Transient exposure to miR-203 enhances the differentiation capacity of established pluripotent stem cells

EMBO J. 2020 Aug 17;39(16):e104324. doi: 10.15252/embj.2019104324. Epub 2020 Jul 2.

Abstract

Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs. Short exposure to miR-203 in PSCs (miPSCs) induces a transient expression of 2C markers that later results in expanded differentiation potency to multiple lineages, as well as improved efficiency in tetraploid complementation and human-mouse interspecies chimerism assays. Mechanistically, these effects are at least partially mediated by direct repression of de novo DNA methyltransferases Dnmt3a and Dnmt3b, leading to transient and reversible erasure of DNA methylation. These data support the use of transient exposure to miR-203 as a versatile method to reset the epigenetic memory in PSCs, and improve their effectiveness in regenerative medicine.

Keywords: differentiation; epigenetics; microRNAs; pluripotency; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Line
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*

Substances

  • MIRN203 microRNA, human
  • MIRN203 microRNA, mouse
  • MicroRNAs
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • DNA methyltransferase 3B

Associated data

  • GEO/GSE81571
  • GEO/GSE86653