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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.

Recombination activating gene-2null severe combined immunodeficient pigs and mice engraft human induced pluripotent stem cells differently