Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Neonatal testicular cell transplantation restores murine spermatogenesis damaged in the course of herpes simplex virus-induced orchitis

Ekaterina A. Malolina A B C , Andrey Yu. Kulibin B and Alla A. Kushch A
+ Author Affiliations
- Author Affiliations

A Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, Gamaleya str. 16, 123098, Moscow, The Russian Federation.

B Kol’tsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilova str. 26, 119071, Moscow, The Russian Federation.

C Corresponding author. Email: kate.ma85@gmail.com

Reproduction, Fertility and Development 28(6) 757-764 https://doi.org/10.1071/RD14255
Submitted: 18 July 2014  Accepted: 19 September 2014   Published: 17 November 2014

Abstract

Genital tract infection and inflammation may affect male fertility, causing germ and Sertoli cell loss. We determined if testicular cell transplantation is effective at repairing testicular injury induced by herpes simplex virus (HSV) orchitis. ROSA26 mice were used as donors and the recipients were C57BL/6 mice after HSV testicular inoculation; some of the recipients were treated with the antiviral drug acyclovir (ACV). ACV reduced the amount of HSV antigen in testes on Day 3 after transplantation and enhanced the efficacy of transplantation at Day 30. In recipient testes, donor Sertoli cells formed new seminiferous tubules; significantly more new tubules were observed in the testes of ACV-treated mice compared with mice not treated with ACV (17.8% vs 3.6%). Over half (50.4%) of new tubules in ACV-treated testes contained germ cells and round spermatids were detected in 14.2% of new tubules compared with 15.9% and 5.3% in testes not treated with ACV, respectively. At Day 150 the seminiferous epithelium was completely recovered in some donor tubules and elongated spermatids were observed inside it. Thus, our findings reveal the effectiveness of the combination of antiviral therapy with neonatal testis-cell transplantation for the restoration of spermatogenesis damaged by viral infection.

Additional keywords: acyclovir, germ cells, male fertility, Sertoli cells.


References

Bairy, K. L., Kumar, G., and Rao, Y. (2009). Effect of acyclovir on the sperm parameters of albino mice. Indian J. Physiol. Pharmacol. 53, 327–333.
| 1:CAS:528:DC%2BC3cXjslCjs7c%3D&md5=696b4ada249784998419f5323bcc78dbCAS | 20509324PubMed |

Beyer, C. F., Arens, M. Q., Hill, G. A., Rose, B. T., Beyer, L. R., and Schanzlin, D. J. (1989). Oral acyclovir reduces the incidence of recurrent herpes simplex keratitis in rabbits after penetrating keratoplasty. Arch. Ophthalmol. 107, 1200–1205.
Oral acyclovir reduces the incidence of recurrent herpes simplex keratitis in rabbits after penetrating keratoplasty.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1MXlt1KmsL8%3D&md5=c03e24787a4459e44398cc82ce05cbacCAS | 2547352PubMed |

Bezold, G., Politch, J. A., Kiviat, N. B., Kuypers, J. M., Wolff, H., and Anderson, D. J. (2007). Prevalence of sexually transmissible pathogens in semen from asymptomatic male infertility patients with and without leukocytospermia. Fertil. Steril. 87, 1087–1097.
Prevalence of sexually transmissible pathogens in semen from asymptomatic male infertility patients with and without leukocytospermia.Crossref | GoogleScholarGoogle Scholar | 17433312PubMed |

Brinster, R. L., and Avarbock, M. R. (1994). Germline transmission of donor haplotype following spermatogonial transplantation. Proc. Natl. Acad. Sci. USA 91, 11 303–11 307.
Germline transmission of donor haplotype following spermatogonial transplantation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXitlyku7g%3D&md5=72a173350b4fc9037bfc5f408e6d032eCAS |

Buganim, Y., Itskovich, E., Hu, Y. C., Cheng, A. W., Ganz, K., Sarkar, S., Fu, D., Welstead, G. G., Page, D. C., and Jaenisch, R. (2012). Direct reprogramming of fibroblasts into embryonic Sertoli-like cells by defined factors. Cell Stem Cell 11, 373–386.
Direct reprogramming of fibroblasts into embryonic Sertoli-like cells by defined factors.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtlCjtbnE&md5=8719f3085f43847f17c801df6e057dcbCAS | 22958931PubMed |

Dejucq, N., and Jégou, B. (2001). Viruses in the mammalian male genital tract and their effects on the reproductive system. Microbiol. Mol. Biol. Rev. 65, 208–231.
Viruses in the mammalian male genital tract and their effects on the reproductive system.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXkvVKmu7k%3D&md5=70eb4b7e858929572d3b04e329ac375cCAS | 11381100PubMed |

Dohle, G. R., Diemer, T., Giwercman, A., Jungwirth, A., Kopa, Z., and Krausz, C. (2010). ‘Guidelines on Male Infertility’. (European Association of Urology: Arnhem, The Netherlands.)

Durruthy Durruthy, D. J., Ramathal, C., Sukhwani, M., Fang, F., Cui, J., Orwig, K. E., and Reijo Pera, R. A. (2014). Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules. Hum. Mol. Genet. 23, 3071–3084.
Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXosVOmsb0%3D&md5=6ba65bb30d7c8c10b031a0812d2fc5a8CAS |

El Borai, N., LeFevre, Ch., Inoue, M., Naumova, E. N., Sato, K., Suzuki, S., Tsuji, K., and Yamamura, M. (1998). Presence of HSV-1 DNA in semen and menstrual blood. J. Reprod. Immunol. 41, 137–147.
Presence of HSV-1 DNA in semen and menstrual blood.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXhtVWmur0%3D&md5=f102c74ab5c218bf5f86404aa9392b1dCAS | 10213306PubMed |

Faes, K., Tournaye, H., Goethals, L., Lahoutte, T., Hoorens, A., and Goossens, E. (2013). Testicular cell transplantation into the human testes. Fertil. Steril. 100, 981–988.
Testicular cell transplantation into the human testes.Crossref | GoogleScholarGoogle Scholar | 23850302PubMed |

Field, H. J., and De Clercq, E. (1981). Effects of oral treatment with acyclovir and bromovinyldeoxyuridine on the establishment of maintenance of latent herpes simplex virus infection in mice. J. Gen. Virol. 56, 259–265.
Effects of oral treatment with acyclovir and bromovinyldeoxyuridine on the establishment of maintenance of latent herpes simplex virus infection in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL38XksF2htQ%3D%3D&md5=b802e9e6159106f61333964665268386CAS | 6273499PubMed |

Kanatsu-Shinohara, M., Miki, H., Inoue, K., Ogonuki, N., Toyokuni, S., Ogura, A., and Shinohara, T. (2005). Germline niche transplantation restores fertility in infertile mice. Hum. Reprod. 20, 2376–2382.
Germline niche transplantation restores fertility in infertile mice.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD2MvnvFGhug%3D%3D&md5=06a8df4988a472d12fc4d2dfd6321734CAS | 15919776PubMed |

Kapranos, N., Petrakou, E., Anastasiadou, C., and Kotronias, D. (2003). Detection of herpes simplex virus, cytomegalovirus and Epstein-Barr virus in the semen of men attending an infertility clinic. Fertil. Steril. 79, 1566–1570.
Detection of herpes simplex virus, cytomegalovirus and Epstein-Barr virus in the semen of men attending an infertility clinic.Crossref | GoogleScholarGoogle Scholar | 12801561PubMed |

Klimova, R. R., Masalova, O. V., Atanadze, S. N., and Kushch, A. A. (1999). Monoclonal antibodies in the diagnosis of infections caused by the herpes simplex virus. Zh. Mikrobiol. Epidemiol. Immunobiol. 5, 99–103.
| 10852033PubMed |

Klimova, R. R., Chichev, E. V., Naumenko, V. A., Gadzhieva, Z. S., Tsibisov, A. S., Adieva, A. A., L’vov, D. K., Kurilo, L. F., Shileĭko, L. V., Ostroumova, T. V., Sorokina, T. M., Gavrilov, Iu. A., Levchuk, T. N., Iakovenko, S. A., Vasil’eva, S. G., Voznesenskaia, Iu. V., Simonenko, E. Iu., Kushch, A. A., and Sukhikh, G. T. (2010). Herpes simplex virus and cytomegalovirus in male ejaculate: herpes simplex virus is more frequently encountered in idiopathic infertility and correlates with the reduction in sperm parameters. Vopr. Virusol. 55, 27–31.
| 1:STN:280:DC%2BC3c3js1SqtA%3D%3D&md5=5c4d3f5425421ddb6794772b84061541CAS | 20364668PubMed |

Kotronias, D., and Kapranos, N. (1998). Detection of herpes simplex virus DNA in human spermatozoa by in situ hybridisation technique. In Vivo 12, 391–394.
| 1:CAS:528:DyaK1cXlt1Wntb8%3D&md5=acd28c79e7293d0427092ae5ba013e44CAS | 9706490PubMed |

Malolina, E. A., and Kulibin, A. Yu. (2012). Heat treatment enhances regeneration capacity of Sertoli cells. Mol. Med. 4, 49–58.

Malolina, E. A., Kulibin, A. Y., Marshak, T. L., and Zakhidov, S. T. (2011). Regeneration potential of transplanted adult mouse Sertoli cells. Bull. Exp. Biol. Med. 151, 646–649.
Regeneration potential of transplanted adult mouse Sertoli cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXht1Gntb%2FK&md5=a47bd860e51ab66ca2dc12253c4927f9CAS | 22462068PubMed |

Malolina, E. A., Kulibin, A. Yu., Naumenko, V. A., Gushchina, E. A., Zavalishina, L. E., and Kushch, A. A. (2014). Herpes simplex virus inoculation in murine rete testis results in irreversible testicular damage. Int. J. Exp. Pathol. 95, 120–130.
Herpes simplex virus inoculation in murine rete testis results in irreversible testicular damage.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXktlChtLc%3D&md5=03c96be1b7abb3151d33e2bd780897eeCAS | 24673915PubMed |

McLean, D. J. (2008). Spermatogonial stem cell transplantation, testicular function and restoration of male fertility in mice. Methods Mol. Biol. 450, 149–162.
Spermatogonial stem cell transplantation, testicular function and restoration of male fertility in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXkslOht7c%3D&md5=7e11861e4861d5848a43342bad6bb9d0CAS | 18370058PubMed |

Nakaki, F., Hayashi, K., Ohta, H., Kurimoto, K., Yabuta, Y., and Saitou, M. (2013). Induction of mouse germ-cell fate by transcription factors in vitro. Nature 501, 222–226.
Induction of mouse germ-cell fate by transcription factors in vitro.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXht1Whs7rL&md5=dafabf3ba894ad3c7762bd8c2521f1f1CAS | 23913270PubMed |

Naumenko, V. A., Tyulenev, IuA., Pushkar’, Dlu., Segal, A. S., Kovalev, V. A., Kurilo, L. F., Shileĭko, L. V., Klimova, R. R., Al’khovskiĭ, S. V., and Kushch, A. A. (2011). Effect of herpes simplex virus to spermatogenesis. Urologiia 6, 32–36.
| 22448478PubMed |

Naumenko, V., Tyulenev, Y., Kurilo, L., Shileiko, L., Sorokina, T., Evdokimov, V., Yakovleva, V., Kovalyk, V., Malolina, E., Kulibin, A., Gomberg, M., and Kushch, A. (2014). Detection and quantification of human herpes viruses types 4–6 in sperm samples of patients with fertility disorders and chronic inflammatory urogenital tract diseases. Andrology 2, 687–694.
| 1:CAS:528:DC%2BC2cXhtlymsLzL&md5=8fe9d06e94f0fb989317b42c852d32deCAS | 24903066PubMed |

O’Bryan, M. K., and Hedger, M. P. (2008). Inflammatory networks in the control of spermatogenesis: chronic inflammation in an immunologically privileged tissue? Adv. Exp. Med. Biol. 636, 92–114.
Inflammatory networks in the control of spermatogenesis: chronic inflammation in an immunologically privileged tissue?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlKisb%2FN&md5=3ac0ffbbfbf3dcc487b951b582e956f6CAS | 19856164PubMed |

Ogawa, T., Aréchaga, J. M., Avarbock, M. R., and Brinster, R. L. (1997). Transplantation of testis germinal cells into mouse seminiferous tubules. Int. J. Dev. Biol. 41, 111–122.
| 1:STN:280:DyaK2s3ivV2itQ%3D%3D&md5=56fbe5d33c71ff52b416b911d86ff63fCAS | 9074943PubMed |

Salameh, W. A., and Swerdloff, R. S. (2005). Conditions affecting Sertoli cells. In ‘Sertoli Cell Biology’. (Eds M. K. Skinner and M. D. Griswold.) pp. 383–413. (Elsevier Academic Press: San Diego and London.)

Schuppe, H. C., Meinhardt, A., Allam, J. P., Bergmann, M., Weidner, W., and Haidl, G. (2008). Chronic orchitis: a neglected cause of male infertility? Andrologia 40, 84–91.
Chronic orchitis: a neglected cause of male infertility?Crossref | GoogleScholarGoogle Scholar | 18336456PubMed |

Shinohara, T., Orwig, K. E., Avarbock, M. R., and Brinster, R. L. (2003). Restoration of spermatogenesis in infertile mice by Sertoli cell transplantation. Biol. Reprod. 68, 1064–1071.
Restoration of spermatogenesis in infertile mice by Sertoli cell transplantation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXhsFGksLs%3D&md5=643e37cff03a8dbed883f4777d33c389CAS | 12604661PubMed |

Tarulli, G. A., Stanton, P. G., and Meachem, S. J. (2012). Is the adult Sertoli cell terminally differentiated? Biol. Reprod. 87, 13.
Is the adult Sertoli cell terminally differentiated?Crossref | GoogleScholarGoogle Scholar | 22492971PubMed |

Tullo, A. (2003). Pathogenesis and management of herpes simplex virus keratitis. Eye (Lond.) 17, 919–922.
Pathogenesis and management of herpes simplex virus keratitis.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3srltVKitA%3D%3D&md5=5bcc93cf146348a39f8f896bb5906995CAS | 14631397PubMed |

Zhang, Z., Shao, S., Shetty, G., and Meistrich, M. L. (2009). Donor Sertoli cells transplanted into irradiated rat testes stimulate partial recovery of endogenous spermatogenesis. Reproduction 137, 497–508.
Donor Sertoli cells transplanted into irradiated rat testes stimulate partial recovery of endogenous spermatogenesis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXovV2ktr0%3D&md5=81350da9010e44ffb9d2cbfbb6ee8c2cCAS | 19036951PubMed |