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      Is Open Access

      Pericytes, an overlooked player in vascular pathobiology

      review-article
      , , , , *
      Pharmacology & Therapeutics
      Pergamon Press
      AGE, Advanced Glycation End-Products, ANG1, angiopoietin-1, ANG2, angiopoietin-2, BBB, blood-brain barrier, BRB, blood-retina barrier, CKD, chronic kidney disease, CNS, blood-retinal barrier, CSC, cancer stem cell, DAN, diabetic autonomous neuropathy, DME, diabetic macular oedema, DN, diabetic nephropathy, DPN, diabetic peripheral neuropathy, DR, diabetic retinopathy, EC, endothelial cells, ECM, extracellular matrix, ED, erectile dysfunction, EGFR, EGF receptor, EMT, epithelial-mesenchymal transition, FGF-9, fibroblastic growth factor 9, GFR, glomerular filtration rate, GSC, glioblastoma CSC, GSI, g-secretase inhibitor, HB-EGF, heparin-binding EGF-like growth factor, HIF, hypoxia inducible factor, HPC, hemangiopericytoma, I/R, ischemia-reperfusion, IL-6, interleukin 6, IL-8, interleukin 8, iPS, induced pluripotent stem cells, MAPK, mitogen-activated protein kinase, MDSC, myeloid-derived suppressor cells, MF-EGF8, milk fat globule epidermal growth factor VIII, MI, myocardial infarction, MMP, matrix metalloproteinases, MSC, mesenchymal stromal cell, NRF2, nuclear factor (erythroid-derived 2)-like 2, NG2, neural/glial antigen 2, NPDR, non-proliferative diabetic retinopathy, Olmfl3, Olfactomedin-like 3, PDL-1, programmed death-ligand 1, PDGFb, platelet-derived growth factor B, PDGFRβ, platelet derived growth factor receptor β, PDR, proliferative diabetic retinopathy, PEDF, Pigment Epithelium-Derived Factor, PKC, protein kinase C, PSC, perivascular stem cell, RAGE, receptors of AGEs, ROS, reactive oxygen species, SDF-1, stromal derived factor 1, SFT, solitary fibrous tumour, SMA, smooth muscle actin, SOD, super oxide dismutase, T1D, type 1 diabetic, T2D, type 2 diabetic, TGF β, transforming growth factor β, TME, tumour microenvironment, Treg, regulatory T cells, UUO, unilateral ureteric obstruction, VEGF, vascular endothelial growth factor, Pericytes, Perivascular stem cells, Diabetic retinopathy, Diabetic nephropathy, Cancer stem cells, Pericyte fibrosis

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          Abstract

          Pericytes are a heterogeneous population of cells located in the blood vessel wall. They were first identified in the 19th century by Rouget, however their biological role and potential for drug targeting have taken time to be recognised. Isolation of pericytes from several different tissues has allowed a better phenotypic and functional characterization. These findings revealed a tissue-specific, multi-functional group of cells with multilineage potential. Given this emerging evidence, pericytes have acquired specific roles in pathobiological events in vascular diseases. In this review article, we will provide a compelling overview of the main diseases in which pericytes are involved, from well-established mechanisms to the latest findings. Pericyte involvement in diabetes and cancer will be discussed extensively. In the last part of the article we will review therapeutic approaches for these diseases in light of the recently acquired knowledge. To unravel pericyte-related vascular pathobiological events is pivotal not only for more tailored treatments of disease but also to establish pericytes as a therapeutic tool.

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          Most cited references139

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          Origin and function of myofibroblasts in kidney fibrosis.

          Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.
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            Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.

            Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Blood-brain barrier delivery.

              Neuropharmaceutics is the largest potential growth sector of the pharmaceutical industry. However, this growth is blocked by the problem of the blood-brain barrier (BBB). Essentially 100% of large-molecule drugs and >98% of small-molecule drugs do not cross the BBB. The BBB can be traversed because there are multiple endogenous transporters within this barrier. Therefore, brain drug development programs of the future need to be re-configured so that drugs are formulated to enable transport into the brain via endogenous BBB transporters.
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                Author and article information

                Contributors
                Journal
                Pharmacol Ther
                Pharmacol. Ther
                Pharmacology & Therapeutics
                Pergamon Press
                0163-7258
                1879-016X
                1 March 2017
                March 2017
                : 171
                : 30-42
                Affiliations
                Division of Experimental Cardiovascular Medicine, School of Clinical Sciences, Bristol Heart Institute, University of Bristol, United Kingdom
                Author notes
                [* ]Corresponding author at: Bristol Heart Institute, Bristol Royal Infirmary Level 7, Upper Maudlin Street, BS2 8HW, United Kingdom. mangialardig@ 123456gmail.com Giuseppe.Mangialardi@ 123456bristol.ac.uk
                Article
                S0163-7258(16)30234-0
                10.1016/j.pharmthera.2016.11.008
                6008604
                27916653
                6b2b8386-4052-4d7b-8e54-4a246af6cd9a
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Article

                Pharmacology & Pharmaceutical medicine
                age, advanced glycation end-products,ang1, angiopoietin-1,ang2, angiopoietin-2,bbb, blood-brain barrier,brb, blood-retina barrier,ckd, chronic kidney disease,cns, blood-retinal barrier,csc, cancer stem cell,dan, diabetic autonomous neuropathy,dme, diabetic macular oedema,dn, diabetic nephropathy,dpn, diabetic peripheral neuropathy,dr, diabetic retinopathy,ec, endothelial cells,ecm, extracellular matrix,ed, erectile dysfunction,egfr, egf receptor,emt, epithelial-mesenchymal transition,fgf-9, fibroblastic growth factor 9,gfr, glomerular filtration rate,gsc, glioblastoma csc,gsi, g-secretase inhibitor,hb-egf, heparin-binding egf-like growth factor,hif, hypoxia inducible factor,hpc, hemangiopericytoma,i/r, ischemia-reperfusion,il-6, interleukin 6,il-8, interleukin 8,ips, induced pluripotent stem cells,mapk, mitogen-activated protein kinase,mdsc, myeloid-derived suppressor cells,mf-egf8, milk fat globule epidermal growth factor viii,mi, myocardial infarction,mmp, matrix metalloproteinases,msc, mesenchymal stromal cell,nrf2, nuclear factor (erythroid-derived 2)-like 2,ng2, neural/glial antigen 2,npdr, non-proliferative diabetic retinopathy,olmfl3, olfactomedin-like 3,pdl-1, programmed death-ligand 1,pdgfb, platelet-derived growth factor b,pdgfrβ, platelet derived growth factor receptor β,pdr, proliferative diabetic retinopathy,pedf, pigment epithelium-derived factor,pkc, protein kinase c,psc, perivascular stem cell,rage, receptors of ages,ros, reactive oxygen species,sdf-1, stromal derived factor 1,sft, solitary fibrous tumour,sma, smooth muscle actin,sod, super oxide dismutase,t1d, type 1 diabetic,t2d, type 2 diabetic,tgf β, transforming growth factor β,tme, tumour microenvironment,treg, regulatory t cells,uuo, unilateral ureteric obstruction,vegf, vascular endothelial growth factor,pericytes,perivascular stem cells,diabetic retinopathy,diabetic nephropathy,cancer stem cells,pericyte fibrosis
                Pharmacology & Pharmaceutical medicine
                age, advanced glycation end-products, ang1, angiopoietin-1, ang2, angiopoietin-2, bbb, blood-brain barrier, brb, blood-retina barrier, ckd, chronic kidney disease, cns, blood-retinal barrier, csc, cancer stem cell, dan, diabetic autonomous neuropathy, dme, diabetic macular oedema, dn, diabetic nephropathy, dpn, diabetic peripheral neuropathy, dr, diabetic retinopathy, ec, endothelial cells, ecm, extracellular matrix, ed, erectile dysfunction, egfr, egf receptor, emt, epithelial-mesenchymal transition, fgf-9, fibroblastic growth factor 9, gfr, glomerular filtration rate, gsc, glioblastoma csc, gsi, g-secretase inhibitor, hb-egf, heparin-binding egf-like growth factor, hif, hypoxia inducible factor, hpc, hemangiopericytoma, i/r, ischemia-reperfusion, il-6, interleukin 6, il-8, interleukin 8, ips, induced pluripotent stem cells, mapk, mitogen-activated protein kinase, mdsc, myeloid-derived suppressor cells, mf-egf8, milk fat globule epidermal growth factor viii, mi, myocardial infarction, mmp, matrix metalloproteinases, msc, mesenchymal stromal cell, nrf2, nuclear factor (erythroid-derived 2)-like 2, ng2, neural/glial antigen 2, npdr, non-proliferative diabetic retinopathy, olmfl3, olfactomedin-like 3, pdl-1, programmed death-ligand 1, pdgfb, platelet-derived growth factor b, pdgfrβ, platelet derived growth factor receptor β, pdr, proliferative diabetic retinopathy, pedf, pigment epithelium-derived factor, pkc, protein kinase c, psc, perivascular stem cell, rage, receptors of ages, ros, reactive oxygen species, sdf-1, stromal derived factor 1, sft, solitary fibrous tumour, sma, smooth muscle actin, sod, super oxide dismutase, t1d, type 1 diabetic, t2d, type 2 diabetic, tgf β, transforming growth factor β, tme, tumour microenvironment, treg, regulatory t cells, uuo, unilateral ureteric obstruction, vegf, vascular endothelial growth factor, pericytes, perivascular stem cells, diabetic retinopathy, diabetic nephropathy, cancer stem cells, pericyte fibrosis

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