Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation

Cell Stem Cell. 2012 May 4;10(5):520-30. doi: 10.1016/j.stem.2012.04.007.


The decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC aging and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging.

Publication types

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

MeSH terms

  • Acetylation
  • Aging, Premature / genetics
  • Animals
  • Cell Polarity / genetics
  • Cells, Cultured
  • Cellular Senescence*
  • GTPase-Activating Proteins / genetics
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / physiology*
  • Histones / metabolism*
  • Mice
  • Mice, Knockout
  • Myeloid Cells / physiology
  • Protein Transport / genetics
  • Rejuvenation
  • Tubulin / metabolism*
  • cdc42 GTP-Binding Protein / metabolism*
  • cdc42 GTP-Binding Protein / pharmacology


  • Arhgap1 protein, mouse
  • GTPase-Activating Proteins
  • Histones
  • Tubulin
  • cdc42 GTP-Binding Protein