Cdc42 Activity Regulates Hematopoietic Stem Cell Aging and Rejuvenation

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. [Display omitted] ► Constitutively increasing Cdc42 activity causes aging of young HSCs ► Elevated Cdc42 activity correlates with a loss of cell polarity in aged HSCs ► Inhibition of Cdc42 activity rejuvenates aged LT-HSC function ► Cdc42 inhibition restores the level and spatial distribution of AcH4K16