Short CommunicationProgenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion
Introduction
Progenitor cells (PCs) comprise an heterogeneous population uniquely capable of both self-renewal and multi-lineage differentiation (Weissman, 2000). They replenish specialized somatic cells and maintain the normal turnover of regenerative tissues and organs, such as the blood and skin. PCs generally reside in the bone marrow, with a small number continually migrating into the circulation and tissues (Mazo et al., 2011). Enhanced mobilization of endothelial PCs (EPCs) into the blood has been associated with improved endothelial function and repair (Foresta et al., 2010). Conversely, low circulating PC number and reduced PC function are associated with cardiovascular disease and mortality. Likewise, successful reconstitution of the obliterated haematopoietic system in chemotherapeutic or radiation treated patients is critically dependent on mobilizing at least 2 × 106 HSCs per kg body mass from the donor (Winkler and Levesque, 2006). Thus, there is clinical potential for methods that could aid mobilization of stem cells.
The bone marrow receives dense sympathetic innervation (Elenkov et al., 2000). Animal studies show that sympathetic nervous system activation induces the release of PCs into the blood, that this mobilization can be replicated by administration of a β2AR-agonist, and that increased circulating PC numbers correlate with circadian sympathetic oscillations (Katayama et al., 2006, Spiegel et al., 2007, Mendez-Ferrer et al., 2008, Dar et al., 2011). Further, both murine and human PCs express functional adrenergic receptors (Muthu et al., 2007, Spiegel et al., 2007). In humans the number of circulating PCs is increased by sympathetic stimuli such as exercise and acute myocardial infarction, and can be reduced by treatment with βAR-antagonist (Barrett et al., 1978, Shintani et al., 2001, Bible et al., 2014).
The above observations are remarkably similar to those reported for lymphocytes, which are likewise mobilized during sympathetic activation via stimulation of β2AR expressed on these cells (Benschop et al., 1996, Dimitrov et al., 2010). Stress and beta-adrenergic induced lymphocytosis is a rapid response, observable within minutes. Considering the strong resemblance between observations and mechanisms of PC and lymphocyte mobilization, the present study tested if acute stress and brief infusion of the βAR agonist isoproterenol may promote rapid mobilization of HSC and EPC into peripheral blood in humans.
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Participants
The stress study was performed at the University of Birmingham (UoB) and the infusion study at the University of California San Diego (UCSD). Methods and procedures were rigorously standardized to ensure comparability between results obtained between each site (further detailed below). All participants reported to be in good health and were non-medicated with exception of the contraceptive pill. Volunteers were instructed not to engage in strenuous physical exercise, to refrain from consuming
Anxiety and cardiovascular responses
Increases in the tension-anxiety POMS subscale confirmed that the speech tasks were perceived as stressful (Mean + 8.2 (SEM 0.8); F(2,48) = 102.3, p < .001). A physiological stress response was confirmed by significant increases in HR, SBP and DBP (Fig. 1, all p < .001). These cardiovascular changes appeared driven by an increase in sympathetic cardiac drive, as reflected by a decrease in PEP (Mean – 12.1 ms (SEM 2.3); F(2,26) = 14.9, p < .001), and a vagal withdrawal, as evidenced by a decrease in RMSSD
Discussion
The present study demonstrated, for the first time, that PC subsets can be mobilized rapidly during acute psychological stress in humans. Unexpectedly, this effect was not replicated by infusion of the βAR-agonist isoproterenol, although infusion effectively replicated the robust effects of stress on lymphocytes and monocytes as well as CD8+ T lymphocytes, similar to previous findings (Anane et al., 2009). Further, the percentage increase in HR seen during the stress study and infusion study
Acknowledgments
We would like to thank the volunteers, nurses at UCSD GCRC, and Charlotte Dennis, Fay Kitchen, Gareth Price, Katy Wilson, Merrly Spencer and Sara Cunliff for their help in running the study. This work was supported by grants from the NIH (HL-073355 to P.J. Mills), Wellcome Trust (VIP to J.A. Bosch), BSI (Travel Award to N.E. Riddell), and JEB (Travelling Fellowship to N.E. Riddell).
References (30)
- et al.
The role of NOS3 in stem cell mobilization
Trends Mol. Med.
(2004) - et al.
Catecholamine-induced leukocytosis: early observations, current research, and future directions
Brain Behav. Immun.
(1996) - et al.
Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to cardiovascular disease
Brain Behav. Immun.
(2003) - et al.
Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow
Cell
(2006) - et al.
Hematopoietic stem and progenitor cell trafficking
Trends Immunol.
(2011) - et al.
Leukocyte adhesion molecule expression and T cell naive/memory status following isoproterenol infusion
J. Neuroimmunol.
(2000) - et al.
Murine hematopoietic stem cells and progenitors express adrenergic receptors
J. Neuroimmunol.
(2007) - et al.
Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD34+ CD38− progenitor cells
Blood
(1991) Stem cells: units of development, units of regeneration, and units in evolution
Cell
(2000)- et al.
Mechanisms of hematopoietic stem cell mobilization: when innate immunity assails the cells that make blood and bone
Exp. Hematol.
(2006)
Mobilization of gammadelta T lymphocytes in response to psychological stress, exercise, and beta-agonist infusion
Brain Behav. Immun.
Mobilization of CFU-C by exercise and ACTH induced stress in man
Exp. Hematol.
Early propranolol administration to severely injured patients can improve bone marrow dysfunction
J Trauma Acute Care Surg
Differential mobilization of functionally distinct natural killer subsets during acute psychologic stress
Psychosom. Med.
A general enhancement of autonomic and cortisol responses during social evaluative threat
Psychosom. Med.
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