Endurance Exercise Mobilizes Developmentally Early Stem Cells into Peripheral Blood and Increases Their Number in Bone Marrow: Implications for Tissue Regeneration

Abstract

Endurance exercise has been reported to increase the number of circulating hematopoietic stem/progenitor cells (HSPCs) in peripheral blood (PB) as well as in bone marrow (BM). We therefore became interested in whether endurance exercise has the same effect on very small embryonic-like stem cells (VSELs), which have been described as a population of developmentally early stem cells residing in BM. Mice were run daily for 1 hour on a treadmill for periods of 5 days or 5 weeks. Human volunteers had trained in long-distance running for one year, six times per week. FACS-based analyses and RT-PCR of murine and human VSELs and HSPCs from collected bone marrow and peripheral blood were performed. We observed that endurance exercise increased the number of VSELs circulating in PB and residing in BM. In parallel, we observed an increase in the number of HSPCs. These observations were subsequently confirmed in young athletes, who showed an increase in circulating VSELs and HSPCs after intensive running exercise. We provide for the first time evidence that endurance exercise may have beneficial effects on the expansion of developmentally early stem cells. We hypothesize that these circulating stem cells are involved in repairing minor exercise-related tissue and organ injuries.

Figure 1

Effect of short (45 min) exercise on a rotating wheel on stem cell mobilization in mice. (a, b) The number of VSELs (a) and HSPCs (b) circulating in PB after 45 min of exercise on a rotating wheel (effort) compared with nonexercising mice (control). (c) Activation of the complement cascade in PB after 45 min of exercise on a rotating wheel (effort) compared with nonexercising mice (control) measured by C5b-C9 (MAC) ELISA. (d) The increase in the number of clonogenic progenitors circulating in PB after 45 min of exercise on rotating wheels (effort) compared with nonexercising mice (control) (n = 6 mice/group).

Figure 2

Effect of 5 days or 5 weeks of exercise on a treadmill on the number of VSELs in PB and BM. (a) The number of VSELs circulating in PB (left panel) and BM (right panel) after 5 days or 5 weeks of exercise on a treadmill (effort) compared with nonexercising mice (control). (b) Quantitative real-time PCR changes in expression of Oct4, Sox2, and Nanog in PB mononuclear cells after 5 days or 5 weeks of exercise on a treadmill (effort) compared with nonexercising mice (control), whose expression level was defined as 100%. (c) Activation of the complement cascade in PB measured by C5b-C9 (MAC) ELISA after 5-week exercise on a treadmill (effort) compared with nonexercising mice (control) (n = 6 mice/group).

Figure 3

Effect of 5 days or 5 weeks of exercise on a treadmill on the number of HSPCs in PB and BM. (a) The number of HSPCs circulating in PB (left panel) and BM (right panel) after 5 days or 5 weeks of exercise on a treadmill (effort) compared with nonexercising mice (control). (b) The increase in the number of clonogenic progenitors (CFU-GM, left panel, and BFU-E, right panel) in BM after 5 days or 5 weeks of exercise on a treadmill (effort) compared with nonexercising mice (control) (n = 6 mice/group).

Figure 4

Effect of exercise on stem cell mobilization in healthy young volunteers. (a) The number of CD133⁺ and CD34⁺ VSELs (left) and CD133⁺ and CD34⁺ HSPCs (right) circulating in PB in young athletes after not exercising (control) or after running exercise (effort). (b) Quantitative real-time PCR changes in expression of Oct4, Sox2, and Nanog in PB mononuclear cells after running exercise (effort) compared with nonexercising subjects (control). Changes are shown compared with values detected in control volunteers (defined as 100%). (c) The number of EPCs (left panel) and MSCs (right panel) circulating in PB in young athletes after not exercising (control) or after running exercise (effort) (n = 6 volunteers/group).