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Exercise and Cardiovascular Progenitor Cells

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ABSTRACT

Autologous stem/progenitor cell‐based methods to restore blood flow and function to ischemic tissues are clinically appealing for the substantial proportion of the population with cardiovascular diseases. Early preclinical and case studies established the therapeutic potential of autologous cell therapies for neovascularization in ischemic tissues. However, trials over the past ∼15 years reveal the benefits of such therapies to be much smaller than originally estimated and a definitive clinical benefit is yet to be established. Recently, there has been an emphasis on improving the number and function of cells [herein generally referred to as circulating angiogenic cells (CACs)] used for autologous cell therapies. CACs include of several subsets of circulating cells, including endothelial progenitor cells, with proangiogenic potential that is largely exerted through paracrine functions. As exercise is known to improve CV outcomes such as angiogenesis and endothelial function, much attention is being given to exercise to improve the number and function of CACs. Accordingly, there is a growing body of evidence that acute, short‐term, and chronic exercise have beneficial effects on the number and function of different subsets of CACs. In particular, recent studies show that aerobic exercise training can increase the number of CACs in circulation and enhance the function of isolated CACs as assessed in ex vivo assays. This review summarizes the roles of different subsets of CACs and the effects of acute and chronic exercise on CAC number and function, with a focus on the number and paracrine function of circulating CD34+ cells, CD31+ cells, and CD62E+ cells. © 2019 American Physiological Society. Compr Physiol 9:767‐797, 2019.

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Figure 1. Figure 1. Timeline of critical developments in autologous intracoronary stem cell transplantation. The authors of selected key articles and a very brief summary are included in the vertical boxes along the timeline. The left Y‐axis (blue) is graphical presentation of the perceptions of the current authors of the variations in the potential Therapeutic Promise for these cells over the last 20 years. The right Y‐axis (red) is the number of articles published in each of these years based on a Web of Science search for “endothelial progenitor cells.”
Figure 2. Figure 2. Discrepancies in autologous cell therapy trials. Data represent mean ejection fraction (EF) effect size by number of discrepancies in trials’ reports. Reprinted, with permission, from ().
Figure 3. Figure 3. Exploring the full continuum of circulating angiogenic cell function.
Figure 4. Figure 4. Effects of intensive and moderate running exercise on circulating endothelial progenitor cell (CD34+/VEGFR2+) number in healthy adults (* P < 0.05 compared with preexercise values). Adapted, with permission, from Laufs et al. ().
Figure 5. Figure 5. Time course of circulating endothelial progenitor cell (CD34+/VEGFR2+) number after 30 min of intensive running (* P < 0.05). Adapted, with permission, from Laufs et al. ().
Figure 6. Figure 6. Circulating CD34+/VEGFR2+ (A), and CD34+ (B) cell number in older adults with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM), before and 30 min after a 30‐min bout of submaximal treadmill exercise. Data are means ± SEM. *Significant difference compared with NGT subjects within the same condition (basal or exercise), P < 0.05. †Significant within‐group difference after acute exercise, P ≤ 0.01. Adapted, with permission, from Lutz et al. ().
Figure 7. Figure 7. Circulating numbers of CD34+/KDR+ cells (A) and CD34+ cells (B) before and after 10 days of endurance‐exercise training in healthy older men and women (n = 10). Left panels represent means and right panels represent individual data with black lines indicating men and gray lines indicating women (* P < 0.05 compared with baseline). Adapted, with permission, from Landers‐Ramos et al. ().
Figure 8. Figure 8. Human umbilical vein endothelial cells (HUVEC) capillary‐like network length after culture with conditioned media (CM) from CD34+ cells. * P ≤ 0.05, statistically significant difference compared with endurance‐trained subjects. Adapted, with permission, from Landers‐Ramos et al. ().
Figure 9. Figure 9. Number of circulating CD31+ cells expressed as % of CD3+ cells (A) and correlation between CD31+ cell number and age (B) in young, middle‐aged, and older men. * P < 0.05 compared with young men. Adapted, with permission, from Kushner et al. ().
Figure 10. Figure 10. Age group differences in circulating CD31+/CD3+ cell numbers in men. * P < 0.05 compared with the 18‐ to 30‐year‐old group. Adapted, with permission, from Ross et al. ().
Figure 11. Figure 11. Circulating CD31+/CD3+ cell changes in response to acute moderate exercise in young and older healthy men. * P < 0.05 for main effect of exercise; δ P < 0.05 for exercise * age interaction. Adapted, with permission, from Ross et al. ().
Figure 12. Figure 12. Circulating CD14+/CD31+ cell number before and after 3 weeks of aerobic exercise training in healthy young men supplemented with either placebo (white bars) or antioxidant (MitoQ) supplementation (gray bars). Adapted, with permission, from Shill et al. ().
Figure 13. Figure 13. Human umbilical vein endothelial cells (HUVEC) capillary‐like network length after culture with conditioned media (CM) from CD31+/CD34‐ cells. * P < 0.05, statistically significant difference compared with endurance‐trained subjects. Adapted, with permission, from Landers‐Ramos et al. ().
Figure 14. Figure 14. Exercise‐induced increases in circulating CD62E+ cells. The relative increases in CD62E+ CACs from baseline among the few investigations examining the impact of exercise. It is hypothesized that exercise intensity does not influence circulating levels of CD62E+ cells, but rather the cumulative volume (i.e., frequency × intensity × time) of the exercise determines extent of CD62E expression on CACs. However, further research is necessary to fully understand the interactive effects of exercise frequency, intensity, and duration on CD62E+ cells. Total exercise volume was estimated by utilizing exercise variables from the available studies. Data represented by bars were adapted, with permission, from ().
Figure 15. Figure 15. Intramuscular injections of EPC conditioned medium (CM) and EPCs resulted in equivalent recovery of blood flow and capillarization in rat hindlimbs following chronic ischemia. Four weeks after occlusion of the femoral artery, serial intramuscular injections of EPC, EPC‐CM, or control medium were given. (A) Hindlimb blood flow and was measured by laser Doppler immediately after the first injection (iDAY 1) and 5 weeks later (iDAY 35). (B) Capillary density was assessed 5 weeks after treatment. Adapted, with permission, from DiSanto et al. ().
Figure 16. Figure 16. Circulating angiogenic cells (CAC) release a myriad of factors including proteins and microRNAs (miRs). These molecules can act as paracrine factors to induce effects upon cell types of the cardiovascular system (and others), or as autocrine factors to affect CAC functions. Extracellular vesicles (ECVs), such as microvesicles and exosomes, are additionally secreted and act as a means of intercellular transport of paracrine factors. Acutely, exercise and sedentary behavior may alter the expression and secretion of proteins, miRs, and ECVs. Long‐term health status, spanning from disease to the exercise trained state, ultimately determines the paracrine function of CAC.
Figure 17. Figure 17. CD34+ cell‐derived exosomes induce therapeutic angiogenesis by transferring miR‐126. Immediately following induction of hindlimb ischemia, mice received injections of PBS (control), CD34+ cells, CD34+ cell conditioned medium (CM), CD34+ exosomes (CD34Exo), CD34+ exosome‐depleted CM, or mononuclear cell (MNC) exosomes. (A) Pictures were taken 28 days after injection of the indicated treatment. (B) Exosomes derived from CD34+ cells knocked down for miR‐126 (miR126‐KD‐Exo) exhibited reduced effects on limb reperfusion compared with exosomes from cells treated with a scrambled miR control. Adapted, with permission, from Mathiyalagan et al. ().


Figure 1. Timeline of critical developments in autologous intracoronary stem cell transplantation. The authors of selected key articles and a very brief summary are included in the vertical boxes along the timeline. The left Y‐axis (blue) is graphical presentation of the perceptions of the current authors of the variations in the potential Therapeutic Promise for these cells over the last 20 years. The right Y‐axis (red) is the number of articles published in each of these years based on a Web of Science search for “endothelial progenitor cells.”


Figure 2. Discrepancies in autologous cell therapy trials. Data represent mean ejection fraction (EF) effect size by number of discrepancies in trials’ reports. Reprinted, with permission, from ().


Figure 3. Exploring the full continuum of circulating angiogenic cell function.


Figure 4. Effects of intensive and moderate running exercise on circulating endothelial progenitor cell (CD34+/VEGFR2+) number in healthy adults (* P < 0.05 compared with preexercise values). Adapted, with permission, from Laufs et al. ().


Figure 5. Time course of circulating endothelial progenitor cell (CD34+/VEGFR2+) number after 30 min of intensive running (* P < 0.05). Adapted, with permission, from Laufs et al. ().


Figure 6. Circulating CD34+/VEGFR2+ (A), and CD34+ (B) cell number in older adults with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM), before and 30 min after a 30‐min bout of submaximal treadmill exercise. Data are means ± SEM. *Significant difference compared with NGT subjects within the same condition (basal or exercise), P < 0.05. †Significant within‐group difference after acute exercise, P ≤ 0.01. Adapted, with permission, from Lutz et al. ().


Figure 7. Circulating numbers of CD34+/KDR+ cells (A) and CD34+ cells (B) before and after 10 days of endurance‐exercise training in healthy older men and women (n = 10). Left panels represent means and right panels represent individual data with black lines indicating men and gray lines indicating women (* P < 0.05 compared with baseline). Adapted, with permission, from Landers‐Ramos et al. ().


Figure 8. Human umbilical vein endothelial cells (HUVEC) capillary‐like network length after culture with conditioned media (CM) from CD34+ cells. * P ≤ 0.05, statistically significant difference compared with endurance‐trained subjects. Adapted, with permission, from Landers‐Ramos et al. ().


Figure 9. Number of circulating CD31+ cells expressed as % of CD3+ cells (A) and correlation between CD31+ cell number and age (B) in young, middle‐aged, and older men. * P < 0.05 compared with young men. Adapted, with permission, from Kushner et al. ().


Figure 10. Age group differences in circulating CD31+/CD3+ cell numbers in men. * P < 0.05 compared with the 18‐ to 30‐year‐old group. Adapted, with permission, from Ross et al. ().


Figure 11. Circulating CD31+/CD3+ cell changes in response to acute moderate exercise in young and older healthy men. * P < 0.05 for main effect of exercise; δ P < 0.05 for exercise * age interaction. Adapted, with permission, from Ross et al. ().


Figure 12. Circulating CD14+/CD31+ cell number before and after 3 weeks of aerobic exercise training in healthy young men supplemented with either placebo (white bars) or antioxidant (MitoQ) supplementation (gray bars). Adapted, with permission, from Shill et al. ().


Figure 13. Human umbilical vein endothelial cells (HUVEC) capillary‐like network length after culture with conditioned media (CM) from CD31+/CD34‐ cells. * P < 0.05, statistically significant difference compared with endurance‐trained subjects. Adapted, with permission, from Landers‐Ramos et al. ().


Figure 14. Exercise‐induced increases in circulating CD62E+ cells. The relative increases in CD62E+ CACs from baseline among the few investigations examining the impact of exercise. It is hypothesized that exercise intensity does not influence circulating levels of CD62E+ cells, but rather the cumulative volume (i.e., frequency × intensity × time) of the exercise determines extent of CD62E expression on CACs. However, further research is necessary to fully understand the interactive effects of exercise frequency, intensity, and duration on CD62E+ cells. Total exercise volume was estimated by utilizing exercise variables from the available studies. Data represented by bars were adapted, with permission, from ().


Figure 15. Intramuscular injections of EPC conditioned medium (CM) and EPCs resulted in equivalent recovery of blood flow and capillarization in rat hindlimbs following chronic ischemia. Four weeks after occlusion of the femoral artery, serial intramuscular injections of EPC, EPC‐CM, or control medium were given. (A) Hindlimb blood flow and was measured by laser Doppler immediately after the first injection (iDAY 1) and 5 weeks later (iDAY 35). (B) Capillary density was assessed 5 weeks after treatment. Adapted, with permission, from DiSanto et al. ().


Figure 16. Circulating angiogenic cells (CAC) release a myriad of factors including proteins and microRNAs (miRs). These molecules can act as paracrine factors to induce effects upon cell types of the cardiovascular system (and others), or as autocrine factors to affect CAC functions. Extracellular vesicles (ECVs), such as microvesicles and exosomes, are additionally secreted and act as a means of intercellular transport of paracrine factors. Acutely, exercise and sedentary behavior may alter the expression and secretion of proteins, miRs, and ECVs. Long‐term health status, spanning from disease to the exercise trained state, ultimately determines the paracrine function of CAC.


Figure 17. CD34+ cell‐derived exosomes induce therapeutic angiogenesis by transferring miR‐126. Immediately following induction of hindlimb ischemia, mice received injections of PBS (control), CD34+ cells, CD34+ cell conditioned medium (CM), CD34+ exosomes (CD34Exo), CD34+ exosome‐depleted CM, or mononuclear cell (MNC) exosomes. (A) Pictures were taken 28 days after injection of the indicated treatment. (B) Exosomes derived from CD34+ cells knocked down for miR‐126 (miR126‐KD‐Exo) exhibited reduced effects on limb reperfusion compared with exosomes from cells treated with a scrambled miR control. Adapted, with permission, from Mathiyalagan et al. ().
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Teaching Material

R. Q. Landers-Ramos, R. M. Sapp, D. D. Shill, J. M. Hagberg, S. J. Prior. Exercise and Cardiovascular Progenitor Cells. Compr Physiol 9: 2019, 767-797.

Didactic Synopsis

Major Teaching Points:

  • Autologous progenitor cell therapies to treat cardiovascular diseases (particularly myocardial ischemia) have proven safe, but definitive efficacy has not been established.
  • The number and function of circulating angiogenic cells (CACs, including progenitor cells with paracrine, pro-angiogenic function) are typically reduced in those with cardiovascular disease, possibly attenuating the benefit of autologous therapies using these cells.
  • Aerobic exercise is a potential strategy to enhance the number and function of CACs. Studies to date reveal:
    1. Acute bouts of aerobic exercise appear to increase the numbers and paracrine function of certain subsets of CD34 + , CD31 + and CD62E + CACs.
    2. Short- or long-term exercise interventions may further augment the increases in the numbers of these CAC subtypes.
    3. These effects are potentially dependent on the mode, intensity and duration of acute exercise or training.
  • The optimal exercise prescription for enhancing CAC function is yet to be determined; however, there is promise for exercise interventions to improve CAC function with implications for the development and treatment of CVD.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching Points: This figure illustrates key developments in therapeutic autologous cell transplantation in conjunction with our perceptions of the potential the therapeutic promise for these cells over the last 20 years. Early studies established high therapeutic promise followed by great scientific interest and a dramatic rise in scientific publications. More recent studies raise doubts about the efficacy of this treatment in its current form, tempering the therapeutic promise although scientific interest remains high.

Figure 2 Teaching Points: This figure illustrates the number of discrepancies in autologous cell therapy trials, with discrepancies defined as two or more logically or mathematically incompatible statements in the reporting of the design, methods, baseline characteristics, and results of trials. These discrepancies cast some doubt on the efficacy of autologous cell therapy in its current form.

Figure 3 Teaching Points: This figure shows a putative model for the spectrum of circulating angiogenic cell (CAC) function among adults of differing age, disease and fitness status. To date, most studies of CAC function have focused on adults with, or at high risk for, cardiovascular diseases, sometimes compared with “healthy” age-matched adults. In order to fully understand the spectrum of CAC function, we propose extending this continuum to incorporate the study of young, exercise-trained adults who are likely to exhibit greater CAC function.

Figure 4 Teaching Points: Acute aerobic exercise has been investigated as a way to increase the circulating numbers of certain progenitor and pro-angiogenic cells. This figure shows results from one representative study finding a substantial increase in the circulating number of CD34 + /KDR + cells and CD34 + /CD133 + cells within 10 minutes after completing a 30-minute bout of running at either moderate or high intensity.

Exercise-stimulated muscle contraction and shear stress on the endothelium provide stimuli for mobilizing CD34 + cells from the bone marrow to increase their circulating concentrations. Laufs et al. first assessed the effects of physical activity on different CD34 + cell populations in healthy young adults. They found 30 minutes of running at either high intensity (∼82% VO2max) or moderate intensity (∼68% VO2max) increased CD34 + /KDR + and CD34 + /CD133 + cell numbers (Figure 4) within 10 minutes of completion of the exercise, while moderate running for just 10 minutes did not have an effect on numbers of either CD34 + subpopulations. For both CD34 + /CD133 + and CD34 + /KDR + cell types, the peak in number occurred between 10 and 30 minutes after completion of exercise (Figure 5).

Figure 5 Teaching Points: This figure illustrates the time course of increases in CD34 + / VEGFR2 + circulating angiogenic cells after 30 minutes of intensive running. The peak increase in CD34 + / VEGFR2 + cell number occurred within 10-30 minutes after the bout of exercise, but the effects of acute exercise were short-lasting with the number of CD34 + / VEGFR2 + cells retuning to baseline within 6 hours.

Figure 6 Teaching Points: The number of circulating angiogenic cells is known to be affected by various aging-related cardiometabolic diseases. As one example, the data shown here demonstrate that older adults with either impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM) have lower numbers of circulating CD34 + / VEGFR2 + cells compared with normal glucose tolerant (NGT) adults. Furthermore, the adults with IGT and T2DM showed no increase in the circulating numbers of these cells after exercise, suggesting a defect in mobilization of these cells that coincides with impaired glucose metabolism.

Figure 7 Teaching Points: Short-term aerobic exercise training interventions may also affect the number of circulating angiogenic cells in older adults. This figure illustrates the changes in the numbers of CD34 + cells and CD34 + KDR + cells after 10 days of vigorous aerobic exercise training. For both the total CD34 + cell population and the CD34 + /KDR + cell subpopulation, substantial increases were observed with a relatively short exercise intervention.

Figure 8 Teaching Points: CD34 + cells play an important role in the repair and maintenance of the vascular endothelium and promote physiological angiogenesis. One of the main ways in which CD34 + cells function is through paracrine mechanisms, whereby they secrete factors that influence nearby endothelial cells. This can be studied experimentally by culturing CD34 + cells using the cell culture media (called “conditioned media” because after culture it contains factors that have been secreted by the cells) and using this in an assay to see how the factors present in the media affect the ability of endothelial cells to form capillary-like structures (a means of assessing angiogenesis). This figure illustrates the differences that factors secreted by CD34 + cells from endurance trained, active and inactive individuals have on the ability of endothelial cells (HUVECs) to form capillary-like structures. The factors secreted into the media from moderately active and inactive individuals’ CD34 + cells resulted in reduced capillary-like structure formation compared with the factors secreted from endurance trained individuals’ CD34 + cells. This suggests that there are factors being secreted by CD34 + cells in low or inactive individuals that may be impairing normal angiogenesis.

Figure 9 Teaching Points: CD31 + /CD3 + cells demonstrate vasculoprotective properties and promote neovascularization. Thus, higher numbers of CD31 + /CD3 + cells in circulation are generally beneficial. Figure 9A illustrates that young (25 ± 1 years) and middle-aged (46 ± 1 years) men have higher circulating numbers of CD31 + /CD3 + cells compared with older men (64 ± 2 years) and Figure 9B demonstrates an inverse relationship between CD31 + /CD3 + cell number and age. Together this suggests that older adults may have impaired vascular repair systems due, in part, to lower numbers of CD31 + /CD3 + cells in circulation.

Figure 10 Teaching Points: This figure illustrates that younger men (18-30 years) have higher CD31 + /CD3 + cells (also called angiogenic T-cells or AngT) compared with both middle-aged (31-50 years) and older men (51-75 years). Compared with the data in Figure 9, this figure demonstrates more of a graded effect of advancing age on CD31 + /CD3 + cell number. Older age is associated with reduced angiogenic potential and this may be due to reduced circulating numbers of CD31 + /CD3 + cells.

Figure 11 Teaching Points: Acute moderate-intensity exercise has been found to mobilize different sub-populations of cells, including CD31 + /CD3 + cells (also called angiogenic T cells or Ang T), into circulation. This figure demonstrates that a single bout of cycling exercise for 30 minutes at a moderate intensity (70% individual VO2max) successfully increased circulating number of CD31 + /CD3 + cells in younger adults but the response in older adults was attenuated. This impaired ability of older adults to mobilize angiogenic cells may explain the reduced angiogenic potential associated with older age.

Figure 12 Teaching Points: This figures shows that three weeks of aerobic exercise training increases the number of CD31 + /CD14 + cells in young, healthy men. Supplementation with a mitochondrial-specific antioxidant (MitoQ) did not alter these responses, suggesting mitochondrial-derived reactive oxygen species do not appear to influence this exercise training-induced augmentation of CD31 + /CD14 + cells. Higher basal CD31 + /CD14 + levels after endurance exercise training may be indicative of an anti-inflammatory state and active endothelial repair, as monocytes home to sites of vascular injury, but it is necessary to address the impact of short-term aerobic exercise training on the overall function of this cell population.

Figure 13 Teaching Points: Chronic endurance exercise augments the paracrine capacity of CD31 + /CD34- cells to contribute to the maintenance and repair of the endothelium. As paracrine-mediated signaling is described as the major mechanism by which CACs exert their pro-endothelial properties, the implementation of an endurance-based exercise-training program elicits favorable adaptations in ability of CD31 + /CD34- cells to contribute vascular integrity. Alternatively, it could be viewed that a lack of chronic exercise (physical inactivity) exerts a deleterious effect on the pro-angiogenic properties of CD31 + /CD34- cells.

Figure 14 Teaching Points: CD62E + cells are an exercise-inducible subpopulation of circulating cells contributing to the maintenance and repair of the endothelium. Maximal, submaximal, and a short-term endurance exercise-training intervention increase the number of CD62E + cells. Estimating the cumulative exercise volume (by multiplying the exercise frequency, intensity, and time) from the available literature suggests a higher collective exercise load will elicit a greater increase in CD62E + cells. Although submaximal exercise augments the capacity for CD62E + cells to exert their favorable angiogenic properties via a paracrine-mediated fashion, the impact of maximal exercise and endurance training has yet to be addressed. Nonetheless, more research is necessary to understand how the interactive effects of exercise frequency, intensity, and duration impact CD62E + cell numbers and function.

Figure 15 Teaching points: The angiogenic effects of paracrine factors secreted by endothelial progenitor cells (EPCs) are similar to those induced by the cells themselves. This is shown by an equivalent recovery of (A) blood flow and (B) capillary density in rats with hindlimb ischemia that recived either injections of EPCs or the conditioned media generated by EPCs.

Figure 16 Teaching points: Paracrine factors including proteins, microRNAs, and extracellular vesicles are released by circulating angiogenic cells (CACs) and are taken up by other cells of the cardiovascular system, where they can induce effects which are dependent on the stimulus for CAC release. Namely, acute exercise causes the release of beneficial paracrine factors, and when repeated over time this results in beneficial remodeling of the cardiovascular system. Chronic sedentary behavior likely has the opposite effect and favors the release of factors which lead to the development of diseases.

Figure 17 Teaching points: Exosomes are extracellular vesicles that carry paracrine factors, such as microRNAs (miR), released by circulating angiogenic cells (CAC) to other cells of the cardiovascular system. Figure 17A shows that CAC-derived exosomes alone were able to induce recovery from hindlimb ischemia in a comparable manner to CAC and CAC conditioned medium. When exosomes were removed from conditioned medium, the therapeutic benefits were lost. Figure 17B shows that miR-126 in the exosomes was found to be necessary for the therapeutic function of exosomes. This suggests that miR “cargo” carried by exosomes is a key factor for CAC angiogenic paracrine function.

 


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Rian Q. Landers‐Ramos, Ryan M. Sapp, Daniel D. Shill, James M. Hagberg, Steven J. Prior. Exercise and Cardiovascular Progenitor Cells. Compr Physiol 2019, 9: 767-797. doi: 10.1002/cphy.c180030