Attenuated Innate Immunity in Mouse Embryonic Stem Cells as a Self‐Protective Mechanism for Early Embryogenesis

Abstract

Embryonic stem cells (ESCs) have been intensively studied as a promising cell source for regenerative medicine. However, their immunological property is an important yet poorly understood issue in the therapeutic application of ESCs and in developmental biology. Innate immune responses are critical defense mechanisms that are well‐developed in somatic cells, however, a series of our recent studies demonstrated that ESCs are deficient in innate immune responses to viral/bacterial infections and inflammatory cytokines. These findings raised an intriguing question about the rationale for ESCs, the progenitors of all tissue cells, to not have an innate immunity that has adapted so well in somatic cells. Immune and inflammatory responses have been viewed as a double‐edged sword. On the one hand, they defend the organism against pathogens; on the other hand, they can cause collateral damage to the tissue cells, such as cell cycle inhibition and even cell death. From this perspective, we hypothesize that the attenuated innate immunity could be a self‐protective mechanism for ESCs to avoid the cytotoxic effect of immune/inflammatory responses. To test this hypothesis, we differentiated ESCs to fibroblast‐like cells (ESC‐FBs), which have gained partial innate immunity. In comparative analyses, we exposed ESCs and ESC‐FBs to several inflammatory conditions, including inflammatory cytokines (TNFα and IFNγ), lipopolysaccharide (LPS), the conditioned medium collected from LPS‐stimulated macrophages, and heat killed bacteria. The effects were assessed by cell viability analysis and the induction of inflammatory genes. In all conditions tested, ESCs were less susceptible to the cytotoxic effects of the inflammatory insults and showed diminished induction of inflammatory genes than ESC‐FBs. At the molecular level, the signaling pathways that mediate the effects of LPS, TNFα and IFNγ are mostly defective in ESCs. We conclude that the attenuated innate immune responses could be an adaptive mechanism for ESCs to avoid the cytotoxicity caused by immune reactions resulting from embryo implantation or pathogen infection at the early stage of embryogenesis.Support or Funding InformationThis work was supported by National Institutes of Health Grants R15GM109299 and R15GM128196 (to Y‐L. G.). We thank Mississippi‐INBRE for the use of the imaging facility, funded by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103476This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.