https://doi.org/10.1016/j.gene.2021.145851

    Article  CAS  PubMed  Google Scholar 

  89. Kasak L, Punab M, Nagirnaja L et al (2018) Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia. Am J Hum Genet 103:200–212. https://doi.org/10.1016/j.ajhg.2018.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li Z, Huang Y, Li H et al (2015) Excess of rare variants in genes that are key epigenetic regulators of spermatogenesis in the patients with non-obstructive azoospermia. Sci Rep 5:8785. https://doi.org/10.1038/srep08785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Luddi A, Crifasi L, Quagliarello A et al (2016) Single nucleotide polymorphisms of USP26 in azoospermic men. Syst Biol Reprod Med 62:372–378. https://doi.org/10.1080/19396368.2016.1238116

    Article  CAS  PubMed  Google Scholar 

  92. Ma Q, Li Y, Guo H et al (2016) A novel missense mutation in USP26 gene is associated with nonobstructive azoospermia. Reprod Sci Thousand Oaks Calif 23:1434–1441. https://doi.org/10.1177/1933719116641758

    Article  CAS  Google Scholar 

  93. Paduch DA, Mielnik A, Schlegel PN (2005) Novel mutations in testis-specific ubiquitin protease 26 gene may cause male infertility and hypogonadism. Reprod Biomed Online 10:747–754. https://doi.org/10.1016/s1472-6483(10)61119-4

    Article  PubMed  Google Scholar 

  94. Gershoni M, Hauser R, Yogev L et al (2017) A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes. Genet Med 19:998–1006. https://doi.org/10.1038/gim.2016.225

    Article  CAS  PubMed  Google Scholar 

  95. Yatsenko AN, Roy A, Chen R et al (2006) Non-invasive genetic diagnosis of male infertility using spermatozoal RNA: KLHL10 mutations in oligozoospermic patients impair homodimerization. Hum Mol Genet 15:3411–3419. https://doi.org/10.1093/hmg/ddl417

    Article  CAS  PubMed  Google Scholar 

  96. Colombo R, Pontoglio A, Bini M (2017) Two novel TEX15 mutations in a family with nonobstructive azoospermia. Gynecol Obstet Invest 82:283–286. https://doi.org/10.1159/000468934

    Article  CAS  PubMed  Google Scholar 

  97. Okutman O, Muller J, Baert Y et al (2015) Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family. Hum Mol Genet 24:5581–5588. https://doi.org/10.1093/hmg/ddv290

    Article  CAS  PubMed  Google Scholar 

  98. Wang X, Jin H-R, Cui Y-Q et al (2018) Case study of a patient with cryptozoospermia associated with a recessive TEX15 nonsense mutation. Asian J Androl 20:101–102. https://doi.org/10.4103/1008-682X.194998

    Article  PubMed  Google Scholar 

  99. Wong JCY, Alon N, Mckerlie C et al (2003) Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia. Hum Mol Genet 12:2063–2076. https://doi.org/10.1093/hmg/ddg219

    Article  CAS  PubMed  Google Scholar 

  100. Tang D, Li K, Geng H et al (2022) Identification of deleterious variants in patients with male infertility due to idiopathic non-obstructive azoospermia. Reprod Biol Endocrinol RBE 20:63. https://doi.org/10.1186/s12958-022-00936-z

    Article  CAS  Google Scholar 

  101. St B, Hj van de V, Ma R, et al (2009) Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M. Hum Mol Genet. https://pubmed.ncbi.nlm.nih.gov/19561169/. Accessed 2 Dec 2020

  102. Yin H, Ma H, Hussain S et al (2019) A homozygous FANCM frameshift pathogenic variant causes male infertility. Genet Med Off J Am Coll Med Genet 21:266. https://doi.org/10.1038/s41436-018-0127-0

    Article  Google Scholar 

  103. Zhang Y, Li P, Liu N et al (2021) Novel bi-allelic variants of FANCM cause Sertoli cell-only syndrome and non-obstructive azoospermia. Front Genet 12:799886. https://doi.org/10.3389/fgene.2021.799886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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. https://doi.org/10.1126/science.1172645

    Article  CAS  PubMed  Google Scholar 

  105. Greenbaum MP, Iwamori T, Buchold GM, Matzuk MM (2011) Germ cell intercellular bridges. Cold Spring Harb Perspect Biol 3:a005850. https://doi.org/10.1101/cshperspect.a005850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vockel M, Riera-Escamilla A, Tüttelmann F, Krausz C (2019) The X chromosome and male infertility. Hum Genet. https://doi.org/10.1007/s00439-019-02101-w

    Article  PubMed  PubMed Central  Google Scholar 

  107. Felipe-Medina N, Gómez-H L, Condezo YB et al (2019) Ubiquitin-specific protease 26 (USP26) is not essential for mouse gametogenesis and fertility. Chromosoma 128:237–247. https://doi.org/10.1007/s00412-019-00697-6

    Article  CAS  PubMed  Google Scholar 

  108. Araujo TF, Friedrich C, Grangeiro CHP et al (2020) Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes. Andrology 8:434–441. https://doi.org/10.1111/andr.12704

    Article  CAS  PubMed  Google Scholar 

  109. Agbor VA, Tao S, Lei N, Heckert LL (2013) A Wt1-Dmrt1 transgene restores DMRT1 to Sertoli Cells of Dmrt1−/− testes: a novel model of DMRT1-deficient germ cells. Biol Reprod. https://doi.org/10.1095/biolreprod.112.103135

    Article  PubMed  Google Scholar 

  110. Yang F, Eckardt S, Leu NA et al (2008) Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis. J Cell Biol 180:673. https://doi.org/10.1083/jcb.200709057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yan W, Ma L, Burns KH, Matzuk MM (2004) Haploinsufficiency of kelch-like protein homolog 10 causes infertility in male mice. Proc Natl Acad Sci U S A 101:7793. https://doi.org/10.1073/pnas.0308025101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Anand R, Buechelmaier E, Belan O et al (2022) HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51. Nature 601:268–273. https://doi.org/10.1038/s41586-021-04261-0

    Article  CAS  PubMed  Google Scholar 

  113. Zhao J, Lu P, Wan C et al (2021) Cell-fate transition and determination analysis of mouse male germ cells throughout development. Nat Commun 12:6839. https://doi.org/10.1038/s41467-021-27172-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhang H, Zhou D, Zhu F et al (2019) Disordered APC/C-mediated cell cycle progression and IGF1/PI3K/AKT signalling are the potential basis of Sertoli cell-only syndrome. Andrologia 51:e13288. https://doi.org/10.1111/and.13288

    Article  CAS  PubMed  Google Scholar 

  115. Chen T, Wang Y, Tian L et al (2022) Aberrant gene expression profiling in men with Sertoli cell-only syndrome. Front Immunol 13:821010. https://doi.org/10.3389/fimmu.2022.821010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tian R, Yao C, Yang C et al (2019) Fibroblast growth factor-5 promotes spermatogonial stem cell proliferation via ERK and AKT activation. Stem Cell Res Ther 10:40. https://doi.org/10.1186/s13287-019-1139-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Alikhani M, Mirzaei M, Sabbaghian M et al (2017) Quantitative proteomic analysis of human testis reveals system-wide molecular and cellular pathways associated with non-obstructive azoospermia. J Proteomics 162:141–154. https://doi.org/10.1016/j.jprot.2017.02.007

    Article  CAS  PubMed  Google Scholar 

  118. Li J, Guo W, Li F et al (2012) HnRNPL as a key factor in spermatogenesis: Lesson from functional proteomic studies of azoospermia patients with sertoli cell only syndrome. J Proteomics 75:2879–2891. https://doi.org/10.1016/j.jprot.2011.12.040

    Article  CAS  PubMed  Google Scholar 

  119. Noveski P, Popovska-Jankovic K, Kubelka-Sabit K et al (2016) MicroRNA expression profiles in testicular biopsies of patients with impaired spermatogenesis. Andrology 4:1020–1027. https://doi.org/10.1111/andr.12246

    Article  CAS  PubMed  Google Scholar 

  120. Dabaja AA, Mielnik A, Robinson BD et al (2015) Possible germ cell-Sertoli cell interactions are critical for establishing appropriate expression levels for the Sertoli cell-specific MicroRNA, miR-202-5p, in human testis. Basic Clin Androl 25:2. https://doi.org/10.1186/s12610-015-0018-z

    Article  PubMed  PubMed Central  Google Scholar 

  121. Abu-Halima M, Backes C, Leidinger P et al (2014) MicroRNA expression profiles in human testicular tissues of infertile men with different histopathologic patterns. Fertil Steril 101:78-86.e2. https://doi.org/10.1016/j.fertnstert.2013.09.009

    Article  CAS  PubMed  Google Scholar 

  122. Zhang W, Zhang Y, Zhao M et al (2021) MicroRNA expression profiles in the seminal plasma of nonobstructive azoospermia patients with different histopathologic patterns. Fertil Steril 115:1197–1211. https://doi.org/10.1016/j.fertnstert.2020.11.020

    Article  CAS  PubMed  Google Scholar 

  123. Yao C, Sun M, Yuan Q et al (2016) MiRNA-133b promotes the proliferation of human Sertoli cells through targeting GLI3. Oncotarget 7:2201–2219. https://doi.org/10.18632/oncotarget.6876

    Article  PubMed  PubMed Central  Google Scholar 

  124. Zhu F, Luo Y, Bo H et al (2021) Trace the profile and function of circular RNAs in Sertoli cell only syndrome. Genomics 113:1845–1854. https://doi.org/10.1016/j.ygeno.2021.04.022

    Article  CAS  PubMed  Google Scholar 

  125. Bo H, Liu Z, Zhu F et al (2020) Long noncoding RNAs expression profile and long noncoding RNA-mediated competing endogenous RNA network in nonobstructive azoospermia patients. Epigenomics 12:673–684. https://doi.org/10.2217/epi-2020-0008

    Article  CAS  PubMed  Google Scholar 

  126. Willems M, Vloeberghs V, Gies I et al (2020) Testicular immune cells and vasculature in Klinefelter syndrome from childhood up to adulthood. Hum Reprod Oxf Engl 35:1753–1764. https://doi.org/10.1093/humrep/deaa132

    Article  CAS  Google Scholar 

  127. Asadpor U, Totonchi M, Sabbaghian M et al (2013) Ubiquitin-specific protease (USP26) gene alterations associated with male infertility and recurrent pregnancy loss (RPL) in Iranian infertile patients. J Assist Reprod Genet 30:923–931. https://doi.org/10.1007/s10815-013-0027-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Faure AK, Pivot-Pajot C, Kerjean A et al (2003) Misregulation of histone acetylation in Sertoli cell-only syndrome and testicular cancer. Mol Hum Reprod 9:757–763. https://doi.org/10.1093/molehr/gag101

    Article  CAS  PubMed  Google Scholar 

  129. Eelaminejad Z, Favaedi R, Sodeifi N et al (2017) Deficient expression of JMJD1A histone demethylase in patients with round spermatid maturation arrest. Reprod Biomed Online 34:82–89. https://doi.org/10.1016/j.rbmo.2016.09.005

    Article  CAS  PubMed  Google Scholar 

  130. Yang C, Yao C, Tian R et al (2019) miR-202-3p regulates Sertoli cell proliferation, synthesis function, and apoptosis by targeting LRP6 and cyclin D1 of Wnt/β-catenin signaling. Mol Ther Nucleic Acids 14:1–19. https://doi.org/10.1016/j.omtn.2018.10.012

    Article  CAS  PubMed  Google Scholar 

  131. Hwang B, Lee JH, Bang D (2018) Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med 50:96. https://doi.org/10.1038/s12276-018-0071-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Guo J, Grow EJ, Mlcochova H et al (2018) The adult human testis transcriptional cell atlas. Cell Res 28:1141–1157. https://doi.org/10.1038/s41422-018-0099-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Soraggi S, Riera M, Rajpert-De Meyts E et al (2020) Evaluating genetic causes of azoospermia: what can we learn from a complex cellular structure and single-cell transcriptomics of the human testis? Hum Genet. https://doi.org/10.1007/s00439-020-02116-8

    Article  PubMed  Google Scholar 

  134. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. https://doi.org/10.1016/j.cell.2007.11.019

    Article  CAS  PubMed  Google Scholar 

  135. Sasaki K, Yokobayashi S, Nakamura T et al (2015) Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell 17:178–194. https://doi.org/10.1016/j.stem.2015.06.014

    Article  CAS  PubMed  Google Scholar 

  136. Zhao Y, Ye S, Liang D et al (2018) In vitro modeling of human germ cell development using pluripotent stem cells. Stem Cell Rep 10:509–523. https://doi.org/10.1016/j.stemcr.2018.01.001

    Article  Google Scholar 

  137. Easley CA, Phillips BT, McGuire MM et al (2012) Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep 2:440–446. https://doi.org/10.1016/j.celrep.2012.07.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Liang J, Wang N, He J et al (2019) Induction of Sertoli-like cells from human fibroblasts by NR5A1 and GATA4. Elife 8:e48767. https://doi.org/10.7554/eLife.48767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sun M, Yuan Q, Niu M et al (2018) Efficient generation of functional haploid spermatids from human germline stem cells by three-dimensional-induced system. Cell Death Differ 25:749–766. https://doi.org/10.1038/s41418-017-0015-1

    Article  PubMed  Google Scholar 

  140. Zhang W, Chen W, Cui Y et al (2021) Direct reprogramming of human Sertoli cells into male germline stem cells with the self-renewal and differentiation potentials via overexpressing DAZL/DAZ2/BOULE genes. Stem Cell Rep 16:2798–2812. https://doi.org/10.1016/j.stemcr.2021.09.011

    Article  CAS  Google Scholar 

  141. Wang X, Qu M, Li Z et al (2021) Valproic acid promotes the in vitro differentiation of human pluripotent stem cells into spermatogonial stem cell-like cells. Stem Cell Res Ther 12:553. https://doi.org/10.1186/s13287-021-02621-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wang X, Li Z, Qu M et al (2022) A homozygous PIWIL2 frameshift variant affects the formation and maintenance of human-induced pluripotent stem cell-derived spermatogonial stem cells and causes Sertoli cell-only syndrome. Stem Cell Res Ther 13:480. https://doi.org/10.1186/s13287-022-03175-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ramathal C, Durruthy-Durruthy J, Sukhwani M et al (2014) Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. Cell Rep 7:1284–1297. https://doi.org/10.1016/j.celrep.2014.03.067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Li M, Suzuki K, Kim NY et al (2014) A cut above the rest: targeted genome editing technologies in human pluripotent stem cells. J Biol Chem 289:4594–4599. https://doi.org/10.1074/jbc.R113.488247

    Article  CAS  PubMed  Google Scholar 

  145. Mulder CL, Zheng Y, Jan SZ et al (2016) Spermatogonial stem cell autotransplantation and germline genomic editing: a future cure for spermatogenic failure and prevention of transmission of genomic diseases. Hum Reprod Update 22:561–573. https://doi.org/10.1093/humupd/dmw017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Wu Y, Zhou H, Fan X et al (2015) Correction of a genetic disease by CRISPR-Cas9-mediated gene editing in mouse spermatogonial stem cells. Cell Res 25:67–79. https://doi.org/10.1038/cr.2014.160

    Article  CAS  PubMed  Google Scholar 

  147. Stimpfel M, Skutella T, Kubista M et al (2012) Potential stemness of frozen-thawed testicular biopsies without sperm in infertile men included into the in vitro fertilization programme. J Biomed Biotechnol. https://doi.org/10.1155/2012/291038

    Article  PubMed  PubMed Central  Google Scholar 

  148. Gauthier-Fisher A, Kauffman A, Librach CL (2020) Potential use of stem cells for fertility preservation. Andrology 8:862–878. https://doi.org/10.1111/andr.12713

    Article  CAS  PubMed  Google Scholar 

  149. Hermann BP, Cheng K, Singh A et al (2018) The Mammalian spermatogenesis single-cell transcriptome, from spermatogonial stem cells to spermatids. Cell Rep 25:1650-1667.e8. https://doi.org/10.1016/j.celrep.2018.10.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Fayomi AP, Peters K, Sukhwani M et al (2019) Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring. Science 363:1314–1319. https://doi.org/10.1126/science.aav2914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Luetjens CM, Stukenborg J-B, Nieschlag E et al (2008) Complete spermatogenesis in orthotopic but not in ectopic transplants of autologously grafted marmoset testicular tissue. Endocrinology 149:1736–1747. https://doi.org/10.1210/en.2007-1325

    Article  CAS  PubMed  Google Scholar 

  152. Jahnukainen K, Ehmcke J, Nurmio M, Schlatt S (2012) Autologous ectopic grafting of cryopreserved testicular tissue preserves the fertility of prepubescent monkeys that receive sterilizing cytotoxic therapy. Cancer Res 72:5174–5178. https://doi.org/10.1158/0008-5472.CAN-12-1317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Xu H, Yang M, Tian R et al (2020) Derivation and propagation of spermatogonial stem cells from human pluripotent cells. Stem Cell Res Ther 11:408. https://doi.org/10.1186/s13287-020-01896-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Durruthy Durruthy J, Ramathal C, Sukhwani M et al (2014) Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules. Hum Mol Genet 23:3071–3084. https://doi.org/10.1093/hmg/ddu012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. De Oliveira CS, Nixon B, Lord T (2022) A scRNA-seq approach to identifying changes in spermatogonial stem cell gene expression following in vitro culture. Front Cell Dev Biol 10:782996. https://doi.org/10.3389/fcell.2022.782996

    Article  PubMed  PubMed Central  Google Scholar 

  156. Zahiri M, Movahedin M, Mowla SJ et al (2022) Genetic and epigenetic evaluation of human spermatogonial stem cells isolated by MACS in different two and three-dimensional culture systems. Cell J 24:481–490. https://doi.org/10.22074/cellj.2022.7888

    Article  PubMed  PubMed Central  Google Scholar 

  157. Bhartiya D, Shaikh A, Anand S et al (2016) Endogenous, very small embryonic-like stem cells: critical review, therapeutic potential and a look ahead. Hum Reprod Update 23:41–76. https://doi.org/10.1093/humupd/dmw030

    Article  CAS  PubMed  Google Scholar 

  158. Anand S, Patel H, Bhartiya D (2015) Chemoablated mouse seminiferous tubular cells enriched for very small embryonic-like stem cells undergo spontaneous spermatogenesis in vitro. Reprod Biol Endocrinol RBE 13:33. https://doi.org/10.1186/s12958-015-0031-2

    Article  CAS  Google Scholar 

  159. 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 Thousand Oaks Calif 22:884–903. https://doi.org/10.1177/1933719115576727

    Article  CAS  Google Scholar 

  160. Parte S, Bhartiya D, Telang J 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 20:1451–1464. https://doi.org/10.1089/scd.2010.0461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Vassal M, Rebelo S, de Pereira ML (2021) metal oxide nanoparticles: evidence of adverse effects on the male reproductive system. Int J Mol Sci 22:8061. https://doi.org/10.3390/ijms22158061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Barkalina N, Jones C, Wood MJA, Coward K (2015) Extracellular vesicle-mediated delivery of molecular compounds into gametes and embryos: learning from nature. Hum Reprod Update 21:627–639. https://doi.org/10.1093/humupd/dmv027

    Article  CAS  PubMed  Google Scholar 

  163. Afifi M, Almaghrabi OA, Kadasa NM (2015) Ameliorative effect of zinc oxide nanoparticles on antioxidants and sperm characteristics in streptozotocin-induced diabetic rat testes. BioMed Res Int. https://doi.org/10.1155/2015/153573

    Article  PubMed  PubMed Central  Google Scholar 

  164. Kim WJ, Kim BS, Kim HJ et al (2020) Intratesticular peptidyl prolyl isomerase 1 protein delivery using cationic lipid-coated fibroin nanoparticle complexes rescues male infertility in mice. ACS Nano 14:13217–13231. https://doi.org/10.1021/acsnano.0c04936

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the associate editor and the reviewers for their useful feedback that improved this paper.

Funding

This work was supported by the Youth Fund Project of National Natural Science Foundation of China (No. 82201770), the National Key Research and Development Program of China (2022YFC2702704), and the grant from Wuhan Municipal Health Commission (WX21B05).

Author information

Author notes

  1. Xiaotong Wang, Xinyu Liu have contributed equally.

Authors and Affiliations

  1. Institute of Reproductive Health/Center of Reproductive Medicine, Huazhong University of Science and Technology, Wuhan, 430000, China

    Xiaotong Wang, Xinyu Liu, Mengyuan Qu & Honggang Li

  2. The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Xiaotong Wang

  3. Wuhan Tongji Reproductive Medicine Hospital, Wuhan, 430000, China

    Honggang Li

Authors
  1. Xiaotong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengyuan Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Honggang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XW and XL contributed equally to the study design, literature searching and drafting of the article. MQ contributed to the study design and literature research. HL supervised the study design and reviewed the article.

Corresponding author

Correspondence to Honggang Li.

Ethics declarations

Conflict of interest

The authors report no financial or other conflict of interest relevant to the subject of this article.

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 118 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Liu, X., Qu, M. et al. Sertoli cell-only syndrome: advances, challenges, and perspectives in genetics and mechanisms. Cell. Mol. Life Sci. 80, 67 (2023). https://doi.org/10.1007/s00018-023-04723-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-023-04723-w

Keywords

Search

Navigation