Adeno-associated-virus-mediated gene delivery to ovaries restores fertility in congenital infertile mice.
Adeno-associated-virus-mediated gene delivery to ovaries restores fertility in congenital infertile mice.
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DOI：
10.1016/j.xcrm.2022.100606
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发表时间：
2022-05-17
影响因子：
14.3
通讯作者：
Shinohara, Takashi
中科院分区：
文献类型：
--
作者：
Kanatsu-Shinohara, Mito;Lee, Jiyoung;Miyazaki, Takehiro;Morimoto, Hiroko;Shinohara, Takashi
卵母细胞和颗粒细胞在卵泡发育过程中密切相互作用，它们之间缺乏适当的信号传导会导致不孕。血卵泡屏障（BFB）的不渗透性阻碍了对卵母细胞微环境的调控。为了建立一种操纵卵子发生的策略，我们使用腺相关病毒（AAV），它具有独特的转胞吞能力。将AAV显微注射到卵巢基质中穿透BFB并实现长期基因表达。引入携带小鼠Kitl基因的AAV恢复先天性不育KitlSl-t/KitlSl-t突变小鼠卵巢中的卵子发生，所述卵巢缺乏Kitl表达但仅含有原始卵泡。没有AAV整合的健康后代通过自然交配出生。因此，AAV介导的基因递送不仅提供了一种通过操纵卵母细胞微环境来研究卵母细胞-颗粒相互作用的手段，而且也可能是治疗由体细胞缺陷引起的女性不育症的有力方法。AAVs可以穿透血卵泡屏障并感染颗粒细胞AAVs挽救由颗粒缺陷引起的先天性不育症在后代的基因组中没有发现转基因整合后代显示正常的基因组印记模式Kanatsu-Shinohara et al.引入基因疗法治疗由颗粒层缺陷引起的先天性女性不育症。AAV穿透血卵泡屏障并感染颗粒细胞，而不整合到后代的基因组中。研究结果为开发治疗人类不育症的技术提供了依据。
Oocytes and granulosa cells closely interact with each other during follicular development, and a lack of appropriate signaling between them results in infertility. Attempts to manipulate oocyte microenvironment have been impeded by the impermeability of the blood-follicle barrier (BFB). To establish a strategy for manipulating oogenesis, we use adeno-associated viruses (AAVs), which have a unique ability of transcytosis. Microinjecting of AAVs into the ovarian stroma penetrates the BFB and achieves long-term gene expression. Introduction of an AAV carrying the mouse Kitl gene restores oogenesis in congenitally infertile KitlSl-t/KitlSl-t mutant mouse ovaries, which lack Kitl expression but contain only primordial follicles. Healthy offspring without AAV integration are born by natural mating. Therefore, AAV-mediated gene delivery not only provides a means for studying oocyte-granulosa interactions through the manipulation of the oocyte microenvironment but could also be a powerful method to treat female infertility resulting from somatic cell defects. AAVs can penetrate the blood-follicle barrier and infect granulosa cells AAVs rescue congenital infertility resulting from a granulosa defect No transgene integration is found in the genome of the offspring Offspring show normal genomic imprinting patterns Kanatsu-Shinohara et al. introduce a gene therapy for the treatment of congenital female infertility resulting from a granulosa defect. AAVs penetrate the blood-follicle barrier and infect granulosa cells without integration into the genome of the offspring. Results provide a basis of developing technologies for the treatment of human infertility.
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3.1
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