Activation of Innate Immunity Is Required for Efficient Nuclear Reprogramming

• Type of Material: Article
• Authors: Jieun Lee, Stanford University; Nazish Sayed, Stanford University; Arwen Hunter, Stanford University; Kin Fai Au, Stanford University; Wing H. Wong, Stanford University; Edward S Mocarski, Emory University; Renee Reijo Pera, Stanford University; Eduard Yakubov, Stanford University; John P. Cooke, Stanford University
• Language: English
• Date: 2012-10-26
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2012.09.034
• Title of Journal or Parent Work: Analytical Cellular Pathology / Cellular Oncology
• ISSN: 1570-5870
• Volume: 151
• Issue: 3
• Start Page: 547
• End Page: 558
• Grant/Funding Information: N.S was supported by NRSA grant (HL098049-01A1).; J.L was supported by grant from the Tobacco Related Disease Research Program of the University of California.; This work was supported by grants to J.P.C from National Institutes of Health (U01HL100397, RC2HL103400).
• Keywords: LYSINE 9; Biochemistry & Molecular Biology; Science & Technology; GENE-EXPRESSION; SOMATIC-CELLS; Cell Biology; BINDING-SITE; PLURIPOTENT STEM-CELLS; NF-KAPPA-B; Life Sciences & Biomedicine; TOLL-LIKE RECEPTOR-3; FIBROBLASTS; MURINE LEUKEMIA-VIRUS; HISTONE H3
• Research Categories: Health Sciences, Oncology; Biology, Cell

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.