抑制升高的Cdc42活性可促进衰老肠道干细胞的再生潜能。
Suppression of elevated Cdc42 activity promotes the regenerative potential of aged intestinal stem cells.
作者信息
Nalapareddy Kodandaramireddy, Hassan Aishlin, Sampson Leesa L, Zheng Yi, Geiger Hartmut
机构信息
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
出版信息
iScience. 2021 Mar 26;24(4):102362. doi: 10.1016/j.isci.2021.102362. eCollection 2021 Apr 23.
Homeostasis 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 potential . Consistent with a critical role of elevated Cdc42 activity in aged ISCs for a reduced regenerative capacity of aged ISCs, suppression of Cdc42 activity improves crypt regeneration in aged mice. Thus, pharmacological reduction of Cdc42 activity can improve the regeneration of aged intestinal epithelium.
位于隐窝底部的Lgr5阳性肠干细胞（ISC）维持着肠上皮的稳态。ISC的功能会随着衰老而降低，这会导致肠上皮再生能力下降。我们报告称，衰老的肠隐窝中小RhoGTP酶Cdc42的活性升高。通过基因手段提高幼龄动物体内Cdc42的活性会导致ISC过早衰老，而对升高的Cdc42活性进行药理学抑制则可恢复类器官形成潜能。与衰老ISC中升高的Cdc42活性对衰老ISC再生能力降低起关键作用一致，抑制Cdc42活性可改善老年小鼠的隐窝再生。因此，通过药理学方法降低Cdc42活性可改善衰老肠上皮的再生。
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