Recombination activating gene-2(null) severe combined immunodeficient pigs and mice engraft human induced pluripotent stem cells differently.
Recombination activating gene-2(null) severe combined immunodeficient pigs and mice engraft human induced pluripotent stem cells differently.
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DOI：
10.18632/oncotarget.20626
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发表时间：
2017-09-19
期刊：
影响因子：
--
通讯作者：
Kim JH
中科院分区：
文献类型：
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作者：
Choi YJ;Kim E;Reza AMMT;Hong K;Song H;Park C;Cho SK;Lee K;Prather RS;Kim JH
本研究比较研究了严重联合免疫缺陷（SCID）小鼠和猪模型免疫紊乱的转录、生理和表型差异。我们发现重组激活基因2 (Rag-2) SCID小鼠，而不是Rag-2 SCID猪，分别表现出强烈、不频繁和轻度的CD3+-、CD4+-和CD8+信号聚集，这表明存在不同的物种特异性效应。此外，6个相关基因（NFATC1、CD79B、CD2、BLNK、FOXO1和CD40）的表达比rag2 SCID小鼠更下调，这为rag2 SCID猪淋巴器官T/B细胞死亡而rag2 SCID小鼠T/B细胞死亡提供了部分原因。此外，NK细胞成熟相关基因在rag2 SCID猪中的表达明显低于rag2 SCID小鼠。一致地，rag2 SCID猪，而不是rag2 SCID小鼠，产生了与穿孔素/ rag2 SCID小鼠相同的人类诱导的多能干细胞来源的畸胎瘤。因此，这些意想不到的发现表明，rag2 SCID猪比rag2 SCID小鼠更适合作为研究人类疾病的模型。
This study comparatively investigated the transcriptional, physiological, and phenotypic differences of the immune disorder between severe combined immunodeficient (SCID) mouse and pig models. We discovered that the recombination activating gene-2 (Rag-2) SCID mice, but not RAG-2 SCID pigs, showed intense, infrequent, and mild cluster of CD3+-, CD4+-, and CD8+ signals respectively, suggesting that distinct species-specific effects exist. Furthermore, the expression of six relevant genes (NFATC1, CD79B, CD2, BLNK, FOXO1, and CD40) was more downregulated than that in the Rag-2 SCID mice, which provides a partial rationale for the death of T/B cells in the lymphoid organs of RAG-2 SCID pigs but not in Rag-2 SCID mice. Further, NK cell maturation-related gene expression was significantly lower in RAG-2 SCID pigs than in Rag-2 SCID mice. Consistently, the RAG-2 SCID pigs, but not Rag-2 SCID mice, developed human induced pluripotent stem cell-derived teratomas that were the same as those of perforin/Rag-2 SCID mice. Therefore, these unexpected findings indicate the superiority of RAG-2 SCID pigs over Rag-2 SCID mice as a suitable model for investigating human diseases.