Pluripotent stem cells are insensitive to the cytotoxicity of TNFα and IFNγ.

Recent studies have demonstrated that embryonic stem cells (ESCs) have an underdeveloped innate immune system, but the biological implications of this finding are poorly understood. In this study, we compared the responses of mouse ESCs (mESCs) and mESC differentiated fibroblasts (mESC-FBs) to tumor necrosis factor alpha (TNF alpha) and interferons (IFNs). Our data revealed that TNF alpha, IFN alpha, IFNI), or IFN gamma alone do not cause apparent effects on mESCs and mESC-FBs, but the combination of TNF alpha and IFN gamma (TNF alpha/ IFN gamma) showed toxicity to mESC-FBs as indicated by cell cycle inhibition and reduced cell viability, correlating with the expression of inducible nitric oxide synthase (iNOS). However, none of these effects were observed in mESCs that were treated with TNF alpha/IFN gamma. Furthermore, mESC-FBs, but not mESCs, are vulnerable to cytotoxicity resulting from lipopolysaccharide (LPS)-activated macrophages. The insensitivity of mESCs to cytotoxicity in all cases is correlated with their lack of responses to TNF alpha and IFN gamma. Similar to mESCs, human ESCs (hESCs) and iPSCs (hiPSCs) do not respond to TNF alpha and are not susceptible to the cytotoxicity of TNF alpha, IFN beta, or IFN gamma alone or in combination that significantly affects human foreskin fibroblast (hFBs) and Hela cells. However, unlike mESCs, hESCs and hiPSCs can respond to IFN gamma, but this does not cause significant cytotoxicity in hESCs and hiPSCs. Our findings in both mouse and human PCS together support the hypothesis that attenuated innate immune responses could be a protective mechanism that limits immunologic cytotoxicity resulting from inflammatory and immune responses.