Li Jing, Kawamura Kazuhiro, Cheng Yuan, Liu Shuang, Klein Cynthia, Liu Shu, Duan En-Kui, Hsueh Aaron J W
Department of Obstetrics and Gynecology, Program of Reproductive and Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305-5317, USA.
Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10280-4. doi: 10.1073/pnas.1001198107. Epub 2010 May 17.
Although multiple follicles are present in mammalian ovaries, most of them remain dormant for years or decades. During reproductive life, some follicles are activated for development. Genetically modified mouse models with oocyte-specific deletion of genes in the PTEN-PI3K-Akt-Foxo3 pathway exhibited premature activation of all dormant follicles. Using an inhibitor of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) phosphatase and a PI3K activating peptide, we found that short-term treatment of neonatal mouse ovaries increased nuclear exclusion of Foxo3 in primordial oocytes. After transplantation under kidney capsules of ovariectomized hosts, treated follicles developed to the preovulatory stage with mature eggs displaying normal epigenetic changes of imprinted genes. After in vitro fertilization and embryo transfer, healthy progeny with proven fertility were delivered. Human ovarian cortical fragments from cancer patients were also treated with the PTEN inhibitor. After xeno-transplantation to immune-deficient mice for 6 months, primordial follicles developed to the preovulatory stage with oocytes capable of undergoing nuclear maturation. Major differences between male and female mammals are unlimited number of sperm and paucity of mature oocytes. Thus, short-term in vitro activation of dormant ovarian follicles after stimulation of the PI3K-Akt pathway allows the generation of a large supply of mature female germ cells for future treatment of infertile women with a diminishing ovarian reserve and for cancer patients with cryo-preserved ovaries. Generation of a large number of human oocytes also facilitates future derivation of embryonic stem cells for regenerative medicine.
尽管哺乳动物卵巢中存在多个卵泡，但大多数卵泡会休眠数年或数十年。在生殖期，一些卵泡会被激活以进行发育。在PTEN-PI3K-Akt-Foxo3通路中具有卵母细胞特异性基因缺失的基因编辑小鼠模型表现出所有休眠卵泡的过早激活。使用10号染色体缺失的张力蛋白同源磷酸酶（PTEN）磷酸酶抑制剂和PI3K激活肽，我们发现对新生小鼠卵巢进行短期处理可增加原始卵母细胞中Foxo3的核排除。在移植到去卵巢宿主的肾包膜下后，处理过的卵泡发育到排卵前阶段，成熟卵子显示出印记基因正常的表观遗传变化。经过体外受精和胚胎移植后，产下了具有生育能力的健康后代。癌症患者的人卵巢皮质碎片也用PTEN抑制剂进行了处理。在异种移植到免疫缺陷小鼠6个月后，原始卵泡发育到排卵前阶段，卵母细胞能够进行核成熟。雄性和雌性哺乳动物的主要区别在于精子数量无限而成熟卵母细胞数量稀少。因此，在刺激PI3K-Akt通路后对休眠卵巢卵泡进行短期体外激活，可以产生大量成熟的雌性生殖细胞，用于未来治疗卵巢储备减少的不孕妇女以及卵巢被冷冻保存的癌症患者。大量人类卵母细胞的产生也有助于未来再生医学中胚胎干细胞的衍生。
