Adenovirus-mediated gene delivery and
            <i>in vitro</i>
            microinsemination produce offspring from infertile male mice

Kanatsu-Shinohara, Mito; Ogura, Atsuo; Ikegawa, Masaya; Inoue, Kimiko; Ogonuki, Narumi; Tashiro, Kei; Toyokuni, Shinya; Honjo, Tasuku; Shinohara, Takashi

doi:10.1073/pnas.022646399

Cited by 73 publications

(59 citation statements)

References 48 publications

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“…This method is theoretically attractive but the efficiency of Sertoli cell transplantation is low, which is a technical hurdle of this method. The third method used a genetherapy strategy to introduce the Steel gene into the defective Sertoli cells of Sl/Sl d mice by adeno-or lenti-viral transductions 32,33 . This method also proved effective to produce fertile sperm in the testes of Sl/Sl d mice.…”

Section: Discussionmentioning

confidence: 99%

In vitro production of fertile sperm from murine spermatogonial stem cell lines

et al. 2011

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spermatogonial stem cells (ssCs) are the only stem cells in the body that transmit genetic information to the next generation. The long-term propagation of rodent ssCs is now possible in vitro, and their genetic modification is feasible. However, their differentiation into sperm is possible only under in vivo conditions. Here we show a new in vitro system that can induce full spermatogenesis from ssC lines or any isolated ssCs. The method depends on an organ culture system onto which ssCs are transplanted. The settled ssCs form colonies and differentiate up into sperm. The resultant haploid cells are fertile, and give rise to healthy offspring through micro-insemination. In addition, the system can induce spermatogenesis from ssCs that show spermatogenic failure due to a micro-environmental defect in their original testes. Thus, an in vitro system is established that can be used to correct or manipulate the micro-environmental conditions required for proper spermatogenesis from murine ssC lines.

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Section: Discussionmentioning

confidence: 99%

In vitro production of fertile sperm from murine spermatogonial stem cell lines

et al. 2011

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“…Additionally, the lack of long-term expression because of immune problems will be a handicap. However, Kanatsu-Shinohara et al, using lower viral titers, succeeded in expressing the transgene over 3 mo with decreased transduction efficiency (26). No transduction of seminiferous tubules could be observed with AAV vectors (Fig.…”

Section: Discussionmentioning

confidence: 99%

Restoration of spermatogenesis by lentiviral gene transfer: Offspring from infertile mice

Ikawa

Tergaonkar

Ogura

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Disruption of spermatogenesis found in azoospermia and oligozoospermia is thought to be of primarily genetic origin. Sl͞Sl d mutant mice offer a model system in which lack of transmembrane type c-kit ligand (KL2) expression on the somatic Sertoli cell surface results in disruption of spermatogenesis. We investigated the ability of adeno-, adeno-associated-, retro-, and lentiviral vectors to transduce Sertoli cells and found that transduction with either adeno-or lentiviral vectors led to reporter gene expression for more than 2 mo after testicular tubule injection. Because adenoviral vectors showed toxicity, lentiviral vectors were used to express the c-kit ligand in Sl͞Sl d Sertoli cells. Restoration of spermatogenesis was observed in all recipient testes. Furthermore, the sperm collected from recipient testes were able to generate normal pups after intracytoplasmic sperm injection. None of the offspring carried the transgene, suggesting the inability of lentiviral vectors to infect spermatogenic cells in vivo. We propose that lentiviral vectors can be used for gene therapy of male infertility without the risk of germ-line transmission.

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“…S4D). Two studies using adenovirus and lentivirus succeeded in making Sertoli cells of Sl/Sl d mice produce mKITL, thereby inducing spermatogenesis in their testes (22,23). This strategy appears more realistic for clinical application than the first two.…”

Section: Discussionmentioning

confidence: 99%

Testis tissue explantation cures spermatogenic failure in c-Kit ligand mutant mice

Sato

Yokonishi

Komeya

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Male infertility is most commonly caused by spermatogenic defects or insufficiencies, the majority of which are as yet cureless. Recently, we succeeded in cultivating mouse testicular tissues for producing fertile sperm from spermatogonial stem cells. Here, we show that one of the most severe types of spermatogenic defect mutant can be treated by the culture method without any genetic manipulations. The Sl/Sl d mouse is used as a model of such male infertility. The testis of the Sl/Sl d mouse has only primitive spermatogonia as germ cells, lacking any sign of spermatogenesis owing to mutations of the c-kit ligand (KITL) gene that cause the loss of membrane-bound-type KITL from the surface of Sertoli cells. To compensate for the deficit, we cultured testis tissues of Sl/Sl d mice with a medium containing recombinant KITL and found that it induced the differentiation of spermatogonia up to the end of meiosis. We further discovered that colony stimulating factor-1 (CSF-1) enhances the effect of KITL and promotes spermatogenesis up to the production of sperm. Microinsemination of haploid cells resulted in delivery of healthy offspring. This study demonstrated that spermatogenic impairments can be treated in vitro with the supplementation of certain factors or substances that are insufficient in the original testes.

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Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice

Cited by 73 publications

References 48 publications

In vitro production of fertile sperm from murine spermatogonial stem cell lines

In vitro production of fertile sperm from murine spermatogonial stem cell lines

Restoration of spermatogenesis by lentiviral gene transfer: Offspring from infertile mice

Testis tissue explantation cures spermatogenic failure in c-Kit ligand mutant mice

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