Hematopoietic stem cells (HSCs), responsible for generating blood and immune cells, decline with age. This is one of the reasons why old immune systems suffer from a low rate of replacement of cells. For some years now, researchers have demonstrated that blocking Cdc42 reverses much of this decline, indicating that stem cell inactivity in the old is as much a matter of response to the aged, dysfunction tissue environment as it is a matter of intrinsic damage, at least in this population. Here, researchers review what is presently known on this topic.
Skin, intestine and blood are composed of short-lived cells that require continuous replenishment by somatic stem cells to maintain tissue homeostasis. Current theory is therefore that especially aging of stem cells that form these tissues will greatly contribute to the decline in tissue function with aging. Identifying mechanisms of stem cell aging and conditions under which aged stem cells become functionally similar to young stem cells might be important first steps towards devising treatments of aging-associated imbalance in tissue homeostasis and tissue regeneration with the ultimate goal of allowing for healthy aging.
Cdc42 belongs to the Rho GTPase family of the Ras superfamily, acting as a binary molecular switch that cycles between a GTP-bound active state and GDP-bound inactive state in response to a variety of extracellular stimuli. A key function of Cdc42 is regulation of elements that structure cells like the actin cytoskeleton or part of the microtubule network, which is believed to be a central mechanism for Cdc42-mediated cell polarization, adhesion and migration. Another important function of Cdc42 is to regulate cell growth signaling. It is becoming clear that the function and signaling pathways regulated by Cdc42 are tissue and cell type-specific, and the general principles of Cdc42 function defined by in vitro methods or from one tissue cell type may or may not apply to another cell type in in vivo situations. This also means that observations for example from fibroblasts (from which most of the information stems) might be informative for designing targeted experiments, but ultimately, in which pathway and function Cdc42 may operate in aged HSCs needs to be stringently dissected in HSCs and can not just be inferred from data obtained in other types of cells or systems.
Cell polarity is well characterized in epithelial cells and neuronal stem cells, but was only recently described to also exist in HSCs. Studies support a critical role of polarity in stem cell maintenance. What might be the role of polarity in stem cells? Polarity can be associated with specialized and compartmentalized functions in HSCs, with migration or with division. A defining feature of stem cells is their ability to maintain a balanced number of stem cells (self-renewal), while at the same time being able to generate specialized progeny (differentiation). Both processes depend on the ability of stem cells to undergo either symmetric or asymmetric divisions, which involve cell polarity.
Supporting a determining role for polarity in stem cell aging is a recent study showing that a loss of proper polarity in aged Drosophila germ-line stem cells correlates with their reduced function. To date, the role of HSC polarity with respect to the mode of HSC division and cell fate potential of daughter cells has not been experimentally tested. Given the established role of Cdc42 in mediating morphologic polarity in many cell types and in regulating HSC differentiation, it has been somewhat logical to postulate that Cdc42 plays a role in coordinating polarity in HSCs.
Genome-wide association studies of longevity in humans linked elevated expression of Cdc42 in hematopoietic cells to increased morbidity and aging. The holy grail of aging research is the question of rejuvenation. Are molecular mechanisms of aging reversible? If elevated Cdc42 activity is causally linked to stem cell aging and apolarity, then reversion of the level to the level found in young HSCs might result in "younger" HSCs. Aged HSCs, in which Cdc42 activity level was, via pharmacological inhibition, reduced to the level found in young mice, presented functionally and upon transplantation almost identically to young HCS. This suggests that Cdc42 activity might represent a novel target to rejuvenate aged HSCs via altering stem cell polarity.