Molecular Insights into Reprogramming-initiation Events Mediated by the OSKM Gene Regulatory Network

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Sep 13

PMID 21909390

Citations 40

Authors

Nancy Mah

Ying Wang

Mei-Chih Liao

Alessandro Prigione

Justyna Jozefczuk

Bjorn Lichtner

Katharina Wolfrum

Manuela Haltmeier

Max Flottmann

Martin Schaefer

Alexander Hahn

Ralf Mrowka

Edda Klipp

Miguel A Andrade-Navarro

James Adjaye

Affiliations

Soon will be listed here.

Abstract

Somatic cells can be reprogrammed to induced pluripotent stem cells by over-expression of OCT4, SOX2, KLF4 and c-MYC (OSKM). With the aim of unveiling the early mechanisms underlying the induction of pluripotency, we have analyzed transcriptional profiles at 24, 48 and 72 hours post-transduction of OSKM into human foreskin fibroblasts. Experiments confirmed that upon viral transduction, the immediate response is innate immunity, which induces free radical generation, oxidative DNA damage, p53 activation, senescence, and apoptosis, ultimately leading to a reduction in the reprogramming efficiency. Conversely, nucleofection of OSKM plasmids does not elicit the same cellular stress, suggesting viral response as an early reprogramming roadblock. Additional initiation events include the activation of surface markers associated with pluripotency and the suppression of epithelial-to-mesenchymal transition. Furthermore, reconstruction of an OSKM interaction network highlights intermediate path nodes as candidates for improvement intervention. Overall, the results suggest three strategies to improve reprogramming efficiency employing: 1) anti-inflammatory modulation of innate immune response, 2) pre-selection of cells expressing pluripotency-associated surface antigens, 3) activation of specific interaction paths that amplify the pluripotency signal.

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