SUMMARY The functional decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs 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, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a similar status as seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging.
IntroductionHematopoietic stem and progenitor cells (HSPCs) are located in the bone marrow (BM) in close association with a highly organized 3-dimensional structure formed by stroma cells, referred to as the niche. 1,2 It has been demonstrated that these cell-cell interactions are vital for the biology of HSPCs. Systemic administration of cytokines and chemokines or cytotoxic agents mobilize HSPCs from the BM into peripheral blood (PB), where they are collected in clinically useful quantities for stem cell therapies. 3,4 Mobilization of HSPCs in response to these factors requires the de-adhesion of HSPCs from the niche. 5,6 Evidence accumulating over the past decade has proven that there is a measurable and successive functional decline in hematopoietic, intestinal, and muscle stem cell function. 7,8 Given that stem cell activity is necessary to replenish lost differentiated cells, it has been hypothesized that aging of hematopoietic stem cells (HSCs) leads to reduced stem cell renewal and thus reduced tissue homeostasis in aged animals, [7][8][9][10][11] which is emphasized by ageassociated anemia and a decline in function of immune cells in elderly persons. 12-19 HSC aging is intrinsic to the aged cell and cannot be reverted by exposing HSCs from aged animals to a young microenvironment. [18][19][20] The ability of healthy, older patients to undergo stem cell mobilization in response to granulocyte colony-stimulating factor (G-CSF), the standard regimen used for clinical HSPC mobilization, has thus far not been investigated in detail because autologous hematopoietic stem cell transplantation is most often administered to adults younger than 50 years and rarely to patients older than 60 years. 21,22 The limited available information is not conclusive in terms of efficiency of mobilization because it is based primarily on the analysis of mobilization of elderly patients after severe chemotherapy 23,24 and possibly also because 2 different methods of determining mobilization efficiency are used (colony-forming cell [CFC] frequency vs CD34 ϩ cell frequency in PB). Combining general clinical wisdom and these published reports, it is anticipated that the ability to mobilize HSPCs in response to G-CSF may be reduced in elderly patients, [23][24][25][26] hampering the efficient collection of HSPCs for subsequent hematopoietic stem cell therapies. Whether a negative correlation exists between age and mobilization is still under debate. 24,25 The mouse has been used in a wide variety of studies to model human G-CSF-induced mobilization of HSCs, with an overall good correlation between results obtained from murine studies and subsequent results obtained in humans. By investigating mobilization proficiency in aged mice, we report here that aged mice show not only decreased but increased efficiency in mobilizing hematopoietic progenitor cells (HPCs) and HSCs to PB. Materials and methods AnimalsYoung C57BL/6J mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were subsequently housed in the animal barrier ...
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