Activation of p38, p21, and NRF-2 mediates decreased proliferation of human dental pulp stem cells cultured under 21% O2

Stem Cell Reports. 2014 Oct 14;3(4):566-73. doi: 10.1016/j.stemcr.2014.08.002. Epub 2014 Sep 18.


High rates of stem cell proliferation are important in regenerative medicine and in stem cell banking for clinical use. Ambient oxygen tensions (21% O2) are normally used for in vitro culture, but physiological levels in vivo range between 3% and 6% O2. We compared proliferation of human dental pulp stem cells (hDPSCs) cultured under 21% versus 3% O2. The rate of hDPSC proliferation is significantly lower at 21% O2 compared to physiological oxygen levels due to enhanced oxidative stress. Under 21% O2, increased p38 phosphorylation led to activation of p21. Increased generation of reactive oxygen species and p21 led to activation of the NRF-2 signaling pathway. The upregulation of NRF-2 antioxidant defense genes under 21% O2 may interact with cell-cycle-related proteins involved in regulating cell proliferation. Activation of p38/p21/NRF-2 in hDPSCs cultured under ambient oxygen tension inhibits stem cell proliferation and upregulates NRF-2 antioxidant defenses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / metabolism*
  • Adult Stem Cells / physiology
  • Cell Proliferation*
  • Cells, Cultured
  • Dental Pulp / cytology*
  • Humans
  • Male
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress*
  • Oxygen / pharmacology
  • Young Adult
  • p21-Activated Kinases / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • p21-Activated Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Oxygen