The underdeveloped innate immunity in embryonic stem cells: The molecular basis and biological perspectives from early embryogenesis

Abstract

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.

Single and repeated intra‐articular injections in the tarsocrural joint with allogeneic and autologous equine bone marrow‐derived mesenchymal stem cells are safe, but did not reduce acute inflammation in an experimental interleukin‐1β model of synovitis

“…IL‐1β is a cytokine produced by joint tissues (unlike LPS); therefore, the rIL‐1β model may be more clinically relevant . In addition, MSCs derived from various tissues may respond differently to inflammation . BMDMSCs are commonly used in equine practice.…”

Dicer represses the interferon response and the double-stranded RNA-activated protein kinase pathway in mouse embryonic stem cells

“…While this could be tolerated by tissues of developed organisms, it could cause serious damage to ESCs in an early embryo. From this perspective, an attenuated immunological response could serve as a self-protective mechanism in ESCs by minimizing immunological cytotoxicity at early stages of embryogenesis ( 8 ). From the perspective of ESC biology, IFN response does not appear to be compatible with the pluripotency of ESCs, as demonstrated by a recent study showing that forced activation of the IFN pathway can cause dysregulation of many pluripotency- and lineage-specific genes in ESCs ( 9 ).…”

ATP-binding cassette protein ABCF1 couples gene transcription with maintenance of genome integrity in embryonic stem cells

“…While ES cells do express other known DNA sensors (e.g. cGAS and STING, data not shown) that in theory can detect intracellular DNAs from infection and DNA damage, their downstream signaling pathways required to activate a robust pro-inflammatory response are absent or highly attenuated, in part due to active suppression by stem cell transcription factors including OCT4 and SOX2 (Eggenberger et al, 2019;Guo, 2019). Nonetheless, studies have indicated that ES cells are hypersensitive to DNA damage and readily undergo differentiation and apoptosis (Aladjem et al, 1998;Heyer et al, 2000).…”

“…These cytokines in turn promote the apoptosis and clearance of the affected cells (Jorgensen et al, 2017). Yet, this canonical innate immune pathway is severely attenuated in ES cells and essentially rendered inactive (Guo, 2019). A suppressed innate immune system also suggests that ES cells may lack an effective defense system against pathogen infections.…”

“…Our findings reveal that ABCF1 directly couples sensing of genome instability and infections to the pluripotency gene network through its LCD. Given that the canonical innate immune pathway is severely suppressed in ES cells ( 28, 29 ), leveraging an innate immune DNA sensor such as ABCF1 as transcriptional coactivator could provide a means for ES cells to respond to these cellular insults and maintain a pristine pool of progenitors as they self-renew.…”