Number and Function of Endothelial Progenitor Cells as a Marker of Severity for Diabetic Vasculopathy

Department of Clinical and Experimental Medicine, Division of Metabolic Diseases, University of Padova, School of Medicine, Italy.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 10/2006; 26(9):2140-6. DOI: 10.1161/01.ATV.0000237750.44469.88
Source: PubMed


Peripheral arterial disease (PAD) is a threatening complication of diabetes. As endothelial progenitor cells (EPCs) are involved in neovasculogenesis and maintenance of vascular homeostasis, their impairment may have a role in the pathogenesis of diabetic vasculopathy. This study aimed to establish whether number and function of EPCs correlate with PAD severity in type 2 diabetic patients.
EPCs were defined by the expression of CD34, CD133 and KDR, and quantified by flow cytometry in 127 diabetic patients with and without PAD. PAD severity has been assessed as carotid atherosclerosis and clinical stage of leg atherosclerosis obliterans. Diabetic patients with PAD displayed a significant 53% reduction in circulating EPCs versus non-PAD patients, and EPC levels were negatively correlated with the degree of carotid stenosis and the stage of leg claudication. Moreover, the clonogenic and adhesion capacity of cultured EPCs were significantly lower in diabetic patients with PAD versus patients without.
This study demonstrates that EPC decrease is related to PAD severity and that EPC function is altered in diabetic subjects with PAD, strengthening the pathogenetic role of EPC dysregulation in diabetic vasculopathy. EPC count may be considered a novel biological marker of peripheral atherosclerosis in diabetes.

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Available from: Carlo Agostini, Oct 06, 2015
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    • "The numbers of EPCs could be altered additionally by diabetes complications. Fadini et al. [121] demonstrated that the number of EPCs described as CD34+/CD133+/KDR+ is significantly decreased in diabetic patients with PAD compared to diabetic patients without complications. Additionally, Nowak et al. [117] measured progenitor cells in diabetic patients with or without complications (different forms of diabetic foot ulcer (DFU)). "
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    ABSTRACT: Endothelial progenitor cells (EPCs) have been extensively studied for almost 19 years now and were considered as a potential marker for endothelial regeneration ability. On the other hand, circulating endothelial cells (CEC) were studied as biomarker for endothelial injury. Yet, in the literature, there is also huge incoherency in regards to terminology and protocols used. This results in misleading conclusions on the role of so called "EPCs", especially in the clinical field. The discrepancies are mainly due to strong phenotypic overlap between EPCs and circulating angiogenic cells (CAC), therefore changes in "EPC" terminology have been suggested. Other factors leading to inconsistent results are varied definitions of the studied populations and the lack of universal data reporting, which could strongly affect data interpretation. The current review is focused on controversies concerning the use of "EPCs"/CAC and CEC as putative endothelial diagnostic markers. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
    Pharmacological reports: PR 06/2015; 67(4). DOI:10.1016/j.pharep.2015.05.017 · 1.93 Impact Factor
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    • "There is significant evidence linking impaired neovascularization with delayed diabetic wound closure [13], [22], [23]. Consistent with our findings, several studies have implicated decreased cPCs as a causative factor [11], [13], [23]–[25]. "
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    ABSTRACT: Non-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. Wounded 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%. Combination 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.
    PLoS ONE 03/2014; 9(3):e92667. DOI:10.1371/journal.pone.0092667 · 3.23 Impact Factor
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    • "PGC-1a was similarly induced in ECs in two genetic models of type 2 diabetes (ob/ob and db/db) and in streptozotocin-induced type 1 diabetes (Figure 1A, right panels; Table S1). Human circulating CD34 + cells, which contain significant numbers of endothelial progenitor cells (EPCs) (Asahara et al., 1997; Fadini et al., 2006), isolated from patients with type 2 diabetes (see Table S2) as well as cultured EPCs established from the peripheral blood of diabetic patients also revealed elevated expression levels of PGC-1a, compared with control subjects (Figure 1B). Diabetes thus induces expression of PGC-1a in ECs in vivo in mice, and likely in humans as well. "
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    ABSTRACT: Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.
    Cell metabolism 02/2014; 19(2):246-58. DOI:10.1016/j.cmet.2013.12.014 · 17.57 Impact Factor
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