Ramathal Cyril, Durruthy-Durruthy Jens, Sukhwani Meena, Arakaki Joy E, Turek Paul J, Orwig Kyle E, Reijo Pera Renee A
Institute for Stem Cell Biology & Regenerative Medicine, Departments of Genetics and Obstetrics and Gynecology, Stanford University, Stanford, CA 94305, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh PA 15213.
Cell Rep. 2014 May 22;7(4):1284-97. doi: 10.1016/j.celrep.2014.03.067. Epub 2014 May 1.
Historically, spontaneous deletions and insertions have provided means to probe germline developmental genetics in Drosophila, mouse and other species. Here, induced pluripotent stem cell (iPSC) lines were derived from infertile men with deletions that encompass three Y chromosome azoospermia factor (AZF) regions and are associated with production of few or no sperm but normal somatic development. AZF-deleted iPSC lines were compromised in germ cell development in vitro. Undifferentiated iPSCs transplanted directly into murine seminiferous tubules differentiated extensively to germ-cell-like cells (GCLCs) that localized near the basement membrane, demonstrated morphology indistinguishable from fetal germ cells, and expressed germ-cell-specific proteins diagnostic of primordial germ cells. Alternatively, all iPSCs that exited tubules formed primitive tumors. iPSCs with AZF deletions produced significantly fewer GCLCs in vivo with distinct defects in gene expression. Findings indicate that xenotransplantation of human iPSCs directs germ cell differentiation in a manner dependent on donor genetic status.
从历史上看，自发缺失和插入为探究果蝇、小鼠及其他物种的生殖系发育遗传学提供了手段。在此，诱导多能干细胞（iPSC）系源自患有缺失的不育男性，这些缺失涵盖三个Y染色体无精子症因子（AZF）区域，与极少产生精子或不产生精子但体细胞发育正常有关。AZF缺失的iPSC系在体外生殖细胞发育方面存在缺陷。直接移植到小鼠曲细精管中的未分化iPSC广泛分化为定位于基底膜附近的类生殖细胞（GCLC），其形态与胎儿生殖细胞无异，并表达诊断原始生殖细胞的生殖细胞特异性蛋白。另外，所有从小管中出来的iPSC都会形成原始肿瘤。具有AZF缺失的iPSC在体内产生的GCLC明显较少，且基因表达存在明显缺陷。研究结果表明，人类iPSC的异种移植以依赖供体遗传状态的方式指导生殖细胞分化。
