The ratio of VEGF/PEDF expression in bone marrow mesenchymal stem cells regulates neovascularization

Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Campus, Brisbane Qld 4059, Australia.
Differentiation (Impact Factor: 3.44). 03/2011; 81(3):181-91. DOI: 10.1016/j.diff.2010.12.003
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Angiogenesis, or neovascularization, is a finely balanced process controlled by pro- and anti-angiogenic factors. Vascular endothelial growth factor (VEGF) is a major pro-angiogenic factor, whereas pigment epithelial-derived factor (PEDF) is the most potent natural angiogenesis inhibitor. In this study, the regulatory role of bone marrow stromal cells (BMSCs) during angiogenesis was assessed by the endothelial differentiation potential, VEGF/PEDF production and responses to pro-angiogenic and hypoxic conditions. The in vivo regulation of blood vessel formation by BMSCs was also explored in a SCID mouse model. Results showed that PEDF was expressed more prominently in BMSCs compared to VEGF. This contrasted with human umbilical vein endothelial cells (HUVECs) where the expression of VEGF was higher than that of PEDF. The ratio of VEGF/PEDF gene expression in BMSCs increased when VEGF concentration reached 40ng/ml in the culture medium, but decreased at 80ng/ml. Under CoCl(2)-induced hypoxic conditions, the VEGF/PEDF ratio of BMSCs increased significantly in both normal and angiogenic culture media. There was no expression of endothelial cell markers in BMSCs cultured in either pro-angiogenic or hypoxia culture conditions when compared with HUVECs. The in vivo study showed that VEGF/PEDF expression closely correlated with the degree of neovascularization, and that hypoxia significantly induced pro-angiogenic activity in BMSCs. These results indicate that, rather than being progenitors of endothelial cells, BMSCs play an important role in regulating the neovascularization process, and that the ratio of VEGF and PEDF may, in effect, be an indicator of the pro- or anti-angiogenic activities of BMSCs.

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Available from: Yin Xiao, Oct 07, 2015
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    • "Because MPCs show resistance to trypsin digestion, these cells are expected to be lost during subsequent passages reducing progressively the angiogenic potential of the sub-cultures. Not surprisingly, the most successful endothelial differentiation protocols have been obtained from early passages of MSC's cultures (Oswald et al., 2004; Fan et al., 2011; Janeczek Portalska et al., 2012). Conversely, protocols specific for endothelial differentiation may commit a pure population of MPCs into homogeneous clones of MSCs. "
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    ABSTRACT: Recent investigations have made considerable progress in the understanding of tissue regeneration driven by mesenchymal stromal cells (MSCs). Data indicate the anatomical location of MSC as residing in the “perivascular” space of blood vessels dispersed across the whole body. This histological localization suggests that MSCs contribute to the formation of new blood vessels in vivo. Indeed, MSCs can release angiogenic factors and protease to facilitate blood vessel formation and in vitro are able to promote/support angiogenesis. However, the direct differentiation of MCSs into endothelial cells is still matter of debate. Most of the conflicting data might arise from the presence of multiple subtypes of cells with heterogeneous morpho functional features within the MSC cultures. According to this scenario, we hypothesize that the presence of the recently described Mesodermal Progenitor Cells (MPCs) within the MSCs cultures is responsible for their variable angiogenic potential. Indeed, MPCs are Nestin-positive CD31-positive cells exhibiting angiogenic potential that differentiate in MSC upon proper stimuli. The ISCT criteria do not account for the presence of MPC within MSC culture generating confusion in the interpretation of MSC angiogenic potential. In conclusion, the discover y of MPC gives new insight in defining MSC ancestors in human bone marrow, and indicates the tunica intima as a further, and previously overlooked, possible additional source of MSC.
    Frontiers in Cell and Developmental Biology 05/2014; 2. DOI:10.3389/fcell.2014.00020
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    • "Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is a 50 kDa secreted glycoprotein and reported to be expressed in many tissue and vitreous [36,37]. It belongs to a group of serine protease inhibitors with anti-angiogenic activities [38,39]. SERPINF1 concentration is found to be significantly lower in the vitreous fluid of subjects with PDR [40-42]. "
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    ABSTRACT: Background:The vitreous humor is a transparent, gelatinous mass whose main constituent is water. It plays an important role in providing metabolic nutrient requirements of the lens, coordinating eye growth and providing support to the retina. It is in close proximity to the retina and reflects many of the changes occurring in this tissue. The biochemical changes occurring in the vitreous could provide a better understanding about the pathophysiological processes that occur in vitreoretinopathy. In this study, we investigated the proteome of normal human vitreous humor using high resolution Fourier transform mass spectrometry. Results:The vitreous humor was subjected to multiple fractionation techniques followed by LC-MS/ MS analysis. We identified 1,205 proteins, 682 of which have not been described previously in the vitreous humor. Most proteins were localized to the extracellular space (24%), cytoplasm (20%) or plasma membrane (14%). Classification based on molecular function showed that 27% had catalytic activity, 10% structural activity, 10% binding activity, 4% cell and 4% transporter activity. Categorization for biological processes showed 28% participate in metabolism, 20% in cell communication and 13% in cell growth. The data have been deposited to the ProteomeXchange with identifier PXD000957. Conclusion: This large catalog of vitreous proteins should facilitate biomedical research into pathological conditions of the eye including diabetic retinopathy, retinal detachment and cataract. Keywords: retina, SCX chromatography, OFFGEL electrophoresis, Proteome Discoverer, secreted proteins, protein biomarkers, body fluid proteomics
    Clinical Proteomics 05/2014; 11(1). DOI:10.1186/1559-0275-11-29
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    • "The possibility of using mesenchymal stem cells in the treatment of ED is enticing not only because these cells are known to secrete various growth factors that are beneficial in ED such as IGF-1 [133-135], VEGF [136], and FGF-2 [137], but also because of their anti-inflammatory activities [138], as well as possibility of differentiating into tissue relevant to the penile architecture [139]. To assess whether bone marrow derived MSC had a therapeutic effect on diabetes induced ED, Qiu et al performed intracavernous administration of these cells. "
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    ABSTRACT: While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.
    Journal of Translational Medicine 06/2013; 11(1):139. DOI:10.1186/1479-5876-11-139 · 3.93 Impact Factor
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