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 dem...

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Bibliographic Details
Published in:Cell stem cell 2012-05, Vol.10 (5), p.520-530
Main Authors: Florian, Maria Carolina, Dörr, Karin, Niebel, Anja, Daria, Deidre, Schrezenmeier, Hubert, Rojewski, Markus, Filippi, Marie-Dominique, Hasenberg, Anja, Gunzer, Matthias, Scharffetter-Kochanek, Karin, Zheng, Yi, Geiger, Hartmut
Format: Article
Language:English
Subjects:
Acetylation
Aging, Premature - genetics
Animals
Biological and medical sciences
cdc42 GTP-Binding Protein - metabolism
cdc42 GTP-Binding Protein - pharmacology
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
Cell Polarity - genetics
Cells, Cultured
Cellular Senescence
Fundamental and applied biological sciences. Psychology
GTPase-Activating Proteins - genetics
Hematopoiesis - genetics
Hematopoietic Stem Cells - drug effects
Hematopoietic Stem Cells - physiology
Histones - metabolism
Mice
Mice, Knockout
Molecular and cellular biology
Myeloid Cells - physiology
Protein Transport - genetics
Rejuvenation
Tubulin - metabolism
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Summary: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
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2012.04.007