Elsevier

Brain, Behavior, and Immunity

Volume 49, October 2015, Pages 49-53
Brain, Behavior, and Immunity

Short Communication
Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion

https://doi.org/10.1016/j.bbi.2015.02.028Get rights and content

Highlights

  • Methods that raise circulating PC numbers have great clinical utility.

  • Here we show that psychological stress induces such increases.

  • This was not replicated by infusion of a β-adrenergic receptor agonist in humans.

Abstract

Objectives

Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological β-adrenergic (βAR) stimulation on peripheral PC numbers in humans.

Methods

In two studies, we investigated PC mobilization in response to an acute speech task (n = 26) and βAR-agonist (isoproterenol) infusion (n = 20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs).

Results

Both psychological stress and βAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8+ T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a βAR-agonist did not result in a significant change in circulating PCs.

Conclusion

PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted.

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.

Section snippets

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).

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