Transient activation of the UPR ER is an essential step in the acquisition of pluripotency during reprogramming

Sci Adv. 2019 Apr 10;5(4):eaaw0025. doi: 10.1126/sciadv.aaw0025. eCollection 2019 Apr.

Abstract

Somatic cells can be reprogrammed into pluripotent stem cells using the Yamanaka transcription factors. Reprogramming requires both epigenetic landscape reshaping and global remodeling of cell identity, structure, basic metabolic processes, and organelle form and function. We hypothesize that variable regulation of the proteostasis network and its influence upon the protein-folding environment within cells and their organelles is responsible for the low efficiency and stochasticity of reprogramming. We find that the unfolded protein response of the endoplasmic reticulum (UPRER), the mitochondrial UPR, and the heat shock response, which ensure proteome quality during stress, are activated during reprogramming. The UPRER is particularly crucial, and its ectopic, transient activation, genetically or pharmacologically, enhances reprogramming. Last, stochastic activation of the UPRER predicts reprogramming efficiency in naïve cells. Thus, the low efficiency and stochasticity of cellular reprogramming are due partly to the inability to properly initiate the UPRER to remodel the ER and its proteome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Cellular Reprogramming*
  • Endoplasmic Reticulum / physiology*
  • Endoplasmic Reticulum Stress*
  • Fibroblasts / cytology*
  • Fibroblasts / physiology
  • Heat-Shock Response*
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / physiology
  • Proteome / analysis
  • Signal Transduction
  • Unfolded Protein Response*

Substances

  • Proteome