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

Posted on Posted in AMRC Research

Date: 11 Sep 2012

 

“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/Sld mouse is used as a model of such male infertility. The testis of the Sl/Sld 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/Sld 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.

 

Spermatogenic impairments can be caused by malfunctions of either the germ cell itself or surrounding somatic cells, which collectively constitute the microenvironment for proper spermatogenesis. It is well known that the microenvironmental condition in the testis is under the body’s systemic control, particularly through hormones from the pituitary. It is also well recognized that testicular somatic cells, Sertoli cells in particular, play a pivotal role in spermatogenesis (1, 2). Although it remains to be elucidated what molecules are essential constituents of that microenvironment and how they exert their role in spatial and temporal terms, it is a reasonable assumption that the spermatogenic impairments caused by microenvironmental factors are treatable by correcting the defect(s).

 

Recently, we succeeded in inducing complete spermatogenesis in mice using an organ culture method (3⇓–5). In this culture system, germ cells developed from spermatogonial stem cells through mitotic differentiation of spermatogonia, meiosis in spermatocytes, and morphological transformation in haploid spermatids, to sperm. One of the greatest advantages of the in vitro system is that the culture medium can be modified freely to an extent that would be impossible to achieve in vivo. In the present study, we attempted to treat spermatogenic failure of a mutant mouse by culturing testis tissue fragments in media supplemented with combinations of growth factors.”

 

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