Uta Erdbruegger

University of Virginia, Charlottesville, Virginia, United States

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Publications (27)113.74 Total impact

  • Uta Erdbrügger · Joanne Lannigan
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    ABSTRACT: The interest in extracellular vesicles (EVs) has grown exponentially over the last decade. Evolving evidence is demonstrating that these EVs are playing an important role in health and disease. They are involved in intercellular communication and have been shown to transfer proteins, lipids, and nucleic acids. This review focuses on the most commonly used techniques for detection of EVs, to include microparticles, 100-1,000 nm in size, and exosomes, 50-100 nm in size. Conventional flow cytometry is the most prevalent technique, but nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), and resistive pulse sensing have also been used to detect EVs. The accurate measurement of these vesicles is challenged by size heterogeneity, low refractive index, and the lack of dynamic measurement range for most of the available technologies. Sample handling during the preanalytical phase can also affect the accuracy of measurements. Currently, there is not one single method which allows phenotyping, sizing, and enumerating the whole range of EVs and, therefore, providing all the necessary information to truly understand the biology of these particles. A combination of methods is probably needed which might also include electron and atomic force microscopy and full RNA, lipid, and protein profiling. © 2015 International Society for Advancement of Cytometry.
    No preview · Article · Dec 2015 · Cytometry Part A
  • Dylan Burger · Uta Erdbrügger · Kevin D Burns
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    ABSTRACT: Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
    No preview · Article · Sep 2015 · Kidney International
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    ABSTRACT: Cytomegalovirus (CMV) infection is a frequent complication early post-transplant. This study examines its impact on chronic allograft changes, long-term graft loss and patient survival. We studied 594 patients who had protocol biopsies at 6 weeks, 3 and 6 months post-transplant. Chronic allograft changes were evaluated according to the updated Banff classification (IF/TA (interstitial fibrosis/tubular atrophy), vascular and glomerular lesions). Follow up data was available up to 10 years. CMV infection was diagnosed in 153 of 594 patients (26%) in the first year after transplantation, mostly within the first 3 months. Graft survival was reduced in patients with CMV (p=0.03) as well as the combined allograft/patient survival (p=0.008). Prevalence of IF/TA at 6 weeks after transplantation was already 3-fold higher in patients who experienced CMV infection later-on, compared to patients without CMV (p=0.005). In multivariate analyses CMV viremia or disease were not a significant factor for graft loss or death. In conclusion, patients with CMV infection post-transplant show more chronic allograft changes early-on -even before CMV infection- and development of IF/TA is not more prevalent in patients with CMV. Our data do not support a significant role of CMV in patient and graft outcomes.
    No preview · Article · Sep 2015 · AJP Renal Physiology
  • Uta Erdbrügger · Thu H Le
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    ABSTRACT: Extracellular vesicles from the urine and circulation have gained significant interest as potential diagnostic biomarkers in renal diseases. Urinary extracellular vesicles contain proteins from all sections of the nephron, whereas most studied circulating extracellular vesicles are derived from platelets, immune cells, and the endothelium. In addition to their diagnostic role as markers of kidney and vascular damage, extracellular vesicles may have functional significance in renal health and disease by facilitating communication between cells and protecting against kidney injury and bacterial infection in the urinary tract. However, the current understanding of extracellular vesicles has derived mostly from studies with very small numbers of patients or in vitro data. Moreover, accurate assessment of these vesicles remains a challenge, in part because of a lack of consensus in the methodologies to measure extracellular vesicles and the inability of most techniques to capture the entire size range of these vesicles. However, newer techniques and standardized protocols to improve the detection of extracellular vesicles are in development. A clearer understanding of the composition and biology of extracellular vesicles will provide insights into their pathophysiologic, diagnostic, and therapeutic roles. Copyright © 2015 by the American Society of Nephrology.
    No preview · Article · Aug 2015 · Journal of the American Society of Nephrology
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    ABSTRACT: Microparticles (MPs) are submicron vesicles released from cell membranes in response to activation, cell injury, or apoptosis. The clinical importance of MPs has become increasingly recognized, although no standardized method exists for their measurement. Flow cytometry (FCM) is the most commonly used technique, however, because of the small size of MPs, and the limitations of current FCM instrumentation, accurate identification is compromised by this methodology. We decided to investigate whether the use of FCM combined with imaging, such as is possible with the ImagestreamX imaging FC (ISX), would be a more sensitive approach to characterizing MPs. Combining FCM with imaging eliminates some of the limitations demonstrated by conventional FCM, whereas also providing morphological confirmation and the ability to distinguish true single events from aggregates and cell debris. The detection limit of standard nonspecialized FCM is suboptimal when compared to ISX. Evaluating MPs below 0.200 µm and sizing remain a challenge as some MPs remain below the detection limit of ISX. Standardized calibrators, that more closely reflect the physical characteristics of MPs, need further development. © 2014 International Society for Advancement of Cytometry.
    No preview · Article · Sep 2014 · Cytometry Part A
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    Uta Erdbruegger · Ajay Dhaygude · Alexander Woywodt

    Full-text · Chapter · Oct 2011
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    ABSTRACT: Circulating endothelial cells (CECs) are a novel and valuable marker of endothelial damage in a variety of vascular disorders. There is limited information as to CEC counts and the time course of CECs in subtypes of stroke. We studied 49 patients with stroke (18 with atherothrombotic infarction in the territory of the middle cerebral artery, 16 with cardioembolic stroke, and 15 with lacunar stroke). We also included 16 healthy controls and 64 disease controls. CECs were isolated and enumerated with lectin-augmented CD146-driven immunomagnetic isolation. Neurologic deficit was assessed with the European Stroke Scale (ESS) and the National Institutes of Health Stroke Scale (NIHSS). Recovery was assessed with the modified Rankin scale (mRS). Healthy controls had low numbers of CECs (median, 8 cells/mL; mean, 9 cells/mL; range, 0-16 cells/mL; n = 16). Patients with stroke had markedly elevated numbers of CECs at presentation. Patients with atherothrombotic infarction had 32 cells per milliliter (mean, 42 cells/mL; range, 24-116 cells/mL; n = 18; P < .001 when compared to controls). Patients with lacunar stroke had 68 cells per milliliter (mean, 68 cells/mL; range, 8-144 cells/mL; n = 15; P < .001 when compared to controls). Patients with cardioembolic stroke had 46 cells per milliter (mean, 54 cells/mL; range, 24-116 cells/mL; n = 16; P < .001 when compared to healthy controls). There was a tendency towards higher numbers of CECs in lacunar stroke. The number of CECs peaked at day 7 in patients with atherothrombotic infarction and came back to normal at day 90. In contrast, CECs in patients with acute lacunar stroke and cardioembolic stroke decreased progressively until day 90. CECs are markers of endothelial damage and/or repair in stroke. Differences during the course of disease are likely to reflect different pathophysiology.
    No preview · Article · Aug 2011 · Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association
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    ABSTRACT: Higher rates of acute rejection (AR) and reduced graft survival have been reported in patients with cytomegalovirus (CMV) infection, but an association between these factors remains controversial. In this study, serial protocol biopsies (PBs) and clinically indicated biopsies (IBs) from a large cohort of renal allograft recipients (n &frac14; 594) were analyzed to examine the relation between CMV and AR. Patients with CMV were more likely to receive IB (85 of the 153 patients; 56%) compared to patients without CMV (138 of 441 patients; 32%; P = 0.003). However, this did not translate into a greater number of patients with episodes of acute cellular rejection on histopathology in IBs. Analysis of PBs revealed a significantly higher number of episodes of rejection per patient with CMV infection (P = 0.04), but only in a subgroup of patients with triple immunosuppression. Long-term graft function post-transplantation was analyzed in four different subgroups according to CMV infection and/or AR. Differences in renal function were apparent within the first 6 weeks after transplantation and persisted during follow-up, with the best renal function in patients without AR or CMV, whereas patients with both AR and CMV had the worst (P < 0.012 at 1 year; P < 0.001 at 2 years). On average, the latter group had significantly older donors and more often delayed graft function. Our data suggests that the link between CMV and AR is far less significant than previously thought. Outcome in patients with CMV may be more determined by coexisting conditions like high donor age and delayed graft function.
    Full-text · Article · Jun 2011 · Nephrology Dialysis Transplantation
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    ABSTRACT: The clinical importance of microparticles resulting from vesiculation of platelets and other blood cells is increasingly recognized, although no standardized method exists for their measurement. Only a few studies have examined the analytical and preanalytical steps and variables affecting microparticle detection. We focused our analysis on microparticle detection by flow cytometry. The goal of our study was to analyze the effects of different centrifugation protocols looking at different durations of high and low centrifugation speeds. We also analyzed the effect of filtration of buffer and long-term freezing on microparticle quantification, as well as the role of Annexin V in the detection of microparticles. Absolute and platelet-derived microparticles were 10- to 15-fold higher using initial lower centrifugation speeds at 1500 × g compared with protocols using centrifugation speeds at 5000 × g (P < 0.01). A clear separation between true events and background noise was only achieved using higher centrifugation speeds. Filtration of buffer with a 0.2 μm filter reduced a significant amount of background noise. Storing samples for microparticle detection at -80°C decreased microparticle levels at days 28, 42, and 56 (P < 0.05 for all comparisons with fresh samples). We believe that staining with Annexin V is necessary to distinguish true events from cell debris or precipitates. Buffers should be filtered and fresh samples should be analyzed, or storage periods will have to be standardized. Higher centrifugation speeds should be used to minimize contamination by smaller size platelets.
    Full-text · Article · Dec 2010 · Vascular Health and Risk Management
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    ABSTRACT: About 30 years ago circulating endothelial cells (CEC) were first observed in peripheral blood. Since then CEC have been established as a reliable indicator of vascular injury and damage and more sophisticated detection techniques, such as immunomagnetic isolation and fluorescence-activated cell sorting (FACS), have become available. However even today there remains controversy as to the best approach to isolate and enumerate these cells. Here, we review the isolation and enumeration of CEC with an emphasis on CD146-driven immunomagnetic isolation and FACS as the two competing techniques. We describe advantages and pitfalls of both approaches. Moreover, we provide a list of clinical studies in this field and describe the possible clinical utility of CEC as a surrogate marker for vascular damage and dysfunction. In addition, we review the phenotype of CEC and discuss mechanisms of detachment. Recent evidence has also revealed interesting interactions between CEC and healthy endothelium in vitro although the relevance of these findings for human vascular disease in vivo remains unclear. Finally, we highlight differences between circulating endothelial cells and endothelial progenitor cells. In summary, CEC must be regarded as a sensitive and specific marker of endothelial damage as well as a potential mediator in vascular disease.
    Full-text · Article · Dec 2010 · Current Stem Cell Research & Therapy
  • A Dhaygude · U Erdbruegger · M Haubitz · A Woywodt
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    ABSTRACT: Much has been learned in recent years on the pathogenesis of ANCA-associated small-vessel vasculitis. The interaction of primed neutrophils with ANCA and endothelial cells is crucial to the disease. Next we gained a better understanding, from animal models, of the pathogenetic importance of the ANCA antibody. Very recent evidence provides intriguing data regarding the link between infection and vasculitis, LAMP-2 antibodies as novel markers, and NETs as a novel pathogenetic mechanism. It remains to be seen whether others are able to corroborate these findings and whether testing for LAMP-2 antibodies will become part of the clinical routine in vasculitis. Recent years also saw the emergence of various new markers of endothelial damage and the disease itself, such as circulating endothelial cells and endothelial microparticles. These novel markers correlate well with disease activity; they may well complement traditional diagnostic tools, such as ANCA testing. Preliminary evidence has provided some insight into the balance between endothelial damage and repair. Exciting preliminary data also indicate that circulating endothelial cells may not only be markers of disease activity but that these cells may have pathogenetic importance in their own right. These findings may have profound implications for the pathogenesis of vasculitis and vascular disease in general. Recent years also saw the publication of a number of seminal studies for the treatment of ANCA-associated vasculitis. We now have a much better understanding of the role of pulse intravenous cyclophosphamide and plasma exchange than ten or even five years ago. Further studies must now show whether plasma exchange is also beneficial for less severely ill patients with AASV. Finally, as ever, it is hoped that further progress in understanding the disease pathogenesis will also provide more tailored and less toxic therapies.
    No preview · Article · Dec 2009 · Minerva urologica e nefrologica = The Italian journal of urology and nephrology
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    ABSTRACT: Rapid apoptotic cell engulfment is crucial for prevention of inflammation and autoimmune diseases and is conducted by special immunocompetent cells like macrophages or immature dendritic cells. We recently demonstrated that endothelial cells (ECs) also participate in apoptotic cell clearance. However, in contrast to conventional phagocytes they respond with an inflammatory phenotype. To further confirm these pro-inflammatory responses human ECs were exposed to apoptotic murine ECs and changes in thrombospondin-1 (TSP-1) expression and in activation of intracellular signalling cascades were determined by real-time qPCR, immunoblotting and immunocytochemistry. Human primary macrophages or monocytic lymphoma cells (U937) were incubated with conditioned supernatant of human ECs exposed to apoptotic cells and changes in activation, migration and phagocytosis were monitored. Finally, plasma levels of TSP-1 in patients with anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis (AAV) were determined by ELISA. We provided evidence that apoptotic cells induce enhanced expression of TSP-1 in human ECs and that this increase in TSP-1 is mediated by the mitogen-activated protein kinases (MAPK) ERK1 and 2 and their upstream regulators MEK and B-Raf. We also showed that plasma TSP-1 levels are increased in patients with AAV. Finally, we showed that conditioned supernatant of ECs exposed to apoptotic cells induces pro-inflammatory responses in monocytes or U937 cells and demonstrated that increased TSP-1 expression enhances migration and facilitates engulfment of apoptotic cells by monocyte-derived macrophages or U937 cells. These findings suggest that under pathological conditions with high numbers of uncleared dying cells in the circulation endothelial-derived elevated TSP-1 level may serve as an attraction signal for phagocytes promoting enhanced recognition and clearance of apoptotic cells.
    Preview · Article · Jul 2009 · Journal of Cellular and Molecular Medicine
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    U Erdbruegger · M Grossheim · B Hertel · K Wyss · T Kirsch · A Woywodt · H Haller · M Haubitz
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    ABSTRACT: Endothelial cells play a central pathogenetic role in ANCA-associated small-vessel vasculitis (AAV). Circulating endothelial cells (CECs), as a marker of endothelial damage, have been shown to be elevated in vasculitis. More recently, endothelial microparticles (EMPs) were found to be increased in active childhood vasculitis. The role of EMP in adult AAV and the relationship between EMP and CEC is unclear. We studied 26 patients with AAV, 12 healthy volunteers and 10 patients with IgA nephropathy as disease control. Platelet-poor plasma was ultracentrifuged. MPs were identified and enumerated with flow cytometry, Annexin V, CD62E and CD105 antibodies. Leucocyte- and platelet-derived MPs were also measured. CEC were isolated and enumerated with CD146-driven immuno-magnetic isolation. EMPs are significantly elevated in patients with active vasculitis (CD62E: mean 248 MP/microl +/- 198 s.d.; CD105: 121 +/- 135/microl) compared with patients in remission/partial remission (CD62E: 55 +/- 30/microl, P = 0.001; CD105: 16 +/- 12/microl, P = 0.002) and healthy volunteers (CD62E: 66 +/- 33/microl, P = 0.002; CD105: 25 +/- 26/microl, P = 0.007). The MP count correlates with disease activity measured by the Birmingham Vasculitis Activity Score (BVAS) (CD62E: r = 0.703; CD105: r = 0.445, P < 0.023). EMPs are elevated in active adult AAV. EMP levels correlate with disease activity and might serve as a marker of endothelial activation and damage. Differential detection of endothelial, platelet- and leucocyte-derived MPs may provide more insight in to the pathogenesis of AAV.
    Preview · Article · Oct 2008 · Rheumatology (Oxford, England)
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    ABSTRACT: B-cell depletion with rituximab, a chimeric anti-CD20 antibody, is a novel treatment for refractory and relapsing ANCA-associated small-vessel vasculitis. Data are limited and most reports describe single patients or small numbers of patients followed prospectively. We report a single-centre experience with 15 patients who received rituximab for refractory or relapsing ANCA-associated vasculitis. All patients had been treated with corticosteroids and cyclophosphamide and a variety of other second-line immunosuppressive agents. None of the patients had evidence of infection and received four infusions of 375 mg/m(2) of rituximab. Disease activity was assessed in accordance with the Birmingham Vasculitis Activity Score (BVAS). BVAS, C-reactive protein and ANCA titres were recorded at baseline and during follow-up. B-cell depletion was achieved in all patients. Partial or complete remission was seen in 14 of 15 patients with a significant decline in BVAS compared to baseline (P < 0.007). One patient with granulomatous ANCA-associated vasculitis did not respond to rituximab. There were no side effects during rituximab infusion. Transient leucopenia was observed in two patients. One patient with bronchial stenosis died of pneumonia 5.5 months after the initiation of rituximab treatment. One initially anti-HBc-positive/HBsAg-negative patient experienced a reactivation of hepatitis B, developed end-stage renal failure and died after refusal of dialysis. We report the largest case series of rituximab use for ANCA-associated vasculitis so far. Our data support that the drug is capable of inducing partial or complete remission in refractory or relapsing patients. Leucopenia and infectious complications remain a matter of concern.
    Full-text · Article · Aug 2008 · Nephrology Dialysis Transplantation
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    ABSTRACT: Acute tubular injury (ATI) is commonly observed in renal allografts, especially early after transplantation. This study analyzes prevalence and associated clinical conditions of ATI in serial protocol biopsies (pBx) and indication biopsies (iBx), and its impact on long-term graft function. 612 pBx from 204 patients taken at 6 weeks, 3 and 6 months, and 151 iBx performed within the first year of transplantation were evaluated. Prevalence of ATI in pBx was 40% (6 weeks), 34% (3 months) and 37% (6 months), and 46% in iBx. ATI was associated with delayed graft function and prolonged cold ischemia time in pBx, and with acute rejections in iBx. The GFR at 1 and 2 years after transplantation correlated inversely with the frequency of ATI in both pBx and iBx (p < 0.001). Prevalence of chronic changes at 6 months was not significantly related to ATI (patients without ATI: 36%, patients with multiple ATI findings: 54%). ATI is linked to inferior long-term graft function. While this suggests lack of recovery from ATI with permanent allograft damage, the underlying molecular mechanisms need yet to be uncovered. Prevention of the potential pathogenetic factors identified in this study might be the key point to attain good long-term graft function.
    Full-text · Article · Jun 2008 · American Journal of Transplantation
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    ABSTRACT: Preeclampsia is a disorder of endothelial cells, and novel markers of the disease are eagerly awaited. We tested the hypothesis that circulating endothelial cells (CECs) are elevated in preeclampsia and that cell numbers correlate with disease activity. CECs were measured in 10 patients with preeclampsia as well as pregnant and nonpregnant controls. Cells were enumerated prior to delivery, 1 and 3-5 days thereafter. Enumeration of CECs was performed with anti-CD 146-driven immunomagnetic isolation and subsequent Ulex lectin staining. Markedly elevated CEC numbers were detected in women with preeclampsia (median 88 cells/mL; P < .001) when compared with normal pregnancies (median 16 cells/mL) and healthy nonpregnant women (12 cells/mL). There was a significant correlation of CEC numbers and systolic blood pressure (P < .02). A rapid decline of cell numbers after delivery paralleled the clinical recovery. Circulating endothelial cells are a novel marker of vascular damage in preeclampsia.
    No preview · Article · Apr 2008 · American journal of obstetrics and gynecology
  • P Kümpers · U Erdbrügger · M Grossheim · G P Meyer · M Hiss · W Gwinner · H Haller · M Haubitz
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    ABSTRACT: Churg-Strauss Syndrome (CSS) is characterized by allergic rhinitis, asthma and prominent blood and tissue eosinophilia. Although CSS can affect any organ system, isolated cardiac manifestation is a rare feature that is often characterized by rapidly progressive congestive heart failure. We present the case of a 48-year-old woman with acute dyspnoea and chest pain. Her past medical history was significant for asthma and frequently relapsing minimal-change glomerulonephritis. Echocardiogram and coronary angiography revealed cardiomyopathy and coronary small-vessel vasculitis in the presence of blood eosinophilia and elevated IgE. In the absence of infective agents, neoplastic diseases and further vasculitic manifestations, a flow cytometry-based analysis of markedly elevated endothelial microparticles supported the diagnosis of CSS. Cardiomyopathy resolved completely after initiation of immunosuppressive treatment with corticosteroids and cyclophosphamide pulses. Elevated endothelial, leukocytic and platelet-derived microparticles decreased during follow-up and closely paralleled vasculitic activity. Endothelial microparticles might be an additional tool to diagnose and monitor cases of suspected vasculitic cardiac involvement in CSS.
    No preview · Article · Nov 2007 · Clinical and experimental rheumatology
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    Full-text · Article · Jul 2007 · Nephrology Dialysis Transplantation
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    ABSTRACT: Circulating endothelial cells (CECs) have been detected in a variety of vascular disorders, but their interactions with healthy endothelium remain unknown. The aim of this study was to evaluate the response of human endothelial cells (ECs) to apoptotic or necrotic ECs in an in vitro model and to delineate pathogenetic pathways. Here we show that incubation of the human microvascular endothelial cell line (HMEC-1) with apoptotic ECs resulted in increased expression of chemokines and enhanced binding of leukocytes to HMEC-1 cells, whereas exposure of HMEC-1 cells to necrotic ECs caused no changes in leukocyte-binding affinity. Both apoptotic and necrotic cells were bound and engulfed by HMEC-1 cells and primary human umbilical vein endothelial cells (HUVECs). We therefore suggest that exposures to apoptotic and necrotic ECs induce different patterns of chemokine synthesis and leukocyte adhesion in healthy ECs. These data indicate that CECs are not only markers of vascular damage but may induce proinflammatory signals in the endothelium.
    Full-text · Article · May 2007 · Blood
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    Uta Erdbruegger · Marion Haubitz · Alexander Woywodt
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    ABSTRACT: Circulating endothelial cells (CECs) were first described over 30 years ago in smears of peripheral blood. Since then, more sophisticated techniques for CEC isolation have become available. In particular, immunomagnetic isolation and fluorescence-activated cell sorting (FACS) have been employed with success. We provide a short historical perspective and a comprehensive review on the subject. We review isolation and enumeration of CECs with an emphasis on CD146-driven immunomagnetic isolation and FACS. We describe, in great detail, advantages and pitfalls of both approaches and compare their specificity. Moreover, we provide a comprehensive list of clinical studies in this field and describe the possible clinical use of CECs. We also describe the phenotype of these cells and list typical surface markers. In addition, we review the phenotype of CECs and discuss mechanisms of detachment. We speculate about potential interactions between CECs and other cell subsets. We also describe other serum markers of endothelial damage and compare CECs with these markers. Finally, we highlight differences between circulating endothelial cells and endothelial progenitor cells. In summary, CECs must now be regarded as a sensitive and specific marker of endothelial damage. We emphasize that use of CECs in a clinical setting is on the horizon and pathogenetic clues may also be obtained.
    Full-text · Article · Dec 2006 · Clinica Chimica Acta

Publication Stats

688 Citations
113.74 Total Impact Points

Institutions

  • 2009-2015
    • University of Virginia
      • Department of Medicine
      Charlottesville, Virginia, United States
  • 2006-2011
    • Hannover Medical School
      • Institute for Pathology
      Hanover, Lower Saxony, Germany
  • 2004-2006
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States