The Underdeveloped Innate Immunity in Embryonic Stem Cells: The Molecular Basis and Biological Perspectives from Early Embryogenesis

Embryonic stem cells (ESCs) have been intensively studied as a promising cell source for regenerative medicine. The rapid advancements in the field have not only proven the feasibility of ESC-based cell therapy, but also led to a better understanding of pluripotent stem cells (PSCs) as a unique cell population at an early stage of embryogenesis. Recent studies have revealed that both human and mouse ESCs have attenuated innate immune responses to infectious agents and inflammatory cytokines. These findings raise interesting questions about the rationale for ESCs, the PSCs experimentally derived from preimplantation stage embryos, to not have an innate defense mechanism that has been adapted so well in somatic cells. All somatic cells have innate immune systems that can be activated by pathogen-associated molecular patterns (PAMPs) or cellular damage-associated molecular patterns (DAMPs), leading to production of cytokines. The underdeveloped innate immunity represents a unique property of PSCs that may have important implications. This review discusses the immunological properties of PSCs, the molecular basis underlying their diminished innate immune responses, and the hypothesis that the attenuated innate immune responses could be an adaptive mechanism that allows PSCs to avoid cytotoxicity associated with inflammation and immune responses during early embryogenesis.