Kevin Eggan2014-02-27 11:53 AM

Derivation of induced pluripotent stem cells from the baboon: a nonhuman primate model for preclinical testing of stem cell therapies. 对狒狒诱导多能干细胞的推导:干细胞疗法临床前试验的非人灵长类动物模型

Abstract

Development of effective pluripotent stem cell-based therapies will require safety and efficacy testing in a clinically relevant preclinical model such as nonhuman primates (NHPs). Baboons and macaques are equally similar to humans genetically and both have been extensively used for biomedical research. Macaques are preferred for human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) research whereas baboons are preferred for transplantation studies because of the greater similarity of their anatomy and immunogenetic system to those of humans. We generated four induced pluripotent stem cell (iPSC) lines from skin cells of the olive baboon (Papio anubis). Each line shows the distinct morphology of primate pluripotent stem cells, including flat colonies with well-defined borders and a high nuclear/cytoplasm ratio. Each is positive for the pluripotency markers OCT4, SOX2, NANOG, and SSEA4. Pluripotency was confirmed in two lines by teratoma formation with representative tissues from each germ layer, whereas a third produced cells from all three germ layers following embryoid body differentiation. Three lines have a normal male karyotype and the fourth is missing the short arm of one copy of chromosome 18. This may serve as an in vitro model for the human developmental disorder 18p-, which impacts 1 in 50,000 births/year. These iPSC lines represent the first step toward establishing the baboon as a NHP model for developing stem cell-based therapies.


论文摘要

基于多能性干细胞的有效疗法的发展要求具有临床相关的临床前模型如非人类灵长类动物(NHPS)的安全有效性测试。狒狒和猕猴在基因上均与人类近似且被广泛用于生物医学研究。由于他们在解剖和免疫遗传系统上与人体具有更大相似性,我们将猕猴作为人类免疫缺陷病毒/获得性免疫缺陷综合症(HIV / AIDS)研究的首选,而狒狒则成为移植研究的首选试验动物。我们从黄褐色狒狒(东非狒狒)皮肤细胞中生成了四种诱导多能干细胞(iPSC)系。每种系显示了包括具有良好定义边界和高核/浆比例的平板菌落在内的灵长类多能干细胞的不同形态且对多潜能标志物OCT4SOX2NANOGSSEA4都呈现阳性。多能性通过每一胚层具有代表性组织的畸胎瘤的形成而在两种系中得到证实,而产生自所有三个胚层的第三类细胞则遵循拟胚体分化。三类系具有正常男性染色体核型而第四类系则丢失了18号染色体副本的短臂。这可作为人类发育障碍18P-的体外模型,该疾病的每年出生缺陷率达 150,000。这些iPSC系代表着人类致力于完善基于干细胞治疗方法的发展而将狒狒确立为NHP模型所迈出的第一步。

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Kevin Eggan

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