CDC42 Inhibition via CASIN as a Possible Approach to Rejuvenation of Hematopoietic Stem Cell Function
CDC42 inhibition looks promising as a way to rejuvenate immune function via reversing the age-related disruption of hematopoiesis in bone marrow. At some point hematopoietic stem cells become so damaged that no amount of tinkering with their regulatory functions will help, but the evidence to date suggests that this doesn't occur until quite a way past middle age. In older mice, a single treatment of CDC42 inhibitor CASIN extends life span. Here, researchers report on further evaluations of the ability of CASIN to improve hematopoietic stem cell function, extending the work from mouse cells to human cells.
Aging is associated with tissue degeneration, aging-related diseases, and an increased susceptibility to infections. These hallmarks of aging have been linked to aging-related changes within somatic stem cell compartments, and primarily investigated in animal models like mice. One of the most extensively studied somatic stem cell-based system is the hematopoietic system.
Hematopoietic stem cells (HSCs) maintain blood homeostasis and show an age-related decline in overall function in mice, which includes an increase in myelopoiesis, accumulation of DNA damage, changes in epigenomic and transcriptional programs, decreased cell polarity and aberrant activity of the small RhoGTPase Cdc42. Although significant progress has been achieved in elucidating mechanisms of aging of murine HSCs, it remains unclear whether these mechanisms can be simply extrapolated to other species, including humans. For these reasons, novel studies into understanding mechanisms of aging of human HSCs are warranted and are a prerequisite to bolster the transition of this knowledge into the clinic.
In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSCs). We report increased frequencies of HSC, hematopoetic progenitor cells (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. Xenotransplantation of human HSCs into immunodeficient mice showed elevated chimerism in recipients of aged compared to young HSCs, indicating a worse function in aged HSCs. Aged HSCs treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSCs, however.
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.