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Objectives: Circulating proangiogenic haematopoietic cells (PHCs), including CD34+ cells, play an important role in endothelial homeostasis. Among PHCs, CD34+ cells are the largest cell population, thus, much of the regenerative/reparative potential of PHCs may be attributed to CD34+ cells. Our aim was to determine the association between inflammation and CD34+ cell number, intracellular levels of reactive oxygen species (ROS) and expression of Toll-like receptor 3 (TLR3) and interleukin 1β (IL-1β), arterial stiffness (AS) indices, and carotid intima-media thickness (cIMT) in patients affected by rheumatoid arthritis (RA)., Methods: CD34+ cells were isolated from 24 RA patients and 26 matched controls. ROS levels, TLR3 and IL-1β expression were measured. C-reactive protein (CRP), fibrinogen, AS, and cIMT were also evaluated., Results: CD34+ count was lower in RA patients as compared to controls. In CD34+ cells from RA patients, ROS, TLR3 and IL-1β expressions were increased compared to controls. In RA patients, we found higher CRP and fibrinogen levels, and higher values of Pulse Wave Velocity (PWV) and Augmentation Index (AIx), both AS indices, and of cIMT. CD34+ cell numbers were inversely correlated with CRP, TLR3, IL-1β, ROS, and AS indices. TLR3 levels were related to CRP, IL-1β, fibrinogen and ROS. IL-1β levels were correlated with expression of CRP, ROS, and PWV., Conclusions: Inflammatory status in RA is associated with an increased expression of TLR3 and of IL-1β in CD34+ cells, which appear to affect cell number. These new findings suggest a perspective on accelerated atherosclerosis and vascular damage in RA.

Introduction: End stage renal disease (ESRD) is associated with a high incidence of cardiovascular disease and cancer. Patients undergoing hemodialysis show a reduced number and an impaired function of endothelial progenitor cells (EPCs), which in physiological conditions contribute to repair the vascular damage. In patients with ESRD, massive oxidative genome damage has been demonstrated but the role of HD in causing it is still a controversial issue. The aim of our study was to analyze the effects of a single HD session on the number of cells marked with CD34 (including sub-type cells known to be EPCs); we then evaluated the genomic damage in these cells using COMET assay., Patients and Methods: We quantified CD34(+) cells in blood samples in 30 patients in hemodiafiltration treatment for 3.5 to 4 hours 3 times/week and in 30 healthy volunteers. In HD patients, blood samples were drawn at different time intervals: start of dialysis (T(0)), at the end of the treatment (T(end)) and 24 hours afterwards in the interdialytic day (T(inter)). Staining and analysis was performed using the ISHAGE (International Society of Hematotherapy and Graft Engineering) guidelines. EPCs count was conducted using a multiparameter flow cytometric lyse no-wash method. Genomic damage was evaluated by Comet assay., Results: The number of CD34(+) cells in the HD patients at the beginning of the dialysis session (T(0)) was significantly lower than in healthy controls. HD patients showed a significant increase in CD34 number at the end of the session (T(end)) with respect to T(0). In the interdialytic period (T(int)), the number of CD34(+) cells was significantly reduced with respect to T(end). COMET assay performed on CD34(+) cells showed a higher basal level of genomic damage in HD patients than in controls; it increased in a statistically significant manner after the hemodialysis session, while in the interdialytic period it came back to T(0) level., Conclusions: Uremic status is characterized by lower levels of circulating EPCs, which increase after a single session of HD together with genomic damage to the CD34(+) cells.

Bisphosphonates (BPs) are the current standard of care for bone lesions in patients with multiple myeloma (MM) but they are associated with a number of side effects such as osteonecrosis of the jaw. The exact mechanisms of osteonecrosis are not elucidated, and its physiopathology is based on several hypotheses such as a decrease in bone remodeling or an inhibitory effect on angiogenesis. The aim of our study was to investigate the mechanism involved in the pathogenesis of osteonecrosis. We examined the apoptosis of circulating endothelial progenitor cells in MM subjects before and after BP treatment and in osteonecrosis patients using a flow-cytometric analysis. Our data showed an increase in endothelial cell apoptosis in MM patients after BP administration and in osteonecrosis subjects. Our study seems in agreement with the hypothesis that BPs can inhibit angiogenesis interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis., (Copyright © 2010 S. Karger AG, Basel.)

Bone marrow-derived, CD34+ progenitor cells have been shown to promote the repair of damaged tissues, offering promise for the treatment of hereditary and acquired human diseases. These cells in fact differentiate into endothelia, hematopoietic cells and possibly neurons, fibroblasts and muscle. CD34+ and AC133+ progenitor cells may participate in neovascularization by differentiating into endothelial cells. Circulating bone marrow-derived endothelial cells home to sites of neovascularization and stimulate healing of injured tissues but also promote restenosis, tumor growth and inflammatory disease. These cells may thus participate in tissue regeneration or pathogenesis of several diseases. Although the molecular mechanisms that promote the homing and recruitment of bone marrow-derived progenitor cells to remodeling tissues remain unclear the evidence that these cells promote tissue repair is strong.

Endothelium was initially considered an inert lining of the blood vessels. Recently, it was suggested that damaged cells are continuously replaced by novel cells, hematopoietic stem cells (HSCs), which are directly mobilized by the bone marrow and then transformed into endothelial progenitor cells (EPCs). Initial triggers of vessel remodeling are physical forces such as blood pressure and fluid shear stress. We investigated whether or not a stress stimulus on vessels applied by a cold pressor test (CPT) would stimulate the mobilization of progenitor cells. Twenty-two healthy subjects, 20 patients with essential hypertension, and 18 with chronic kidney disease (CKD) underwent CPT by dipping their hands in icy water for 4 min. Immediately before and after 4 and 60 min, we quantified HSCs and EPCs identified by flow cytometry. We measured also adhesion soluble molecules (sICAM-1, sVCAM-1, and sE-selectin) as markers of endothelial activation. In healthy and hypertensive subjects, but not in CKD subjects, the number of HSCs was elevated as a direct response to CPT stress. Levels of EPCs and adhesion soluble molecules increased significantly, but to a different extent in every group. In CKD patients, the number of EPCs did not return to basal levels either after 60 min. Levels of adhesion soluble molecules directly correlated with the number of progenitor cells in hypertensive and healthy subjects. CPT caused an increase in adhesion soluble molecules. Discrepancies in the numbers of HSCs and EPCs in CKD patients could suggest a specific impairment in blood vessel remodeling correlated with recognized endothelial dysfunction.

During haemodialysis (HD) the endothelium is the first organ to sense and to be impaired by mechanical and immunological stimuli. We hypothesized that a single HD session induces mobilization of endothelial progenitor cells (EPCs) and that cardiovascular risk factors may influence this process. We quantified EPCs at different maturational stages (CD34+, CD133+/VEGFR2+) in blood samples from 30 patients, during HD and on the interdialytic day, and in 10 healthy volunteers. Samples were drawn at the start of HD, 1, 2 and 3 h after, at the end of HD and at 24 h on the interdialytic day. Patients were divided into two groups based on a recent risk scoring system (SCORE project): low-risk (LR) and high-risk groups (HR). HD patients showed a significantly reduced basal number of EPCs with respect to healthy volunteers. In contrast, we observed increasing EPCs during HD whereas they diminished on the interdialytic day. The EPC number was directly correlated with HD time progression. The EPC number during HD was increased in the HR group with respect to the LR group. We had a direct correlation between risk score and number of EPCs. Cardiovascular risk factors influenced the mobilization of stem cells from the bone marrow. This feature could be the direct consequence of an augmented request of stem cells to respond to the most important endothelial impairment but could also show a defective capacity of EPCs to home in and repair the sites of vascular injury., (Copyright 2007 S. Karger AG, Basel.)

Objective: The aim of the present study was to analyze the concentrations of endothelial precursor cells (EPCs) during the 3 trimesters of normal pregnancy and to compare the EPC counts in women with normal pregnancy, gestational diabetes, and gestational hypertension., Study Design: The study was conducted on 21 pregnant women with single pregnancies (age range, 22 to 35 years). EPCs were quantified by flow cytometry. The subjects were divided into 3 groups, each consisting of 7 subjects: patients with gestational diabetes; patients with gestational hypertension; patients with normal pregnancy., Results: A progressive increase was found in the concentrations of EPCs during pregnancy in healthy women. In the third trimester of pregnancy, the number of CD34+ cells was significantly lower in patients with gestational diabetes than in hypertensive patients and controls; no significant differences were found between the levels of circulating CD34+ cells in hypertensive patients and those in controls. There were no significant differences between the diabetic and hypertensive patients for the percentage of cells expressing CD133 and VEGFR2, whereas in both groups the percentage of CD133+/VEGFR2+ elements was significantly higher than in the healthy control subjects., Conclusion: Our findings confirm that EPCs isolated from the maternal circulation increase gradually throughout the gestational trimesters. These cells were derived from the endothelial cells lineage, as demonstrated by CD133+/VEGFR2+ cell assay. Moreover, the concentration of EPCs in pregnant women with gestational diabetes and hypertension differs from that in subjects with a normal pregnancy, CD34+ cells being reduced but CD133+/VEGFR2+ cell concentrations being increased. These results not only substantiate recent insights into the mechanisms regulating maternal vascular modifications during pregnancy but also throw light upon the activation of different patterns in the mobilization of endothelial progenitor cells during pathologic states in which endothelial disorders occur.