title: Activation of innate immunity is required for efficient nuclear reprogramming.
abstract: Retroviral overexpression of reprogramming factors (Oct4, Sox2, Klf4, c-Myc) generates induced pluripotent stem cells (iPSCs). However, the integration of foreign DNA could induce genomic dysregulation. Cell-permeant proteins (CPPs) could overcome this limitation. To date, this approach has proved exceedingly inefficient. We discovered a striking difference in the pattern of gene expression induced by viral versus CPP-based delivery of the reprogramming factors, suggesting that a signaling pathway required for efficient nuclear reprogramming was activated by the retroviral, but not CPP approach. In gain- and loss-of-function studies, we find that the toll-like receptor 3 (TLR3) pathway enables efficient induction of pluripotency by viral or mmRNA approaches. Stimulation of TLR3 causes rapid and global changes in the expression of epigenetic modifiers to enhance chromatin remodeling and nuclear reprogramming. Activation of inflammatory pathways are required for efficient nuclear reprogramming in the induction of pluripotency.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, CA 94305, USA.
authors.forename: Jieun
authors.initials: J
authors.lastname: Lee
authors.forename: Nazish
authors.initials: N
authors.lastname: Sayed
authors.forename: Arwen
authors.initials: A
authors.lastname: Hunter
authors.forename: Kin Fai
authors.initials: KF
authors.lastname: Au
authors.forename: Wing H
authors.initials: WH
authors.lastname: Wong
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
authors.forename: Renee Reijo
authors.initials: RR
authors.lastname: Pera
authors.forename: Eduard
authors.initials: E
authors.lastname: Yakubov
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D002460:Cell Line; D057846:Cell-Penetrating Peptides / Q000378:metabolism*; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D016328:NF-kappa B / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D016328:NF-kappa B; D050814:Octamer Transcription Factor-3; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3