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Morphological damage in Sertoli, myoid and interstitial cells in a mouse model of mucopolysaccharidosis type I (MPS I)

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Abstract

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by a mutation in the IDUA gene, which codes α-l-iduronidase (IDUA), a lysosomal hydrolase that degrades two glycosaminoglycans (GAGs): heparan sulfate (HS) and dermatan sulfate (DS). GAGs are macromolecules found mainly in the extracellular matrix and have important signaling and structural roles which are essential to the maintenance of cell and tissue physiology. Nondegraded GAGs accumulate in various cell types, which characterizes MPS I as a multisystemic progressive disease. Many tissues and vital organs have been described in MPS I models, but there is a lack of studies focused on their effects on the reproductive tract. Our previous studies indicated lower sperm production and morphological damage in the epididymis and accessory glands in male MPS I mice, despite their ability to copulate and to impregnate females. Our aim was to improve the testicular characterization of the MPS I model, with a specific focus on ultrastructural observation of the different cell types that compose the seminiferous tubules and interstitium. We investigated the testicular morphology of 6-month-old male C57BL/6 wild-type (Idua+/+) and MPS I (Idua−/−) mice. We found vacuolated cells widely present in the interstitium and important signs of damage in myoid, Sertoli and Leydig cells. In the cytoplasmic region of Sertoli cells, we found an increased number of vesicles with substrates under digestion and a decreased number of electron-dense vesicles similar to lysosomes, suggesting an impaired flux of substrate degradation. Conclusions: Idua exerts an important role in the morphological maintenance of the seminiferous tubules and the testicular interstitium, which may influence the quality of spermatogenesis, having a greater effect with the progression of the disease.

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References

  1. Neufeld EF, Meunzer J (2001) The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 3421–3452

    Google Scholar 

  2. Clarke LA (2008) The mucopolysaccharidoses: a success of molecular medicine. Expert Rev Mol Med 10:1–18. https://doi.org/10.1017/S1462399408000550

    Article  Google Scholar 

  3. Muenzer J, Wraith JE, Clarke LA (2009) Mucopolysaccharidosis I : Management and treatment guidelines. Pediatrics 123:12–29. https://doi.org/10.1542/peds.2008-0416

    Article  Google Scholar 

  4. Kakkis ED, Muenzer J, Tiller GE (2001) Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 344(3):182–188. https://doi.org/10.1056/NEJM200101183440304

    Article  CAS  PubMed  Google Scholar 

  5. Castorina M, Antuzzi D, Richards SM, Cox GF, Xue Y (2015) Successful pregnancy and breastfeeding in a woman with mucopolysaccharidosis type I while receiving laronidase enzyme replacement therapy. Clin Exp Obstet Gynecol 42(1):108–113

    CAS  PubMed  Google Scholar 

  6. Stewart FJ, Bentley A, Burton BK, Guffon N, Hale SL, Harmatz PR, Kircher SG, Kocchar PK, Mitchell JJ, Plöckinger U, Graham S, Sande S, Sisic Z, Johnston TA (2016) Pregnancy in patients with mucopolysaccharidosis: a case series. Mol Genet Metab Rep 8:111–115. https://doi.org/10.1016/j.ymgmr.2016.08.002

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pereira VG, Gazarini ML, Rodrigues LC, da Silva FH, Han SW, Martins AM, Tersariol IL, D’Almeida V (2010) Evidence of lysosomal membrane permeabilization in Mucopolysaccharidosis Type I: rupture of calcium and proton homeostasis. J Cell Physiol 223:335–342. https://doi.org/10.1002/jcp.22039

    Article  CAS  PubMed  Google Scholar 

  8. Dickson PI, Ellinwood NM, Brown JR, Witt RG, Le SQ, Passage MB, Vera MU, Crawford BE (2012) Specific antibody titer alters the effectiveness of intrathecal enzyme replacement therapy in canine mucopolysaccharidosis I. Mol Genet Metab 106(1):68–72. https://doi.org/10.1016/j.ymgme.2012.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baldo G, Mayer FQ, Martinelli B, Dilda A, Meyer F, Ponder KP, Giugliani R, Matte U (2012) Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice. Behav Brain Res 233(1):169–175. https://doi.org/10.1016/j.bbr.2012.04.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Viana GM, Vin M, Buri I, Paredes-Gamero EJ, Martins AM, D’Almeida V (2016) Impaired hematopoiesis and disrupted monocyte/macrophage homeostasis in mucopolysaccharidosis type i mice. J Cell Physiol 231:698–707. https://doi.org/10.1002/jcp.25120

    Article  CAS  PubMed  Google Scholar 

  11. Viana GM, do Nascimento CC, Paredes-Gamero EJ, D’Almeida V (2017) Altered cellular homeostasis in murine MPS I fibroblasts: evidence of cell-specific physiopathology. JIMD Rep. https://doi.org/10.1007/8904_2017_5

    Article  PubMed  PubMed Central  Google Scholar 

  12. Viana GM, Gonzalez EA, Alvarez MMP, Cavalheiro RP, do Nascimento CC, Baldo G, D’Almeida V, de Lima MA, Pshezhetsky AV, Nader HB (2020) Cathepsin B-associated activation of amyloidogenic pathway in murine mucopolysaccharidosis type I brain cortex. Int J Mol Sci. 21(4):1459. https://doi.org/10.3390/ijms21041459

    Article  CAS  PubMed Central  Google Scholar 

  13. Do Nascimento CC, Aguiar Junior O, Viana GM, D’Almeida V (2019) Evidence that glycosaminoglycan storage and collagen deposition in the cauda epididymis does not impair sperm viability in the Mucopolysaccharidosis type I mouse model. Reprod Fertil Dev 32(3):304–312. https://doi.org/10.1071/RD19144

    Article  CAS  Google Scholar 

  14. Mendes AB, do Nascimento CC, D’Almeida V (2019) Sexual behaviour in a murine model of mucopolysaccharidosis type I (MPS I). PLoS ONE 14(12):e0220429. https://doi.org/10.1371/journal.pone.0220429

    Article  CAS  Google Scholar 

  15. Do Nascimento CC, Aguiar Junior O, D’Almeida V (2014) Analysis of male reproductive parameters in a murine model of mucopolysaccharidosis type I (MPS I). Int J Clin Exp Pathol 7(6):3488–3497

    PubMed  PubMed Central  Google Scholar 

  16. Do Nascimento CC, Aguiar Junior O, D’Almeida V (2019) Morphologic description of male reproductive accessory glands in a mouse model of mucopolysaccharidosis type I (MPS I). J Mol Histol 51(2):137–145. https://doi.org/10.1007/s10735-020-09864-x

    Article  CAS  Google Scholar 

  17. Ohmi K, Greenberg DS, Rajavel KS, Ryazantsev S, Li HH, Neufeld EF (2003) Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. PNAS 100(4):1902–1907. https://doi.org/10.1073/pnas.252784899

    Article  CAS  PubMed  Google Scholar 

  18. Latendresse JR, Warbrittion AR, Jonassen H, Creasy DM (2002) Fixation of testes and eyes using a modified Davidson’s fluid: comparison with Bouin’s fluid and conventional Davidson’s fluid. Toxicol Pathol 30:524–533. https://doi.org/10.1080/01926230290105721

    Article  PubMed  Google Scholar 

  19. Eskelinen E (2005) Maturation of autophagic vacuoles in mammalian cells. Autophagy 1:1–10. https://doi.org/10.4161/auto.1.1.1270

    Article  CAS  PubMed  Google Scholar 

  20. Cortes CJ, Miranda HC, Frankowski H, Batlevi Y, Young JE, Le A, Ivanov N, Sopher BL, Carromeu C, Muotri AR, Garden GA, La Spada AR (2014) Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat Neurosci 17(9):1180–1189. https://doi.org/10.1038/nn.3787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dietrich CP, Nader HB (1974) Fractionation and properties of four heparitin sulfates from beef lung tissue. Isolation and partial characterization of a hemogeneous species of heparitin sulfate. Biochim Biophys Acta 343(1):34–44. https://doi.org/10.1016/0304-4165(74)90237-2

    Article  CAS  PubMed  Google Scholar 

  22. Clarke LA, Russell CS, Pownall S, Warrington CL, Borowski A, Dimmick JE, Toone J, Jirik FR (1997) Murine mucopolysaccharidosis type I : targeted disruption of the murine α - L -iduronidase gene. Hum Mol Genet 6(4):503–511. https://doi.org/10.1093/hmg/6.4.503

    Article  CAS  PubMed  Google Scholar 

  23. Selva DM, Hirsch-Reinshagen V, Burgess B, Zhou S, Chan J, McIsaac S, Hayden MR, Hammond GL, Vogl AW, Wellington CL (2004) The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells and influences male fertility. J Lipid Res 45:1040–1050. https://doi.org/10.1194/jlr.M400007-JLR200

    Article  CAS  PubMed  Google Scholar 

  24. Rato L, Alves MG, Socorro S, Duarte AI, Cavaco JE, Oliveira PF (2012) Metabolic regulation is important for spermatogenesis. Nat Rev Urol 9(6):330–338. https://doi.org/10.1038/nrurol.2012.77

    Article  CAS  PubMed  Google Scholar 

  25. Xiong W, Wang H, Wu H, Chen Y, Han D (2009) Apoptotic spermatogenic cells can be energy sources for Sertoli cells. Reproduction 137(3):469–479. https://doi.org/10.1530/REP-08-0343

    Article  CAS  PubMed  Google Scholar 

  26. Yefimova MG, Messaddeq N, Harnois T, Meunier AC, Clarhaut J, Noblanc A, Weickert JW, Cantereau A, Philippe M, Bourmeyster N, Benzakour O (2013) A chimerical phagocytosis model reveals the recruitment by Sertoli cells of autophagy for the degradation of ingested illegitimate substrates. Autophagy 9(5):653–666. https://doi.org/10.4161/auto.23839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yin J, Ni B, Tian ZQ, Yang F, Liao WG, Gao YQ (2017) Regulatory effects of autophagy on spermatogenesis. Biol Reprod 96(3):525–530. https://doi.org/10.1095/biolreprod.116.144063

    Article  PubMed  Google Scholar 

  28. Glynn RMC, Dobrenis K, Walkley SU (2004) Differential subcellular localization of cholesterol, gangliosides and glycosaminoglycans in murine models of mucopolysaccharide storage disorders. J Comp Neurol 426:415–426. https://doi.org/10.1002/cne.20355

    Article  CAS  Google Scholar 

  29. Walkley SU (2004) Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol 15:433–444. https://doi.org/10.1016/j.semcdb.2004.03.002

    Article  CAS  PubMed  Google Scholar 

  30. Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C, Medina D, de Pablo R, Tacchetti C, Rubinsztein DC, Ballabio A (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17(1):119–129. https://doi.org/10.1093/hmg/ddm289

    Article  CAS  PubMed  Google Scholar 

  31. Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU (2012) Autophagy in lysosomal storage disorders. Autophagy 8(5):719–730. https://doi.org/10.4161/auto.19469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vitry S, Bruyère J, Hocquemiller M, Bigou S, Ausseil J, Colle MA, Prévost MC, Heard JM (2010) Storage vesicles in neurons are related to Golgi complex alterations in mucopolysaccharidosis IIIB. Am J Pathol 177(6):2984–2999. https://doi.org/10.2353/ajpath.2010.100447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pshezhetsky AV (2016) Lysosomal storage of heparan sulfate causes mitochondrial defects, altered autophagy and neuronal death in the mouse model of Mucopolysaccharidosis III type C. Autophagy 12(6):1059–1060. https://doi.org/10.1080/15548627.2015.1046671

    Article  CAS  PubMed  Google Scholar 

  34. Shiratsuchi A, Osada Y, Nakanishi Y (2013) Differences in the mode of phagocytosis of bacteria between macrophages and testicular Sertoli cells. Drug Discov Ther 7(2):73–77

    CAS  PubMed  Google Scholar 

  35. Campos D, Monaga M (2012) Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms. Metab Brain Dis 27:121–129. https://doi.org/10.1007/s11011-012-9302-1

    Article  CAS  PubMed  Google Scholar 

  36. Miqueloto CA, Zorn TM (2007) Characterization and distribution of hyaluronan and the proteoglycans decorin, biglycan and perlecan in the developing embryonic mouse gonad. J Anat 211(1):16–25. https://doi.org/10.1111/j.1469-7580.2007.00741.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Iozzo RV, Schaefer L (2010) Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. FEBS J 277(19):3864–3875. https://doi.org/10.1111/j.1742-4658.2010.07797.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Adam M, Urbanski HF, Garyfallou VT, Welsch U, Köhn FM, Ullrich Schwarzer J, Strauss L, Poutanen M, Mayerhofer A (2012) High levels of the extracellular matrix proteoglycan decorin are associated with inhibition of testicular function. Int J Androl 35(4):550–561. https://doi.org/10.1111/j.1365-2605.2011.01225.x

    Article  CAS  PubMed  Google Scholar 

  39. Maekawa M, Kamimura K, Nagano T (1996) Peritubular myoid cells in the testis: their structure and function. Arch Histol Cytol 59(1):1–13. https://doi.org/10.1679/aohc.59.1

    Article  CAS  PubMed  Google Scholar 

  40. Verhoeven G, Hoeben E, De Gendt K (2000) Peritubular cell-Sertoli cell interactions: factors involved in PmodS activity. Andrologia 32(1):42–45

    CAS  PubMed  Google Scholar 

  41. Parkinson-Lawrence EJ, Shandala T, Prodoehl M, Plew R, Borlace GN (2009) Brooks DA. Lysosomal storage disease: revealing lysosomal function and physiology. Physiology 25:102–115. https://doi.org/10.1152/physiol.00041.2009

    Article  CAS  Google Scholar 

  42. Robaire B, Hinton BT, Orgebin-Crist MC (2006) The epididymis. In: Neill JD (ed) Knobil and Neill’s physiology of reproduction. Elsevier, New York, pp 1071–1148

    Chapter  Google Scholar 

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Acknowledgements

We would like to thank Dr. Marcelo Andrade de Lima and Dra. Helena Bonciani Nader for the use of the facility and advising us on the biochemical analysis of GAGs.

Funding

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Fellowship to CCN and VD’A), the Associação Fundo de Incentivo à Pesquisa (AFIP) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2016/25486-1; scholarship to GMV).

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Authors and Affiliations

  1. Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Cinthia Castro do Nascimento & Vânia D’Almeida

  2. Department of Biosciences, Universidade Federal de São Paulo, Santos, SP, Brazil

    Odair Aguiar Jr.

  3. Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Gustavo Monteiro Viana

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  1. Cinthia Castro do Nascimento
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  2. Odair Aguiar Jr.
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  3. Gustavo Monteiro Viana
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  4. Vânia D’Almeida
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Contributions

CCN performed the experiments, analyzed the data and wrote the manuscript, OAJ was responsible for the study design and participated in the histological and ultrastructural analysis, GMV worked on the biochemical analysis, and VD’A participated in the study design and analysis of the data. All authors contributed to the final revision of the manuscript.

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Correspondence to Vânia D’Almeida.

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11033_2020_6055_MOESM1_ESM.tif

Supplementary file1 S1: Electron supplementary material 1: Morphological characterization of cytoplasmic vesicles found in Sertoli cells. a: vesicles with material under digestion (black arrows); b: electron-dense vesicles similar to lysosomes (white arrows); c: vesicles fused with electron-dense vesicles, similar to autolysosomes (red arrows). (TIF 2710 kb)

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do Nascimento, C.C., Aguiar, O., Viana, G.M. et al. Morphological damage in Sertoli, myoid and interstitial cells in a mouse model of mucopolysaccharidosis type I (MPS I). Mol Biol Rep 48, 363–370 (2021). https://doi.org/10.1007/s11033-020-06055-5

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