Number Of Circulating Progenitor Cells Research Articles

High expression of endothelial progenitor cell-induced angiogenic markers is associated with bile acid levels in HCC.

Endothelial progenitor cell (EPC)-induced angiogenesis activity is enhanced in hepatocellular carcinoma (HCC); however, the contributing factors remain unknown. The present study aimed to investigate the factors influencing the number of EPCs and circulating progenitor cells (CPCs), as well as the expression levels of vascular endothelial growth factor receptor 2 (VEGFR-2) and CD34, in patients with HCC. The expression levels of VEGFR-2 and CD34 were assessed in 72 HCC tumor and matched adjacent tissue microarrays by immunohistochemistry. The associations between VEGFR-2 or CD34 expression in tumors, clinicopathological characteristics and overall survival rates were analyzed. The number of EPCs and CPCs were analyzed in the peripheral blood of patients with HCC. In this study, high expression levels of VEGFR-2 and CD34 were detected in the tumor tissues of 41 (56.9%) and 44 (61.1%) patients, respectively. VEGFR-2 expression was significantly associated with tumor size (P<0.001), bile acid level (P=0.014) and α-fetoprotein level (P=0.011). However, CD34 expression was associated with tumor size (P=0.009), recrudescence (P<0.001) and bile acid (P=0.009). Next, the expression levels of VEGFR-2 and CD34 in tumor and adjacent tissues were compared according to the bile acid level. VEGFR-2 and CD34 expression levels were both higher in the high bile acid group, whereas expression levels of the markers were higher in adjacent tissues compared with tumor tissues. Kaplan-Meier curve analysis identified that patients with low CD34 expression had a longer overall survival compared with patients with high CD34 expression (P=0.029). Multivariate analysis also indicated that both VEGFR-2 (P=0.020) and CD34 (P=0.035) were independent prognostic risk factors. Moreover, flow cytometry demonstrated that the number of EPCs and CPCs was negatively related with the bile acid levels in patients with HCC. In conclusion, in patients with HCC, bile acid promotes EPC-induced angiogenesis. Furthermore, EPCs and CPCs may be activated by bile acid in tumors but are more so in adjacent tissues.

Endothelial progenitor cells and peripheral neuropathy in subjects with type 2 diabetes mellitus

AimsTo examine for differences in circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) in patients with and without diabetic peripheral neuropathy (DPN). MethodsA total of 105 participants were included: 50 patients with type 2 diabetes (T2DM) and DPN, 30 patients with T2DM without DPN and 25 healthy individuals. CPCs and 6 different EPCs phenotypes were assessed with flow cytometry. We also measured plasma levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor 1 (SDF-1), vascular cell adhesion protein-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM) and tumor necrosis factor a (TNFa). ResultsNo difference was observed in the number of CPCs among the 3 groups. Patients with DPN had higher numbers of all 6 EPCs phenotypes when compared with patients without DPN and higher number of 5 EPCs phenotypes when compared with healthy individuals. Plasma VEFG, VCAM-1, ICAM-1 and TNFa levels did not differ among the 3 groups. Patients with DPN had lower SDF-1 levels in comparison with healthy individuals. ConclusionCirculating EPCs are increased while SDF-1 levels are decreased in the presence of DPN. Our findings suggest that DPN may be associated with impaired trafficking of EPCs and impaired EPCs homing to the injured endothelium.

Circulating Progenitor Cells and Racial Differences.

Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs. To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites. CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (-17.6%; [95% confidence interval (CI), -23.5% to -11.3%]; P<0.001), CD34+/CD133+ cells (-15.5%; [95% CI, -22.4% to -8.1%]; P<0.001), CD34+/CXCR4+ cells (-17.3%; [95% CI, -23.9% to -10.2%]; P<0.001), and CD34+/VEGF2R+ cells (-27.9%; [95% CI, -46.9% to -2.0%]; P=0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P=0.02). Blacks had significantly lower plasma MMP-9 levels ( P<0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%-33%). However, VEGF and SDF-1α levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12-7.20]; P=0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09-2.94]; P=0.02) without significant interaction. Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.

Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes.

Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P=0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Bioactive Lipids and Circulating Progenitor Cells in Patients with Cardiovascular Disease.

Bone marrow‐derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine‐1 phosphate (S1P) and ceramide‐1 phosphate (C1P) were quantified using mass spectrometry. CPCs were assessed using flow cytometry. S1P levels correlated with the numbers of CD34+, CD34+/CD133+, and CD34+/CXCR4+ CPCs even after adjustment for potential confounding factors. However, no significant correlation was observed between C1P levels and CPC count. Plasma levels of S1P correlated with the number of CPCs in patients with coronary artery disease, suggesting an important mechanistic role for S1P in stem cell mobilization. The therapeutic effects of adjunctive S1P therapy to mobilize endogenous stem cells need to be investigated. Stem Cells Translational Medicine 2017;6:731–735

Abstract 17106: Nox2-derived Reactive Oxygen Species Impede Vascular Repair in the Context of Endothelium-specific Insulin Resistance

Introduction: Insulin resistance is independently linked to cardiovascular disease, and oxidative stress is recognised as a potential contributor to this relationship. We have previously shown that endothelium-specific insulin resistance promotes endothelial dysfunction, atherosclerosis, and increased vascular NADPH oxidase 2 (NOX2) derived reactive oxygen species (ROS). Oxidative stress may promote vascular disease by impairing endogenous vascular repair. Hypothesis: We hypothesise that deletion of NOX2 in mice with endothelial specific insulin resistance can improve vascular repair. Methods: Mice with endothelial specific insulin resistance (ESMIRO) were bred with mice deficient in NOX2, in order to produce double-cross ESMIRO x NOX2y/- (ExN) offspring. Phenotypic assessment comprised glucose and insulin tolerance tests and ELISA for plasma insulin concentration. In vivo assessment of vascular repair and angiogenesis were undertaken using femoral artery wire injury and hindlimb ischaemia techniques, respectively, whilst flow cytometry was used to quantify circulating progenitor cells (CPCs). Data are expressed as mean [standard error] and compared using unpaired t-tests; *=p&lt;0.05. Results: No significant differences were seen between ExN and ESMIRO in glucose tolerance, insulin sensitivity, or basal insulin level (0.8[0.1]ng/ml vs. 0.8[0.1];p=0.8). ExN mice demonstrated significantly improved vascular regeneration following injury compared to ESMIRO (62%[4%] vs. 46%[3%]*), coupled with a significantly higher number of CPCs (202.6[20.3] per 100000 lymphocytes vs. 134.3[10.6]*). This improvement was not mirrored in ischaemic limb perfusion recovery (Perfusion relative to non-ischaemic limb at 28 days 54%[8%] vs. 53%[4%]). Conclusions: Our data demonstrate that targeting NOX2 can augment vascular repair in the setting of endothelial specific insulin resistance, whilst having no detrimental impact on the response to limb ischaemia, and is associated with an increased abundance of CPCs. These findings support a possible role for NOX2 inhibitors to promote recovery from vascular injury in the setting of insulin resistance.

Circulating CD34+ progenitor cells and risk of mortality in a population with coronary artery disease.

Low circulating progenitor cell numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. To investigate whether low numbers of progenitor cells associate with a greater risk of mortality in a population at high cardiovascular risk. Patients undergoing coronary angiography were recruited into 2 cohorts (1, n=502 and 2, n=403) over separate time periods. Progenitor cells were enumerated by flow cytometry as CD45(med+) blood mononuclear cells expressing CD34, with additional quantification of subsets coexpressing CD133, vascular endothelial growth factor receptor 2, and chemokine (C-X-C motif) receptor 4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary end point of all-cause death. There was an inverse association between CD34(+) and CD34(+)/CD133(+) cell counts and risk of death in cohort 1 (β=-0.92, P=0.043 and β=-1.64, P=0.019, respectively) that was confirmed in cohort 2 (β=-1.25, P=0.020 and β=-1.81, P=0.015, respectively). Covariate-adjusted hazard ratios in the pooled cohort (n=905) were 3.54 (1.67-7.50) and 2.46 (1.18-5.13), respectively. CD34(+)/CD133(+) cell counts improved risk prediction metrics beyond standard risk factors. Reduced circulating progenitor cell counts, identified primarily as CD34(+) mononuclear cells or its subset expressing CD133, are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction, and cell selection for cell-based therapies.

Combination Therapy Accelerates Diabetic Wound Closure

BackgroundNon-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis.Methods and ResultsWounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 μg; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%.ConclusionsCombination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to improve diabetic wound healing using FDA-approved therapies is inherently translatable.

In This Issue

HomeCirculation ResearchVol. 114, No. 2In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published17 Jan 2014https://doi.org/10.1161/01.res.0000442772.20361.20Circulation Research. 2014;114:227Cardiosplenic Axis in Heart Failure (p 266)Download figureDownload PowerPointIsmahil et al report changes in inflammatory cells in mice with chronic heart failure.Persistent inflammation is a characteristic feature of heart failure. Indeed in humans increased levels of pro-inflammatory cytokines correlate with severity of heart failure and, in animal models, inflammation has been shown to contribute to ventricular remodeling and contractile dysfunction. However, in clinical trials cytokine antagonism has failed to provide benefits to patients. Given that cytokines are produced by, and target, immune cells, studying the behavior of these cells during chronic heart failure might provide additional insights into the condition. Ismahil and colleagues found that pro-inflammatory macrophages as well as dendritic cells are increased in the hearts of mice with chronic heart failure, while pro-inflammatory monocytes were more abundant in the blood. In addition, they also found that the spleens of the mice displayed increased numbers of dendritic cells, cytotoxic T cells and helper T cells. Strikingly, removal of the spleen reversed the remodeling and inflammation observed in the failing mouse hearts. Furthermore, when spleen cells from mice with heart failure were transferred into healthy mice, the recipient’s hearts began to fail. These results suggest that targeting specific immune cell populations in the heart and or the spleen might engender more effective therapeutic outcomes in chronic heart failure than targeting cytokines alone.Carotid Intima-Media Thickness in Children with FH (p 307)Download figureDownload PowerPointChildren with familial hypercholesterolemia show evidence of artery thickening from a very young age, report Kusters et al.Familial hypercholesterolemia (FH) is characterized by elevated LDL levels in the blood from birth onwards. The condition elevates the risk of atherosclerosis and cardiovascular disease later in life, but sub-clinical thickening of the carotid artery wall—indicative of atherosclerosis—has been observed in children with FH as young as 12. This early wall thickening is the basis of an ongoing safety and efficacy trial of the LDL-lowering drug rosuvastatin in children. Using ultrasound measurement of the carotid artery, Kusters and colleagues have now examined the wall, or intima-media, thickness in even younger children. They recruited 196 children with FH aged between six and 17 as well as 64 of their unaffected siblings. The ultrasounds revealed that, in general, children with FH had significantly thicker intima-media than their unaffected siblings. Furthermore, this significant difference was discernable even before the age of eight. Thus, the new report extends the findings of the previous study to younger children. It also highlights the importance of testing LDL-lowering therapies, like rovustatin, in children of a very young age–the aim being to stop atherogenesis before it starts.Bone marrow and critical limb ischemia (p 311)Download figureDownload PowerPointCritical limb ischemia is associated with vascular and neuropathic changes in the bone marrow, say Teraa et al.Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease and is associated with a high risk of amputation, and even death. CLI risk is increased by diabetes and the condition is associated with impaired growth of new blood vessels in the lower limbs, which may be due in part to the reduction in circulating progenitor cells observed in these patients. This reduction in progenitor cell levels suggests that CLI patient bone marrow—the source of circulating progenitor cells—may be dysfunctional. To examine whether CLI damages the bone marrow and how this is affected by diabetes, Teraa and colleagues took bone marrow biopsies from 33 patients with CLI, 13 of whom had diabetes, and 12 of whom did not. Their histological analyses revealed that bone marrow from CLI patients had fewer microvessels—capillaries and sinusoids—and fewer nerve terminals than that from healthy controls. However, the team saw no differences in the microvessel density or the degree of innervation between diabetic and non-diabetic CLI patients. These findings demonstrate that independent of diabetes, CLI is associated with altered bone marrow histology, and suggest such alterations may be the root cause of the diminished circulating progenitor cell numbers. Previous Back to top Next FiguresReferencesRelatedDetails January 17, 2014Vol 114, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/01.res.0000442772.20361.20 Originally publishedJanuary 17, 2014 PDF download Advertisement

Abstract 022: Higher Baseline Progenitor Cell Counts in Familial Hypercholesterolemic Patients Compared to Healthy Controls

Background: Endothelial injury from exposure to cardiovascular risk factors leads to atherosclerosis, however, an endogenous response to vascular injury characterized by circulating progenitor cells (CPCs) contributes to endothelial repair and regeneration. Although CPCs are known to be inversely related to cardiovascular risk, it is uncertain whether these risk factors are also a stimulus for CPC mobilization. We measured the number of CPCs in patients with familial hypercholesterolemia (FH) and compared them to patients with hyperlipidemia and healthy controls, with the hypothesis that CPC levels would be modulated by FH. Methods: Eight patients with FH on statin therapy (mean age, 48 ± 17 years) were compared with 16 age- and gender-matched hyperlipidemic patients on statin therapy, and 16 healthy volunteers. CPCs were analyzed using flow cytometry (BD FACS Canto II) for mononuclear cell (CD45dim) surface expression of CD34 and a combination of VEGF2R, CD133, and CXCR4 epitopes. Results are expressed as means ± SD or as proportions, and analysis of variance was used to detect differences between the three groups. Results: FH patients had higher circulating numbers of CD34+/CD133+ cells compared to hyperlipidemic (1.49 ± 1.01 vs. 0.88 ± 0.52 cells/µL, p = 0.04, respectively) and healthy counterparts (0.97 ± 0.61 cells/µL, p = 0.08). Similarly, FH subjects also had higher circulating levels of CD34+/CD133+/CXCR4+ cells compared to both the hyperlipidemic (0.68 ± 0.36 vs. 0.30 ± 0.22 cells/µL, p = 0.002, respectively) and healthy group (0.32 ± 0.25 cells/µL, p = 0.003). Conclusions: CPC counts, particularly of early CPCs characterized by CD133, and also those expressing the homing receptor, CXCR4, are higher in FH patients compared to age- and gender-matched healthy controls and patients with hyperlipidemia, independent of statins. This suggests an activation of reparative and regenerative reserve in FH subjects. The increased level of CPCs in FH subjects compared to hyperlipidemic patients may be a collective result of a higher level of lipid burden, lower therapeutic response to anti-hyperlipidemic pharmacotherapy, and chronic immune-activation due to ongoing subclinical endothelial injury in FH patients.

FRI0103 Vit d deficiency, depletion of circulating endothelial progenitor cells and impaired arterial stiffness in patients with ra

BackgroundVitamin D deficiency was recently acknowledged as an independent predictor of cardiovascular diseases and all-cause mortality in several clinical setting and its serum levels are commonly reduced in Rheumathoid Arthritis....

Relationship Among Endothelial Response to Hyperemia, Bone Marrow-Derived Progenitor Cells, and Parathyroid Hormone in Renal Transplantation

Endothelial dysfunction may contribute to modulate cardiovascular complications in renal transplant recipients (RTRs), and a relationship between endothelial dysfunction and parathyroid hormone (PTH) levels in RTRs has been demonstrated. We evaluated the relationship between endothelial response to hyperemia and circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) PTH, and genetic parameters in RTRs. In 120 RTRs and in healthy subjects without (n=107, group A) and with cardiovascular risk factors (n=109, group B), we evaluated endothelial response to hyperemia through digital tonometry (peripheral arterial tonometry) detected by reactive hyperemia index (RHI) and EPCs and CPCs by flow cytometry. In RTRs, RHI median value was lower than in group A (P=0.05). EPC number was significantly lower in RTRs than in groups A and B (P<0.0001), whereas PTH median value was significantly higher (P<0.0001). In RTRs, RHI values were significantly lower according to the presence of three or more risk factors (P=0.04) and positively correlated with EPCs (P=0.04) but not with PTH (P=0.2). In patients who underwent dialysis for more than 5 years, lower RHI values (P=0.08), EPC number (P=0.5), and higher PTH concentrations (P=0.09) than in patients with less than 1 year dialysis time were observed. No relationship between eNOS gene -786T>C, 894G>T, and 4a/4b polymorphisms and RHI, EPC, and CPC number was found. This study shows an altered endothelial response, associated with reduced EPCs, and increased PTH in RTRs; the evaluation of endothelial status in RTRs may contribute to better assess the risk profile of these patients.

Heavy and moderate interval exercise training alters low‐flow‐mediated constriction but does not increase circulating progenitor cells in healthy humans

Moderate-intensity endurance exercise training improves vascular endothelial vasomotor function; however, the impact of high-intensity exercise training has been equivocal. Thus, the effect of the physiological stress of the exercise remains poorly understood. Furthermore, enhanced vascular repair mediated by circulating progenitor cells may also be improved. To address whether the physiological stress of exercise training is an important factor contributing to these adaptations, 20 healthy participants trained for 6 weeks. Training involved either moderate (MSIT; n= 9) or heavy metabolic stress (HSIT; n= 11) interval exercise training programmes matched for total work and duration of exercise. Before and after training, flow-mediated dilatation, low-flow-mediated constriction and total vessel reactivity were measured at the brachial artery using Doppler ultrasound. Circulating progenitor cells (CD34+, CD133+ and CD309/KDR+) were measured by flow cytometry (means ± SD). Relative (MSIT pre- 5.5 ± 3.4 versus post-training 6.6 ± 2.5%; HSIT pre- 6.6 ± 4.1 versus post-training 7.0 ± 3.4%, P= 0.33) and normalized (P= 0.16) flow-mediated dilatation did not increase with either training programme. However, low-flow-mediated constriction was greater after training in both groups (MSIT pre- −0.5 ± 3.2 versus post-training −1.9 ± 3.1%; HSIT pre- −1.0 ± 1.7 versus post-training −2.9 ± 3.0%, P= 0.04) and contributed to greater total vessel reactivity (MSIT pre- 7.4 ± 3.3 versus post-training 10.1 ± 3.7%; HSIT pre- 10.9 ± 5.9 versus post-training 12.7 ± 6.2%, P= 0.01). Peak reactive hyperaemia and the area under the shear rate curve were not different between groups, either before or after training. Although circulating progenitor cell numbers increased following heavy-intensity interval exercise training, variability was great amongst participants [MSIT pre- 16 ± 18 versus post-training 14 ± 12 cells (ml whole blood)−1; HSIT pre- 8 ± 6 versus post-training 19 ± 23 cells (ml whole blood)−1, P= 0.50]. Overall, vasoconstrictor function may be augmented by moderate- and heavy-intensity interval exercise training in young adults. However, circulating progenitor cell numbers were not increased, suggesting that these cells are not likely to be upregulated as a result of training.

The influence of concomitant type 2 diabetes mellitus on the number of circulating progenitor cells in patients with ischemiccardiomyopathy

Aim. To study effect of concomitant type 2 diabetes mellitus on the number of circulating progenitor cells (CPC) in patients with coronary heart disease(CHD) and postinfarction heart failure (ischemic cardiomyopathy).Methods. The number of CPC (CD34+ cells) was determined by flow cytophotometry in 47 patients with CHD including 14 with CHD + DM2; 12patients without CHD and DM2 made up the control grouP. Enzyme-linked immunosorbent assay was used to measure N-terminal precursor of brainnatriuretic peptide (NT-proBNP), immunoreactive insulin (IRI) and C-peptide levels. Results. The number of CPC in patients with ischemic cardiomyopathy without DM2 was 33.4% greater than in controls. In patients with cardiomyopathyand DM2 the number of CPC depended on the quality of diabetes compensation. It was lowest in case of decompensated DM2 (HbA1c=9.5?1.8%).In patients with compensated/subcompensated DM2 (HbA1c=6.8?0.3%) it was significantly higher than in controls and patients with ischemiccardiomyopathy without DM2 (mean 46.5 (p=0.006) and 40.0% (p=0.02) respectively). Conclusion. The number of CPC in peripheral blood of patients with ischemic cardiomyopathy and DM2 correlated with the level of DM compensation.It was lowest in patients with decompensated DM2 and exceeded the normal number in patients with CHD without DM2. The number of CPC inverselycorrelated with blood glucose level. Positive correlation of CPC number with IRI and C-peptide levels was documented in control subjects and patientswith CHD without DM2.

Circulating progenitor cells are increased in newly diagnosed untreated hypertensive patients with arterial stiffening but normal carotid intima-media thickness

Circulating progenitor cells (CPCs), including endothelial progenitor cells (EPCs), have a key role in endothelium repair. Cellular NADPH oxidase (Nox) enzymes, including Nox-containing gp91phox, represent a source of reactive oxygen species (ROS); ROS trigger protective signals but may also have detrimental effects. Cellular defenses against ROS include the enzymes manganese superoxide dismutase (MnSOD), catalase (CAT) and glutathione peroxidase type-1 (GPx-1). We investigated the relationships of CPCs with cellular gp91phox, MnSOD, CAT, GPx-1 and ROS levels and with carotid intima-media thickness (cIMT) and stiffness in hypertensives without additional risk factors for cardiovascular disease. CPCs from 53 newly diagnosed, untreated hypertensives and from 29 controls were isolated and identified by flow cytometry. gp91phox, MnSOD, CAT, and GPx-1 mRNA and protein expression and ROS generation were evaluated in enriched samples of CD34(+) cells; cIMT and stiffness were assessed. Hypertensives showed higher arterial stiffness (P < 0.001) but no difference in cIMT with respect to controls. ROS generation was slightly increased (P=0.04), whereas gp91phox, MnSOD, CAT and GPx-1 were significantly higher (P < 0.001) with respect to controls, as was CPC number (P < 0.001), but EPCs were no different. CPC and EPC numbers correlated with gp91phox, ROS and fibrinogen (P < 0.001); moreover, gp91phox, MnSOD, CAT and GPx-1 were correlated with CPC number. In early phases of arterial hypertension, before the development of wall thickening and even in the presence of arterial mechanical impairment, CPC number may be increased to maintain an adequate number of EPCs in peripheral blood.

Decreased Circulating Progenitor Cell Number and Failed Mechanisms of Stromal Cell-Derived Factor-1α Mediated Bone Marrow Mobilization Impair Diabetic Tissue Repair

OBJECTIVEProgenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing.RESEARCH DESIGN AND METHODSCutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Leprdb/db) mice. Blood and bone marrow PCs were collected at multiple time points.RESULTSSignificantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin−/sca-1+/ckit+ in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 ± 3.2% lin−/ckit+/sca1+ vs. 13.5 ± 2.8% in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1α (SDF-1α) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1α expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1α switch (54% reduction, P < 0.01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6.8 ± 2.0-fold increase in lin−/ckit+, P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 ± 5.0% vs. 11.9 ± 3% at day 7, P > 0.05; 73.0 ± 6.4% vs. 36.5 ± 7% at day 14, P < 0.05; and 88.0 ± 5.7% vs. 66.7 ± 5% at day 21, P > 0.05, respectively).CONCLUSIONSSuccessful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1α levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemia-mediated pathology associated with diabetes by reducing bone marrow SDF-1α, restoring normal PC mobilization and tissue healing.

Exercise Training in Patients With Advanced Chronic Heart Failure (NYHA IIIb) Promotes Restoration of Peripheral Vasomotor Function, Induction of Endogenous Regeneration, and Improvement of Left Ventricular Function

Attenuated peripheral perfusion in patients with advanced chronic heart failure (CHF) is partially the result of endothelial dysfunction. This has been causally linked to an impaired endogenous regenerative capacity of circulating progenitor cells (CPC). The aim of this study was to elucidate whether exercise training (ET) affects exercise intolerance and left ventricular (LV) performance in patients with advanced CHF (New York Heart Association class IIIb) and whether this is associated with correction of peripheral vasomotion and induction of endogenous regeneration. Thirty-seven patients with CHF (LV ejection fraction 24+/-2%) were randomly assigned to 12 weeks of ET or sedentary lifestyle (control). At the beginning of the study and after 12 weeks, maximal oxygen consumption (Vo(2)max) and LV ejection fraction were determined; the number of CD34(+)/KDR(+) CPCs was quantified by flow cytometry and CPC functional capacity was determined by migration assay. Flow-mediated dilation was assessed by ultrasound. Capillary density was measured in skeletal muscle tissue samples. In advanced CHF, ET improved Vo(2)max by +2.7+/-2.2 versus -0.8+/-3.1 mL/min/kg in control (P=0.009) and LV ejection fraction by +9.4+/-6.1 versus -0.8+/-5.2% in control (P<0.001). Flow-mediated dilation improved by +7.43+/-2.28 versus +0.09+/-2.18% in control (P<0.001). ET increased the number of CPC by +83+/-60 versus -6+/-109 cells/mL in control (P=0.014) and their migratory capacity by +224+/-263 versus -12+/-159 CPC/1000 plated CPC in control (P=0.03). Skeletal muscle capillary density increased by +0.22+/-0.10 versus -0.02+/-0.16 capillaries per fiber in control (P<0.001). Twelve weeks of ET in patients with advanced CHF is associated with augmented regenerative capacity of CPCs, enhanced flow-mediated dilation suggestive of improvement in endothelial function, skeletal muscle neovascularization, and improved LV function. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00176384.

Bone Marrow-Derived Progenitor Cells in the Early Phase of Ischemic Stroke: Relation with Stroke Severity and Discharge Outcome

A limited number of studies suggested that in ischemic stroke patients, the number of bone marrow circulating progenitor cells (CPCs), either endothelial progenitor cells (EPCs) or CPCs, was negatively correlated with the number of infarcts as well as with the outcome. The aim of this study was to simultaneously measure CPCs and EPCs in the acute phase of ischemic stroke, and to establish whether a relationship exists with stroke severity and discharge outcome. In 67 (40 M; 27 F) ischemic stroke patients with a median age of 73 (21 to 91) years, the number of CPCs and EPCs was measured by flow cytometry and analyzed in relation to baseline NIH Stroke Scale score, ischemic stroke syndromes, and discharge outcome. Patients with partial anterior circulation syndrome showed a higher CPCs' number with respect to patients with total anterior circulation syndrome. Moreover, a negative relationship between National Institutes of Health Stroke Scale score at the admission and CPCs number was observed. When the outcome was considered, patients discharged to home had a higher number of CPCs, but not of EPCs, compared with those moved to a rehabilitation unit. We report an association between the number of CPCs measured in the early phase after stroke presentation, neurologic severity, and discharge outcome.

Effects of exercise training on mobilization and functional activity of blood-derived progenitor cells in patients with acute myocardial infarction

BackgroundThe aim of the present study was to determine whether regular exercise training (ET) is effective at promoting the mobilization of CPCs and improving their functional activity in patients with recently acquired myocardial infarction(STEMI). Regular physical training has been shown to improve myocardial perfusion and cardiovascular function. This mayberelatedin part to a mobilization of bonemarrow-derived circulating progenitor cells (CPCs) as well as an enhanced vascularisation.Methods37 patients with STEMI were randomly assigned to an ET group or a non-ET group(controls). Two weeks after STEMI, three weeks after regular ET and three months after ET, BNP levels, exercise echocardiography and exercise spiroergometry were evaluated. The number of CD34+/CD45+ and CD133+/CD45+CPCs was measured by flow cytometry analysis. The migration capacity of the CPCs was determined with a boyden chamber and the clonogenic capacity by CFU-assay.ResultsIn the ET-group the number and migration capacity of CPCs increased significantly after regular exercise training. The BNP level decreased significantly from 121 ± 94 to 75 ± 47 pg/ml (p < 0.001) after the ET period, the left ventricular rejection fraction raised in parallel at peak exercise, and the cardiorespiratory condition improved as demonstrated by an increase of VO2max (from 1641 ± 522 to 1842 ± 724 ml/min, p < 0.02). These three effects persist till three months after the ET period.ConclusionsRegular physical activity appears to predispose the mobilization and enhanced functional activity of CPCs, a phenomenon which might lead to an improved cardiac function in patients with recently acquired acute myocardial infarction.