Heritable Imprinting Defect Caused by Epigenetic Abnormalities in Mouse Spermatogonial Stem Cells
Heritable Imprinting Defect Caused by Epigenetic Abnormalities in Mouse Spermatogonial Stem Cells
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DOI：
10.1095/biolreprod.108.072330
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发表时间：
2009-03-01
影响因子：
3.6
通讯作者：
Shinohara, Takashi
中科院分区：
文献类型：
--
作者：
Lee, Jiyoung;Kanatsu-Shinohara, Mito;Shinohara, Takashi
男性生殖细胞在胎儿发育过程中经历动态表观遗传重编程，最终建立精原干细胞（SSC），可以转化为多能干细胞。然而，对胎儿生殖细胞的发育潜力以及它们如何成熟为SSCs知之甚少。我们开发了一种培养系统，用于长时间增殖的胎儿生殖细胞。胚胎发育12.5-18.5天的雄性生殖细胞可以通过胶质细胞源性神经营养因子（一种精原干细胞的自我更新因子）扩增。这些细胞没有形成畸胎瘤，但重新填充曲细精管，并产生精子发生，表现出精原细胞的潜力。然而，培养细胞的后代显示出生长异常，基因组印记有缺陷。这种印记缺陷在雄性和雌性生殖系中至少持续了四代。此外，后代的生殖细胞显示出异常的组蛋白修饰和DNA甲基化模式。这些结果表明，胎儿生殖细胞具有有限的能力，成为多能细胞，并失去了能力，通过体外培养进行表观遗传重编程。
Male germ cells undergo dynamic epigenetic reprogramming during fetal development, eventually establishing spermatogonial stem cells (SSCs) that can convert into pluripotent stem cells. However, little is known about the developmental potential of fetal germ cells and how they mature into SSCs. We developed a culture system for fetal germ cells that proliferate for long periods of time. Male germ cells from embryos 12.5-18.5 days postcoitum could expand by glial cell line-derived neurotrophic factor, a self-renewal factor for SSCs. These cells did not form teratomas, but repopulated seminiferous tubules and produced spermatogenesis, exhibiting spermatogonia potential. However, the offspring from cultured cells showed growth abnormalities and were defective in genomic imprinting. The imprinting defect persisted in both the male and female germlines for at least four generations. Moreover, germ cells in the offspring showed abnormal histone modifications and DNA methylation patterns. These results indicate that fetal germ cells have a limited ability to become pluripotent cells and lose the ability to undergo epigenetic reprogramming by in vitro culture.