In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSCs). We report increased frequencies of HSC, HPC and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSCs further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSCs upon aging. The frequency of human HSCs polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarisation of aged human HSCs with respect to Cdc42. Elevated activity of Cdc42 in aged HSCs thus contributed to age-related changes in HSCs. Xeno-transplants, using NBSGW mice as recipients, showed elevated chimerism in recipients of aged compared to young HSCs. Aged HSCs treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSCs. Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSCs, and similar to mice, this presents a likely possibility for attenuation of aging in human HSCs.
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