The Molecular Basis for the Lack of Inflammatory Responses in Mouse Embryonic Stem Cells and Their Differentiated Cells

• Published in: The Journal of immunology (1950) 2017-03, Vol.198 (5), p.2147-2155
• Main Authors: D'Angelo, William, Gurung, Chandan, Acharya, Dhiraj, Chen, Bohan, Ortolano, Natalya, Gama, Vivian, Bai, Fengwei, Guo, Yan-Lin
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Chikungunya Fever - immunology; Chikungunya virus - immunology; Developmental biology; Embryo cells; Embryo fibroblasts; Embryogenesis; Embryonic Stem Cells - physiology; Embryos; Fibroblasts; Immunity; Immunology; Infections; Inflammation; Inflammation - immunology; Inflammatory response; Innate immunity; Interferon; Interferons - metabolism; Lipopolysaccharides; Lipopolysaccharides - immunology; Mice; Mice, Inbred DBA; NF-kappa B - metabolism; NF-κB protein; RAW 264.7 Cells; Regenerative medicine; Somatic cells; Stem cell transplantation; Stem cells; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α; Viral infections; Virus Diseases - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601068

We reported previously that mouse embryonic stem cells do not have a functional IFN-based antiviral mechanism. The current study extends our investigation to the inflammatory response in mouse embryonic stem cells and mouse embryonic stem cell-differentiated cells. We demonstrate that LPS, TNF-α, and viral infection, all of which induce robust inflammatory responses in naturally differentiated cells, failed to activate NF-κB, the key transcription factor that mediates inflammatory responses, and were unable to induce the expression of inflammatory genes in mouse embryonic stem cells. Similar results were obtained in human embryonic stem cells. In addition to the inactive state of NF-κB, the deficiency in the inflammatory response in mouse embryonic stem cells is also attributed to the lack of functional receptors for LPS and TNF-α. In vitro differentiation can trigger the development of the inflammatory response mechanism, as indicated by the transition of NF-κB from its inactive to active state. However, a limited response to TNF-α and viral infection, but not to LPS, was observed in mouse embryonic stem cell-differentiated fibroblasts. We conclude that the inflammatory response mechanism is not active in mouse embryonic stem cells, and in vitro differentiation promotes only partial development of this mechanism. Together with our previous studies, the findings described in this article demonstrate that embryonic stem cells are fundamentally different from differentiated somatic cells in their innate immunity, which may have important implications in developmental biology, immunology, and embryonic stem cell-based regenerative medicine.