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: 2.73). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Circulating progenitor cells and stromal-derived factor-1alpha (SDF-1α) have been suggested to participate in tissue repair after ischemic injury. However, the predictive role of circulating CD133+ CD34+ progenitors and plasma SDF-1α in ischemic stroke (IS) patients remains unknown. In this study, we recruited 95 acute IS patients, 40 at-risk subjects, and 30 normal subjects. The National Institutes of Health Stroke Scale (NIHSS), infarct volume, and carotid intima-media thickness (IMT) were determined at day 1 and the modified Rankin scale (mRS) of functional outcome was assessed at day 21. The levels of circulating CD133+ CD34+ cells and plasma SDF-1α were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. Our data showed that: (1) the levels of CD133+ CD34+ cells were lower in at-risk subjects and IS patients at admission (day 1) when compared with normal controls; (2) the day 1 level of CD133+ CD34+ cells varied in IS subgroups and inversely correlated with NIHSS and carotid IMT and the level of SDF-1α inversely correlated with NIHSS and infarct volume; (3) the increment rates of circulating CD133+ CD34+ cells and plasma SDF-1α within the first week were correlated; and (4) patients with a higher level of CD133+ CD34+ cells at day 7 had a low mRS. The increased rate of CD133+ CD34+ cells in the first week was inversely associated with mRS. In conclusion, our findings demonstrate that the circulating CD133+ CD34+ progenitor cells and plasma SDF-1α can be used as predictive parameters for IS severity and outcome. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 11/2014; DOI:10.1016/j.jstrokecerebrovasdis.2014.08.026 · 1.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The patency of synthetic cardiovascular grafts in the long run is synonymous with their ability to inhibit the processes of intimal hyperplasia, thrombosis and calcification. In the human body, the endothelium of blood vessels exhibits characteristics that inhibit such processes. As such it is not surprising that research in tissue engineering is directed towards replicating the functionality of the natural endothelium in cardiovascular grafts. This can be done either by seeding the endothelium within the lumen of the grafts prior to implantation or by designing the graft such that in situ endothelialisation takes place after implantation. Due to certain difficulties identified with in vitro endothelialisation, in situ endothelialisation, which will be the focus of this article, has garnered interest in the last years. To promote in situ endothelialisation, the following aspects can be taken into account: (1) Endothelial progenital cell mobilization, adhesion and proliferation; (2) Regulating differentiation of progenitor cells to mature endothelium; (3) Preventing thrombogenesis and inflammation during endothelialisation. This article aims to review and compile recent developments to promote the in situ endothelialisation of cardiovascular grafts and subsequently improve their patency, which can also have widespread implications in the field of tissue engineering.
    International Journal of Molecular Sciences 01/2014; 16(1):597-627. DOI:10.3390/ijms16010597 · 2.46 Impact Factor


Available from
May 21, 2014