Temporal profile of molecular signatures associated with circulating endothelial progenitor cells in human ischemic stroke

Department of Neurology, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
Journal of Neuroscience Research (Impact Factor: 2.59). 09/2012; 90(9):1788-93. DOI: 10.1002/jnr.23068
Source: PubMed

ABSTRACT Endothelial progenitor cells (EPC) have been associated with good functional outcome in ischemic stroke. From preclinical studies, it has been reported that EPC proliferation is mediated by several molecular markers, including vascular endothelial growth factor (VEGF), stromal cell-derived factor-1α (SDF-1α), and the activity of matrix metalloproteinase-9 (MMP-9). Therefore, our aim was to study the role of these molecular factors in EPC proliferation in human ischemic stroke. Forty-eight patients with first episode of nonlacunar ischemic stroke were prospectively included in the study within 12 hr of symptom onset. EPC colonies were classified as early-outgrowth colony forming unit-endothelial cell (CFU-EC) and quantified at admission, at 24 and 72 hr, at day 7, and at 3 months. At the same time, serum levels of VEGF, SDF-1α, and active MMP-9 were measured by ELISA. The primary endpoint was EPC increment during the first week, which was defined as the difference in the number of CFU-EC between day 7 and admission. We found that VEGF (r = 0.782), SDF-1α (r = 0.828), and active MMP-9 (r = 0.740) levels at 24 hr from stroke onset showed a strong correlation with EPC increment. Similar results were found for VEGF levels at 72 hr (r = 0.839) and at day 7 (r = 0.602) as well as for active MMP-9 levels at 72 hr (r = 0.442) and at day 7 (r = 0.474). In the multivariate analyses, serum levels of VEGF at 72 hr (B: 0.074, P < 0.0001) and SDF-1α at 24 hr (B: 0.049, P = 0.008) were independent factors for EPC increment during the first week of evolution. These findings suggest that VEGF and SDF-1α may mediate EPC proliferation in human ischemic stroke.

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Available from: David Brea, Jan 14, 2014
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    • "Understanding SB623's role in facilitating the migration of endogenous cells via a biobridge exposes the active role of MMPs and ECMs in stroke pathology (Park et al., 2009; el Zoppo et al., 2012) and highlights their increasingly prominent role as therapeutic targets for stroke. Functions and levels of MMPs and ECMs have been shown to be influenced by a variety of cells coming from variable sources including umbilical cord blood, peripheral blood, and the adult brain (Barkho et al., 2008; Sobrino et al., 2012; Lin et al., 2013). This suggests a potential for these molecules to serve as biobridges similar to the current function of Notch-induced SB623 mesenchymal stromal cells. "
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    ABSTRACT: Modified mesenchymal stromal cells (MSCs) display a unique mechanism of action during the repair phase of traumatic brain injury by exhibiting the ability to build a biobridge between the neurogenic niche and the site of injury. Immunohistochemistry and laser capture assay have visualized this biobridge in the area between the neurogenic subventricular zone and the injured cortex. This biobridge expresses high levels of extracellular matrix metalloproteinases (MMPs), which are initially co-localized with a stream of transplanted MSCs, but later this region contains only few to non-detectable grafts and becomes overgrown by newly recruited host cells. We have reported that long-distance migration of host cells from the neurogenic niche to the injured brain site can be attained via these transplanted stem cell-paved biobridges, which serve as a key regenerative process for the initiation of endogenous repair mechanisms. Thus, far the two major schools of discipline in stem cell repair mechanisms support the idea of “cell replacement” and the bystander effects of “trophic factor secretion.” Our novel observation of stem cell-paved biobridges as pathways for directed migration of host cells from neurogenic niche toward the injured brain site adds another mode of action underlying stem cell therapy. More in-depth investigations on graft-host interaction will likely aid translational research focused on advancing this stem cell-paved biobridge from its current place, as an equally potent repair mechanism as cell replacement and trophic factor secretion, into a new treatment strategy for traumatic brain injury and other neurological disorders.
    Frontiers in Systems Neuroscience 06/2014; 8. DOI:10.3389/fnsys.2014.00116
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    • "Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; Pescini et al. 2010) and with leukoaraiosis (Jickling et al. 2009), that are considered manifestations of small-vessel disease with dysfunctional endothelium, have lower levels of EPC also. As in our study and others (Zhou et al. 2009; Yip et al. 2011; Sobrino et al. 2012a) the severity of stroke was not associated with EPC counts, we believe that higher EPC counts do not lead to milder strokes. The fact that only EPC measured within the first 48 h were associated with prognosis suggests that the positive effect of EPC is exerted very soon after the onset of stroke. "
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    ABSTRACT: The levels of circulating endothelial progenitor cells (EPCs) in ischemic stroke have not been studied extensively and reported results are inconsistent. We aimed to investigate the time course, the prognostic relevance, and the variables associated with EPC counts in patients with ischemic stroke at different time points. We studied prospectively 146 consecutive patients with ischemic stroke within the first 48 h from the onset of symptoms (baseline). We evaluated demographic data, classical vascular risk factors, treatment with thrombolysis and statins, stroke etiology, National Institute of Health and Stroke Scale score and outcome (favorable when Rankin scale score 0-2). Blood samples were collected at baseline, at day 7 after stroke (n = 121) and at 3 months (n = 92). The EPC were measured by flow cytometry. We included 146 patients with a mean age of 70.8 ± 12.2 years. The circulating EPC levels were higher on day 7 than at baseline or at 3 months (P = 0.045). Pretreatment with statins (odds ratio [OR] 3.11, P = 0.008) and stroke etiology (P = 0.032) were predictive of EPC counts in the baseline sample. EPC counts were not associated with stroke severity or functional outcome in all the patients. However, using multivariate analyses, a better functional outcome was found in patients with higher EPC counts in large-artery atherosclerosis and small-vessel disease etiologic subtypes. After acute ischemic stroke, circulating EPC counts peaked at day 7. Pretreatment with statins increased the levels of EPC. In patients with large-artery atherosclerosis and small-vessel disease subtypes, higher counts were related to better outcome at 3 months.
    Brain and Behavior 11/2013; 3(6):649-55. DOI:10.1002/brb3.175 · 2.24 Impact Factor
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    ABSTRACT: Background: Intracranial atherosclerotic disease (ICAD) is an important cause of ischemic stroke (IS) and endothelial dysfunction plays a critical role in its onset and progression. Endothelial progenitor cells (EPCs) and endothelial production of angiogenic growth factors (AGFs) may play an essential role in this process. This study investigated the association of EPCs and AGFs with ICAD severity. Methods: A total of 42 patients who had experienced a transient ischemic attack (TIA) or IS attributable to symptomatic ICAD were included. Clinical and neurosonological evaluations were conducted between 2.4 and 8.7 years after the initial cerebrovascular event. Severe ICAD was defined as the presence of at least 1 severe intracranial stenosis, and extensive ICAD as 3 or more intracranial stenoses. Blood samples were obtained to determine EPC levels using flow cytometry (CD34+KDR+ cells), and the plasma levels of several growth factors were assessed with a protein array (Searchlight(®)). Twenty-two individuals without cerebrovascular disease and with normal ultrasonographic examination were also included. Results: No difference in the count of circulating EPCs was found between patients and controls, and a moderate increase in the number of EPCs/ml was noted in patients with extensive ICAD (p = 0.05). Patients presented decreased levels of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF-BB) compared with controls (p = 0.002, p = 0.079 and p = 0.061, respectively). Higher levels of FGF, VEGF and PDGF-BB were found in patients with severe ICAD (p = 0.007, p = 0.07 and p = 0.07, respectively), but there was no correlation between any AGFs and EPCs. Conclusions: Symptomatic ICAD patients have decreased levels of AGFs with no correlation to the number of circulating EPCs, while patients with severe ICAD have higher levels of EPCs, FGF, VEGF and PDGF-BBs. This suggests that reduced EPC and proangiogenic factor production capacity is implicated in ICAD pathogenesis, while the more severe forms of chronic brain hypoperfusion in ICAD patients might stimulate EPC mobilization and AGF production.
    Cerebrovascular Diseases 02/2013; 35(1):81-8. DOI:10.1159/000346097 · 3.75 Impact Factor
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