Type I interferon response impairs differentiation potential of pluripotent stem cells

Julie Eggenberger, Daniel Blanco-Melo, Maryline Panis, Kristen J. Brennand, Benjamin R. Ten Oever

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Upon virus infection, pluripotent stem cells neither induce nor respond to canonical type I interferons (IFN-I). To better understand this biology, we characterized induced pluripotent stem cells (iPSCs) as well as their differentiated parental or rederived counterparts. We confirmed that only iPSCs failed to respond to viral RNA, IFN-I, or viral infection. This lack of response could be phenocopied in fibroblasts with the expression of a reprogramming factor which repressed the capacity to induce canonical antiviral pathways. To ascertain the consequences of restoring the antiviral response in the context of pluripotency, we engineered a system to engage these defenses in iPSCs. Inducible expression of a recombinant virus-activated transcription factor resulted in the successful reconstitution of antiviral defenses through the direct up-regulation of IFN-I–stimulated genes. Induction of the antiviral signature in iPSCs, even for a short duration, resulted in the dys-regulation of genes associated with all three germ layers despite maintaining pluripotency markers. Trilineage differentiation of these same cells showed that engagement of the antiviral defenses compromised ectoderm and endoderm formation and dysregulated the development of mesodermal sublineages. In all, these data suggest that the temporal induction of the antiviral response primes iPSCs away from pluripotency and induces numerous aberrant gene products upon differentiation. Together these results suggest that the IFN-I system and pluripotency may be incompatible with each other and thus explain why stem cells do not utilize the canonical antiviral system.

Original languageEnglish
Pages (from-to)1384-1393
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number4
DOIs
StatePublished - 22 Jan 2019

Keywords

  • IRF7
  • Interferon
  • KLF4
  • Pluripotency
  • Virus

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