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Perivascular PDGFRB+ cells accompany lesion formation and clinical evolution differentially in two different EAE models

Published:November 23, 2022DOI:https://doi.org/10.1016/j.msard.2022.104428

      Highlights

      • Vascular changes in two experimental allergic encephalomyelitis models are evaluated.
      • In both models, fibrosis formation was detected with different characteristics.
      • The PLP-induced animal model fibrosis is predominantly in perivascular locations.
      • In MOG induced model, perivascular cells were accumulated at the lesion sites.
      • Perivascular cells may be taking part in MS lesion progression and healing.

      Abstract

      Background

      Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that may lead to progressive disability. Here, we explored the behavioral pattern and the role of vasculature especially PDGFRB+ pericytes/ perivascular cells, in MS pathogenesis.

      Methods

      We have evaluated vascular changes in two different experimental allergic encephalomyelitis (EAE) mice models (MOG and PLP-induced). PDGFRB+ cells demonstrated distinct and different behavioral patterns. In both models, fibrosis formation was detected via collagen, fibronectin, and extracellular matrix accumulation.

      Results

      The PLP-induced animal model revealed that fibrosis predominantly occurs in perivascular locations and that PDGFRB+ cells are accumulated around vessels. Also, the expression of fibrotic genes and genes coding extracellular matrix (ECM) proteins are upregulated. Moreover, the perivascular thick wall structures in affected vessels of this model presented primarily increased PDGFRB+ cells but not NG2+ cells in the transgenic NG2-DsRed transgenic animal model. On the other hand, in MOG induced model, PDGFRB+ perivascular cells were accumulated at the lesion sites. PDGFRB+ cells colocalized with ECM proteins (collagen, fibronectin, and lysyl oxidase L3). Nevertheless, both MOG and PLP-immunized mice showed increasing EAE severity, and disability parallel with enhanced perivascular cell accumulation as the disease progressed from earlier (day 15) to later (day 40).

      Conclusion

      As a result, we have concluded that PDGFRB+ perivascular cells may be participating in lesion progression and as well as demonstrating different responses in different EAE models.

      Graphical abstract

      Keywords

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      References

        • Armulik A.
        • et al.
        Pericytes regulate the blood-brain barrier.
        Nature. 2010; 468: 557-561
        • Arimura K.
        • et al.
        PDGF receptor β signaling in pericytes following ischemic brain injury.
        Curr. Neurovasc. Res. 2012; 9: 1-9
        • Bell R.D.
        • et al.
        Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.
        Neuron. 2010; 68: 409-427
        • Bhattacharya A.
        • Kaushik D.K.
        • Lozinski B.M.
        • Yong V.W.
        Beyond barrier functions: roles of pericytes in homeostasis and regulation of neuroinflammation.
        J. Neurosci. Res. 2020; 98: 2390-2405
        • Bjarnegård M.
        • et al.
        Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities.
        Development. 2004; 131: 1847-1857
        • Bordenave J.
        • et al.
        Lineage tracing reveals the dynamic contribution of pericytes to the blood vessel remodeling in pulmonary hypertension.
        Arterioscler. Thromb. Vasc. Biol. 2020; 40: 766-782
        • Brown W.R.
        • Thore C.R.
        Review: cerebral microvascular pathology in ageing and neurodegeneration.
        Neuropathol. Appl. Neurobiol. 2011; 37: 56-74
        • Brown W.R.
        • Thore C.R.
        Perivascular fibrosis in multiple sclerosis lesions.
        Brain Pathology (Zurich, Switzerland). 2011; 21: 355
        • Crisan M.
        • et al.
        A perivascular origin for mesenchymal stem cells in multiple human organs.
        Cell Stem Cell. 2008; 3: 301-313
        • Crisan M.
        • Corselli M.
        • Chen W.C.W.
        • Péault B.
        Perivascular cells for regenerative medicine.
        J. Cell. Mol. Med. 2012; 16: 2851-2860
        • Daneman R.
        • Zhou L.
        • Kebede A.A.
        • Barres B.A.
        Pericytes are required for blood–brain barrier integrity during embryogenesis.
        Nature. 2010; 468: 562-566
        • Dias D.O.
        • Göritz C.
        Fibrotic scarring following lesions to the central nervous system.
        Matrix Biol. 2018; 68–69: 561-570
        • Dias D.O.
        • et al.
        Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions.
        Nat. Commun. 2021; 12: 5501
        • Diaz-Flores L.
        • Gutierrez R.
        • Varela H
        Behavior of postcapillary venule pericytes during postnatal angiogenesis.
        J. Morphol. 1992; 213: 33-45
        • Dore-Duffy P.
        Isolation and characterization of cerebral microvascular pericytes.
        Methods Mol. Med. 2003; 89: 375-382
        • Dore-Duffy P.
        • Cleary K
        Morphology and properties of pericytes.
        Methods Mol. Biol. 2011; 686: 49-68
        • Dorrier C.E.
        • et al.
        CNS fibroblasts form a fibrotic scar in response to immune cell infiltration.
        Nat. Neurosci. 2021; 24: 234-244
        • Fernández-Klett F.
        • Priller J
        The fibrotic scar in neurological disorders.
        Brain Pathol. 2014; 24: 404-413
        • Frohman E.M.
        • Racke M.K.
        • Raine C.S.
        Multiple sclerosis–the plaque and its pathogenesis.
        N. Engl. J. Med. 2006; 354: 942-955
        • Gerhardt H.
        • Betsholtz C
        Endothelial-pericyte interactions in angiogenesis.
        Cell Tissue Res. 2003; 314: 15-23
        • Gerhardt H.
        • Betsholtz C.
        How do endothelial cells orientate?.
        EXS. 2005; 3–15https://doi.org/10.1007/3-7643-7311-3_1
        • Girolamo F.
        • et al.
        Defining the role of NG2-expressing cells in experimental models of multiple sclerosis. A biofunctional analysis of the neurovascular unit in wild type and NG2 null mice.
        PLoS One. 2019; 14e0213508
        • Göritz C.
        • et al.
        A pericyte origin of spinal cord scar tissue.
        Science. 2011; 333: 238-242
        • Guo B.
        • Chang E.Y.
        • Cheng G.
        The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice.
        J. Clin. Investig. 2008; 118: 1680-1690
        • Hauser S.L.
        • et al.
        Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions.
        Ann. Neurol. 1986; 19: 578-587
        • Hinz B.
        Formation and function of the myofibroblast during tissue repair.
        J. Investig. Dermatol. 2007; 127: 526-537
        • Hohlfeld R.
        • Wekerle H
        Immunological update on multiple sclerosis.
        Curr. Opin. Neurol. 2001; 14
        • Holm A.
        • Heumann T.
        • Augustin H.G.
        Microvascular mural cell organotypic heterogeneity and functional plasticity.
        Trends Cell Biol. 2018; 28: 302-316
        • Humphreys B.D.
        • et al.
        Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.
        Am. J. Pathol. 2010; 176: 85-97
        • Hurtado-Alvarado G.
        • Cabañas-Morales A.M.
        • Gómez-Gónzalez B.
        Pericytes: brain-immune interface modulators.
        Front. Integr. Neurosci. 2014; 7: 80
        • Iacobaeus E.
        • et al.
        Dynamic changes in brain mesenchymal perivascular cells associate with multiple sclerosis disease duration, active inflammation, and demyelination.
        Stem Cells Transl. Med. 2017; 6: 1840-1851
        • Kilic A.K.
        • et al.
        Promotion of experimental autoimmune encephalomyelitis upon neutrophil granulocytes’ stimulation with formyl-methionyl-leucyl-phenylalanine (fMLP) peptide.
        Autoimmunity. 2015; 48: 423-428
        • Kisseleva T.
        • Brenner D.A.
        Mechanisms of fibrogenesis.
        Exp. Biol. Med. (Maywood). 2008; 233: 109-122
        • Lin S.L.
        • Kisseleva T.
        • Brenner D.A.
        • Duffield J.S
        Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney.
        Am. J. Pathol. 2008; 173: 1617-1627
        • López B.
        • et al.
        Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure.
        Hypertens. (Dallas, Tex. 1979). 2009; 53: 236-242
        • McAnulty R.J.
        Fibroblasts and myofibroblasts: their source, function and role in disease.
        Int. J. Biochem. Cell Biol. 2007; 39: 666-671
        • Morris C.S.
        • Esiri M.M.
        Immunocytochemical study of macrophages and microglial cells and extracellular matrix components in human CNS disease: 1. Gliomas.
        J. Neurol. Sci. 1991; 101: 47-58
        • Mohan H.
        • et al.
        Extracellular matrix in multiple sclerosis lesions: fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells.
        Brain Pathol. 2010; 20: 966-975
        • Murfee W.L.
        • Skalak T.C.
        • Peirce S.M.
        Differential arterial/venous expression of NG2 proteoglycan in perivascular cells along microvessels: identifying a venule-specific phenotype.
        Microcirculation. 2005; 12: 151-160
        • Ooshima A.
        • Midorikawa O
        Increased lysyl oxidase activity in blood vessels of hypertensive rats and effect of beta-aminopropionitrile on arteriosclerosis.
        Jpn. Circ. J. 1977; 41: 1337-1340
        • Ozen I.
        • Boix J.
        • Paul G.
        Perivascular mesenchymal stem cells in the adult human brain: a future target for neuroregeneration?.
        Clin. Transl. Med. 2012; 1: 30
        • Özkan E.
        • et al.
        Blood-brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model. Metab.
        Brain Dis. 2021; https://doi.org/10.1007/s11011-021-00767-8
        • Procaccini C.
        • De Rosa V.
        • Pucino V.
        • Formisano L.
        • Matarese G
        Animal models of multiple sclerosis.
        Eur. J. Pharmacol. 2015; 759: 182-191
        • Qiu J.
        Venous abnormalities and multiple sclerosis: another breakthrough claim?.
        Lancet. Neurol. 2010; 9: 464-465
        • Ren S.
        • et al.
        LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1.
        Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 1440-1445
        • Ribeiro A.L.
        • Kaid C.
        • Silva P.B.G.
        • Cortez B.A.
        • Okamoto O.K
        Inhibition of lysyl oxidases impairs migration and angiogenic properties of tumor-associated pericytes.
        Stem Cells Int. 2017; 20174972078
        • Scholten D.
        • et al.
        Migration of fibrocytes in fibrogenic liver injury.
        Am. J. Pathol. 2011; 179: 189-198
        • Schrimpf C.
        • Teebken O.E.
        • Wilhelmi M.
        • Duffield J.S
        The role of pericyte detachment in vascular rarefaction.
        J. Vasc. Res. 2014; 51: 247-258
        • Sharp A.J.
        • et al.
        P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis.
        J. Neuroinflamm. 2008; 5: 33
        • Smyth L.C.D.
        • et al.
        Markers for human brain pericytes and smooth muscle cells.
        J. Chem. Neuroanat. 2018; 92: 48-60
        • Sobel R.A.
        • Mitchell M.E
        Fibronectin in multiple sclerosis lesions.
        Am. J. Pathol. 1989; 135: 161-168
        • Török O.
        • et al.
        Pericytes regulate vascular immune homeostasis in the CNS.
        Proc. Natl. Acad. Sci. USA. 2021; 118
        • Trapp B.D.
        • Nave K.-A.
        Multiple sclerosis: an immune or neurodegenerative disorder?.
        Annu. Rev. Neurosci. 2008; 31: 247-269
        • Traugott U.
        • Reinherz E.L.
        • Raine C.S.
        Multiple sclerosis: distribution of T cell subsets within active chronic lesions.
        Science. 1983; 219: 308-310
        • van Horssen J.
        • Bö L.
        • Vos C.M.P.
        • Virtanen I.
        • de Vries H.E.
        Basement membrane proteins in multiple sclerosis-associated inflammatory cuffs: potential role in influx and transport of leukocytes.
        J. Neuropathol. Exp. Neurol. 2005; 64: 722-729
        • Winkler E.A.
        • Sengillo J.D.
        • Bell R.D.
        • Wang J.
        • Zlokovic B.V
        Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability.
        J. Cereb. blood flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2012; 32: 1841-1852
        • Wong S.-P.
        • et al.
        Pericytes, mesenchymal stem cells and their contributions to tissue repair.
        Pharmacol. Ther. 2015; 151: 107-120
        • Xu J.
        • Shi G.-P.
        Vascular wall extracellular matrix proteins and vascular diseases.
        Biochim. Biophys. Acta. 2014; 1842: 2106-2119
        • Yahn S.L.
        • et al.
        Fibrotic scar after experimental autoimmune encephalomyelitis inhibits oligodendrocyte differentiation.
        Neurobiol. Dis. 2020; 134104674