Vigorous exercise mobilizes CD34+ hematopoietic stem cells to peripheral blood via the β2-adrenergic receptor

Abstract

Acute dynamic exercise mobilizes CD34+ hematopoietic stem cells (HSCs) to the bloodstream, potentially serving as an economical adjuvant to boost the collection of HSCs from stem cell transplant donors. The mechanisms responsible for HSC mobilization with exercise are unknown but are likely due to hemodynamic perturbations, endogenous granulocyte-colony stimulating factor (G-CSF), and/or β₂-adrenergic receptor (β₂-AR) signaling. We characterized the temporal response of HSC mobilization and plasma G-CSF following exercise, and determined the impact of in vivo β-AR blockade on the exercise-induced mobilization of HSCs. Healthy runners (n = 15) completed, in balanced order, two single bouts of steady state treadmill running exercise at moderate (lasting 90-min) or vigorous (lasting 30-min) intensity. A separate cohort of healthy cyclists (n = 12) completed three 30-min cycling ergometer trials at vigorous intensity after ingesting: (i) 10 mg bisoprolol (β₁-AR antagonist); (ii) 80 mg nadolol (β₁ + β₂-AR antagonist); or (iii) placebo, in balanced order with a double-blind design. Blood samples collected before, during (runners only), immediately after, and at several points during exercise recovery were used to determine circulating G-CSF levels (runners only) and enumerate CD34+ HSCs by flow cytometry (runners and cyclists). Steady state vigorous but not moderate intensity exercise mobilized HSCs, increasing the total blood CD34+ count by ∼4.15 ± 1.62 Δcells/µl (+202 ± 92%) compared to resting conditions. Plasma G-CSF increased in response to moderate but not vigorous exercise. Relative to placebo, nadolol and bisoprolol lowered exercising heart rate and blood pressure to comparable levels. The number of CD34+ HSCs increased with exercise after the placebo and bisoprolol trials, but not the nadolol trial, suggesting β₂-AR signaling mediated the mobilization of CD34+ cells [Placebo: 2.10 ± 1.16 (207 ± 69.2%), Bisoprolol 1.66 ± 0.79 (+163 ± 29%), Nadolol: 0.68 ± 0.54 (+143 ± 36%) Δcells/µL]. We conclude that the mobilization of CD34+ HSCs with exercise is not dependent on circulating G-CSF and is likely due to the combined actions of β₂-AR signaling and hemodynamic shear stress.

Keywords: Bisoprolol; CD133; Exercise immunology; Exercise intensity; Granulocyte colony stimulating factor (G-CSF); Hematopoietic stem cell transplantation; Nadolol; Progenitor cells; β-AR blockade.

Fig. 1.

The effects of exercise intensity (Vigorous or Moderate) on (i) CD34+ and (ii) CD133+ HSCs (cells/μL) in the Part 1 cohort. Values are mean±SD. Differences from pre-exercise indicated by ^*, between trials indicated by ^#, p<.05.

Fig. 2.

The effects of exercise intensity (Vigorous or Moderate) on serum granulocyte colony stimulating factor (G-CSF) (pg/mL) in the Part 1 cohort. During-exercise measures were obtained at +15-min for the vigorous trial and +60-min for the moderate trial. Values are mean±SD. Differences from baseline and exercise trials (Vigorous and Moderate) indicated by ^* and ^#, respectively, p<.05.

Fig. 3.

The effects on nadolol and bisoprolol administration relative to placebo on the mobilization of CD34+ and CD133+ HSCs with exercise. Panel A shows the effects of exercise under placebo, bisoprolol and nadolol trials on (i) CD34+ and (ii) CD133+ HSCs (cells/μL) in the Part 2 cohort. Values are mean±SD. Differences from pre-exercise were found for placebo (^*) and bisoprolol (^), but not for nadolol, p<.05. Differences from the placebo condition were found for CD34+ HSCs at post-exercise for nadolol (^#), p < .05. Panel B shows the absolute number of CD34+ (i) and CD133+ (ii) HSCs mobilized by exercise (Post-Ex – Pre-Ex; Δ) in the placebo, bisoprolol and nadolol trials in the Part 2 cohort. Values are mean±SD. Differences from the placebo and bisoprolol conditions are noted by ^* and ±, respectively, p<.05.