TY - JOUR
T1 - Type I interferon response impairs differentiation potential of pluripotent stem cells
AU - Eggenberger, Julie
AU - Blanco-Melo, Daniel
AU - Panis, Maryline
AU - Brennand, Kristen J.
AU - Ten Oever, Benjamin R.
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
PY - 2019/1/22
Y1 - 2019/1/22
N2 - 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.
AB - 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.
KW - IRF7
KW - Interferon
KW - KLF4
KW - Pluripotency
KW - Virus
UR - http://www.scopus.com/inward/record.url?scp=85060303296&partnerID=8YFLogxK
U2 - 10.1073/pnas.1812449116
DO - 10.1073/pnas.1812449116
M3 - Article
C2 - 30606801
AN - SCOPUS:85060303296
SN - 0027-8424
VL - 116
SP - 1384
EP - 1393
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
ER -