Elevated activity of the small RhoGTPase Cdc42 in aged HSCs (hematopoietic stem cells) 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. CASIN is a selective Cdc42 activity inhibitor. In young cells, treatment with CASIN (5 µM) reduced the elevated level of active Cdc42 observed in aged primitive hematopoietic cells to the level observed in young cells. In response to treatment with 5 µM CASIN, LT-HSCs from aged mice showed a dose-dependent increase in the percentage of polarized cells, becoming progressively indistinguishable from young cells. These data indicated that CASIN treatment reverted aged LT-HSCs to young HSCs with respect to the polarity phenotype. Surprisingly, the increase in the percentage of polar cells among aged LT-HSCs induced by CASIN in vitro remained stable for at least up to 6 hours after CASIN withdrawal. Further, CASIN treatment of aged LT-HSCs resulted in an increase in contribution to the B-cell compartment in PB (peripheral blood) and a reduced contribution to the myeloid lineage. In addition, CASIN treatment increased the contribution to LSK and common lymphoid progenitor (CLP) populations to a level indistinguishable from young LT-HSCs. CASIN treatment induces a sharp decrease of the frequency of AcH4K16low aged LT-HSCs while increasing the frequency of AcH4K16high cells[3].
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