Kanatsu-Shinohara Mito, Morimoto Hiroko, Watanabe Satoshi, Shinohara Takashi
Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
J Reprod Dev. 2018 Dec 14;64(6):511-522. doi: 10.1262/jrd.2018-093. Epub 2018 Sep 1.
Stem cell homing is a complex phenomenon that involves multiple steps; thus far, attempts to increase homing efficiency have met with limited success. Spermatogonial stem cells (SSCs) migrate to the niche after microinjection into seminiferous tubules, but the homing efficiency is very low. Here we report that reversible disruption of the blood-testis barrier (BTB) between Sertoli cells enhances the homing efficiency of SSCs. We found that SSCs on a C57BL/6 background are triggered to proliferate in vitro when MHY1485, which stimulates MTORC, were added to culture medium. However, the cultured cells did not produce offspring by direct injection into the seminiferous tubules. When acyline, a gonadotropin-releasing hormone (GnRH) analogue, was administered into infertile recipients, SSC colonization increased by ~5-fold and the recipients sired offspring. In contrast, both untreated individuals and recipients that received leuprolide, another GnRH analogue, remained infertile. Acyline not only decreased CLDN5 expression but also impaired the BTB, suggesting that increased colonization was caused by efficient SSC migration through the BTB. Enhancement of stem cell homing by tight junction protein manipulation constitutes a new approach to improve homing efficiency, and similar strategy may be applicable to other self-renewing tissues.
干细胞归巢是一个涉及多个步骤的复杂现象；到目前为止，提高归巢效率的尝试取得的成功有限。精原干细胞（SSCs）在显微注射到生精小管后会迁移到特定区域，但归巢效率非常低。在此我们报告，支持细胞之间血睾屏障（BTB）的可逆性破坏可提高SSCs的归巢效率。我们发现，当向培养基中添加刺激MTORC的MHY1485时，C57BL/6背景的SSCs在体外被触发增殖。然而，通过直接注射到生精小管中，培养的细胞并未产生后代。当向不育受体施用促性腺激素释放激素（GnRH）类似物阿西立肽时，SSC定植增加了约5倍，并且受体产生了后代。相比之下，未治疗的个体以及接受另一种GnRH类似物亮丙瑞林的受体仍然不育。阿西立肽不仅降低了CLDN5的表达，还破坏了BTB，这表明定植增加是由SSCs通过BTB的有效迁移所致。通过紧密连接蛋白操作增强干细胞归巢构成了一种提高归巢效率的新方法，并且类似的策略可能适用于其他自我更新组织。
