Inhibiting Necroptosis of Spermatogonial Stem Cell as a Novel Strategy for Male Fertility Preservation
Inhibiting Necroptosis of Spermatogonial Stem Cell as a Novel Strategy for Male Fertility Preservation
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抑制精原干细胞坏死性凋亡作为保留男性生育力的新策略。
DOI：
10.1089/scd.2019.0220
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发表时间：
2020
影响因子：
4
通讯作者：
Liu Guihua
中科院分区：
文献类型：
--
作者：
Xie Yun;Chen Haicheng;Luo Daosheng;Yang Xing;Yao Jiahui;Zhang Chi;Lv Linyan;Guo Zexin;Deng Cuncan;Li Yanqing;Liang Xiaoyan;Deng Chunhua;Sun Xiangzhou;Liu Guihua
生育能力的保持是育龄男性癌症幸存者普遍关心的问题。然而，除了睾丸组织冷冻保存，这是不是很有效，有没有可行的和精确的治疗方法能够保护青春期前男孩的精子发生之前或期间的性腺毒性治疗。本研究旨在探讨抑制精原干细胞（SSC）坏死凋亡在生育力保存中的作用。使用12周龄雄性小鼠，通过两次腹腔注射总剂量为40 mg kg−1的白消安来确定性腺毒性。利用小鼠模型和原代培养的小鼠精原干细胞研究精原干细胞坏死性凋亡与性腺毒性的关系。同时，在白消安诱导的性腺毒性小鼠模型中，在第36天观察了坏死性凋亡通路抑制剂RIPA-56的作用。我们发现，SSC的数量减少，但在白消安治疗后第18天，性腺毒性小鼠睾丸的坏死性凋亡水平上调。在原代培养细胞中的进一步实验表明，在白消安处理的SSC中，坏死性凋亡引起细胞死亡，并且可以被RIPA-56抑制。在抑制SSC的坏死性凋亡后，白消安诱导的小鼠的生精细胞损失减少，如组织学所示，并且Johnsen评分增加。此外，用RIPA-56干预后，SSC和附睾精子的数量恢复，表明通过靶向接受白消安治疗的小鼠中SSC的坏死性凋亡而产生一系列有益效果。总之，我们的研究结果表明，SSCs的坏死性凋亡在白消安诱导的性腺毒性中起着至关重要的作用，并可能是男性生育力保护的潜在目标。
Fertility preservation is a common concern for male cancer survivors of reproductive age. However, except for testicular tissue cryopreservation, which is not very effective, there is no feasible and precise therapy capable of protecting spermatogenesis for prepubertal boys before or during gonadotoxic treatment. This study aims to investigate the effects of inhibiting necroptosis of spermatogonial stem cell (SSC) in fertility preservation. Male mice 12 weeks of age were used to establish gonadotoxicity with two intraperitoneal injections of busulfan at a total dose of 40 mg kg−1. The mouse model and the primary cultured mouse SSCs were used to characterize the relationship between necroptosis of SSC and gonadotoxicity. Meanwhile, the effects of an inhibitor of necroptosis pathway, RIPA-56, were observed on day 36 in the mouse model of busulfan-induced gonadotoxicity. We found that the number of SSCs was decreased, but the level of necroptosis was upregulated on day 18 after busulfan treatment in testes from gonadotoxic mice. Further experiments in primary cultured cells showed that the necroptosis caused cell death in busulfan-treated SSCs and could be inhibited by RIPA-56. After suppressing the necroptosis of SSCs, the busulfan-induced mice had a decreased loss of spermatogenic cells as shown by histology and an increased Johnsen's score. Moreover, the quantities of SSCs and epididymal spermatozoa were restored after intervention with RIPA-56, indicating a series of beneficial effects by targeting the necroptosis of SSCs in mice undergoing busulfan treatment. In conclusion, our findings reveal that the necroptosis of SSCs plays a critical role in busulfan-induced gonadotoxicity and may be a potential target for male fertility preservation.