ABSTRACT Problem We recently reported that trophoblast stem cells (TSCs) and TSC‐differentiated trophoblasts (TSC‐TBs) do not respond to TNFα. This immunological property enables these cells to avoid the cytotoxic effects induced by the combination of TNFα and IFNγ. The goal of this study is to elucidate the molecular basis for the unresponsiveness of TSCs and TSC‐TBs to TNFα and assess the functionality of TNFα signaling pathways in these cells. Method We compared the responses of TSCs and TSC‐TBs to TNFα with those of mouse embryonic fibroblasts (MEFs). Genome‐wide transcriptomic profiling was performed using RNA‐seq data, including the TNFα signaling pathway, TNFα‐induced expression of NFκB target genes, and the transcriptional changes and functional pathway enrichment associated with TSC differentiation. Results The data provide a comprehensive view of TNFα‐induced NFκB activation and the subsequent induction of NFκB target genes with diverse functions. In MEFs, TNFα upregulates or downregulates the transcription of numerous NFκB target genes, but it has little to no effect on gene expression in TSCs and TSC‐TBs. Nevertheless, many NFκB target genes essential for shared or cell type‐specific functions are expressed in TSCs and TSC‐TBs and are regulated in a cell type‐specific manner. Conclusions The results provide the molecular basis for the lack of TNFα‐induced inflammatory responses in TSCs and TSC‐TBs. They also suggest that TSCs and TSC‐TBs have evolved mechanisms to avoid the cytotoxic effects associated with TNFα‐induced inflammation response, while still permitting the expression of other NFκB target genes essential for their cellular functions.
Bae et al. (Thu,) studied this question.