Attenuated Innate Immunity in Embryonic Stem Cells and Its Implications in Developmental Biology and Regenerative Medicine

Abstract

Embryonic stem cells (ESCs) represent a promising cell source for regenerative medicine. Intensive research over the past two decades has led to the feasibility of using ESC-differentiated cells (ESC-DCs) in regenerative medicine. However, increasing evidence indicates that ESC-DCs generated by current differentiation methods may not have equivalent cellular functions to their in vivo counterparts. Recent studies have revealed that both human and mouse ESCs as well as some types of ESC-DCs lack or have attenuated innate immune responses to a wide range of infectious agents. These findings raise important concerns for their therapeutic applications since ESC-DCs, when implanted to a wound site of a patient, where they would likely be exposed to pathogens and inflammatory cytokines. Understanding whether an attenuated immune response is beneficial or harmful to the interaction between host and grafted cells becomes an important issue for ESC-based therapy. A substantial amount of recent evidence has demonstrated that the lack of innate antiviral responses is a common feature to ESCs and other types of pluripotent cells. This has led to the hypothesis that mammals may have adapted different antiviral mechanisms at different stages of organismal development. The underdeveloped innate immunity represents a unique and uncharacterized property of ESCs that may have important implications in developmental biology, immunology and in regenerative medicine.

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

“…Our data from hESCs clearly illustrate that they are similar to mESCs in the lack of NFκB activation and inflammatory response to LPS and TNFα. These results are also in accordance with the fact that both mESCs and hESCs are deficient in the expression of type I IFN in antiviral response, which is an NFκB-dependent process (10). Considering the highly conserved role of NFκB in innate immunity among different species of vertebrates (40), our findings suggest that the lack of NFκB activation in response to immune and inflammatory stimuli is likely an intrinsic property of both hESCs and mESCs.…”

“…Many other functions, such as innate immunity, cannot be assessed unless the cells are exposed to pathogens. Recent studies have reported that several major tissue cell types differentiated from both human and mouse ESCs have limited innate immune response to various pathogens and cytokines (4–9), highlighting the potential functional deficiency of in vitro ESC-differentiated cells, as we have recently discussed (10). …”

“…Our recent studies in mouse ESCs (mESCs) (16–18) and those from other investigators in human ESCs (hESCs) and in induced pluripotent stem cells (iPSCs) (19,20) demonstrated that the IFN system, the central component of innate antiviral immunity in differentiated somatic cells (21), is not fully developed in these cells. Therefore, the lack of innate immune responses to both bacterial and viral infection appears to be an intrinsic property of all pluripotent stem cells (10). …”

Development of Antiviral Innate Immunity During In Vitro Differentiation of Mouse Embryonic Stem Cells

“…Therefore, the IFN system, which is the central part of innate immunity in differentiated somatic cells [14], is not fully functional in ESCs. Together with the similar findings in induced pluripotent stem cells [15] and embryonal carcinoma [16], an underdeveloped antiviral innate immunity represents an intrinsic property of all pluripotent cells (reviewed in Guo et al [17]). …”

“…The underdeveloped innate immunity has been recently characterized as a unique property of pluripotent cells as we have recently discussed (reviewed in Guo et al [17]). Since most types of somatic cells have an effective innate immune system, the attenuated immune and inflammatory responses reported in several ESC-derived tissue cells [3][4][5][6] raise the question of whether the commonly used in vitro differentiation methods can generate cells with competent innate immunity like in vivo differentiated cells.…”