摘要：SummaryHomeostasis in the intestinal epithelium is maintained by Lgr5-positive intestinal stem cells (ISCs) located at the base of the crypt. The function of ISCs is reduced upon aging which leads to a decline of regeneration of the intestinal epithelium. We report that aged intestinal crypts present with an elevated activity of the small RhoGTPase Cdc42. Elevation of Cdc42 activity in young animals by genetic means causes premature ISC aging, whereas pharmacological suppression of elevated Cdc42 activity restores organoid formation potentialin vitro. Consistent with a critical role of elevated Cdc42 activity in aged ISCs for a reduced regenerative capacity of aged ISCs, suppression of Cdc42 activityin vivoimproves crypt regeneration in aged mice. Thus, pharmacological reduction of Cdc42 activity can improve the regeneration of aged intestinal epithelium.Graphical abstractDisplay OmittedHighlights•Intestinal stem cells show high RhoGTPase Cdc42 activity compared to Paneth cells•Cdc42 activity is further increased in aged intestinal stem cells (ISCs)•Attenuation of Cdc42 activityex vivoorin vivoimproves the function of aged ISCsCell Biology; Stem Cells Research; Functional Aspects of Cell Biology
