Recent research has linked blood stem cell aging with increased activity of the cell division cycle 42 (Cdc42) protein. All blood cell types are derived from a population of self renewing hematopoietic (blood) stem cells (HSCs) that first appear during embryonic development. However, there are changes in HSC structure and a decline in function over time that leads to reduced production of both red and white blood cells by the HSC. The molecular mechanisms underlying HSC aging are not known, but previous research has shown that Cdc42 activity is significantly increased in both HSCs and other cell types of old mice when compared with those from young mice. Whether enhanced activity of Cdc42 is responsible, in part, for the aging phenotype is not known.
Using a mouse model that exhibits increased Cdc42 activity due to genetic deletion of an inhibitor of the protein, scientists found that HSCs from young animals with this mutation exhibit a decline in function similar to that observed in normal older animals. HSCs from young mutant mice showed diminished organization of intracellular structures similar to that seen in aged mice. HSCs from the mutant mice that were grown in culture in the presence of a drug that inhibits Cdc42 activity reverted to a “younger” appearance, with intracellular organization restored. This observation provides evidence that Cdc42 activity plays a role in structural degradation seen in the aging of HSC, and that this can be reversed through inhibition of this protein.
Additional studies suggested that Cdc42 plays a role in the decline in HSC function observed during aging. Using an experiment that measures how well HSCs are able to “home” or localize to the bone marrow and begin to grow there, the scientists found that HSCs from a mutant mouse with elevated Cdc42 activity no longer had the ability to repopulate the hematopoietic system of a mouse whose HSCs have been eliminated by prior radiation treatment. In contrast, cells from a mutant mouse that had been treated with a Cdc42 inhibitor in culture prior to being injected into the recipient mouse had an increased ability to repopulate the bone marrow, though not as robustly as normal HSCs from young animals. This finding shows that even a brief exposure to the Cdc42 inhibitor was sufficient to partially restore function lost during aging of HSCs.
Future studies will determine whether drugs that target Cdc42 can restore function in aged human HSCs. As elevated Cdc42 activity has been observed in multiple tissues in aged mice, this finding may have implications that extend beyond the hematopoietic system and blood cell production.
Florian MC Dörr K, Niebel A, et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10: 520-530, 2012.