Folic Acid Supports Pluripotency and Reprogramming by Regulating LIF/STAT3 and MAPK/ERK Signaling

Stem Cells Dev. 2017 Jan 1;26(1):49-59. doi: 10.1089/scd.2016.0091. Epub 2016 Nov 3.


Pluripotent stem cells act as an excellent cell source for disease therapy because of its specific characteristics of self-renewal and differentiation. Pluripotent stem cells are heterogeneous, consisting of naive stem cells as well as primed epiblast stem cells. However, the strategies and mechanisms of maintaining naive pluripotent stem cells remain unclear. In this study, we found that folic acid (FA) sustained mouse embryonic stem cell (ESC) pluripotency and enabled long-term maintenance of the naive state of ESCs under CHIR99021 conditions. Mechanistic experiments showed that STAT3 pathway partially mediated the effect of FA after which the interaction between STAT3 and importin α5 was enhanced. Meanwhile, MEK/ERK signaling also acted downstream of FA in maintaining ESC pluripotency. Furthermore, FA significantly promoted mouse somatic cell reprogramming. Overall, our study identified an effective chemical condition for maintaining homogeneous ESCs and highlighted the important roles of LIF/STAT3 and MEK/ERK signaling in naive ESC pluripotency.

Keywords: ESC; LIF/STAT3; MEK/ERK; folic acid; reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Self Renewal / drug effects
  • Cellular Reprogramming / drug effects*
  • Folic Acid / pharmacology*
  • Leukemia Inhibitory Factor / metabolism*
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mice
  • Mice, SCID
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / drug effects
  • Mouse Embryonic Stem Cells / metabolism
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / drug effects
  • Pluripotent Stem Cells / metabolism*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • STAT3 Transcription Factor / metabolism*
  • Small Molecule Libraries / pharmacology


  • Chir 99021
  • Leukemia Inhibitory Factor
  • Pyridines
  • Pyrimidines
  • STAT3 Transcription Factor
  • Small Molecule Libraries
  • Folic Acid