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dc.contributor.advisorPeault, Bruno
dc.contributor.advisorAhmed, Asif
dc.contributor.advisorHenderson, Neil
dc.contributor.authorMurray, Iain Robert
dc.date.accessioned2017-04-12T09:05:26Z
dc.date.available2017-04-12T09:05:26Z
dc.date.issued2015-07-04
dc.identifier.urihttp://hdl.handle.net/1842/21092
dc.description.abstractPericytes represent a population of potential mesenchymal stem cells (MSC) that reside within a perivascular niche until they are required in normal homeostasis and the response to injury. Their mesenchymal capacities for multipotent differentiation, immune modulation and release of trophic factors hold great promise for regenerative therapies. Pathological expression of these potentials has been described in disease states, while acute or chronic inflammation following injury can lead to the production of signalling molecules that ultimately drive these progenitors to a fibrotic fate. The aim of this work was to explore how fate decisions of pericytes are regulated by their niche (in the setting of osteogenesis), and in the response to acute and chronic injury (in the setting of fibrosis). It was hypothesized that interactions between pericytes and endothelial cells (EC) within their perivascular niche are responsible for regulating mesenchymal differentiation. The osteogenic, adipogenic and chondrogenic potential of pericytes following isolation from multiple human organs was confirmed. The interactions between pericytes and EC in 2D and 3D coculture and the production of basement membrane proteins in these settings were confirmed. The osteogenic differentiation of pericytes was accelerated by EC but no influence of EC on the adipogenic and chondrogenic differentiation of pericytes was detected. Furthermore, data indicated that the influence on pericyte osteogenic potential by EC may occur through wnt signaling. The activation of TGFβ (transforming growth factor beta) through αv integrins has been suggested as central mediator of fibrosis in multiple organs. We hypothesized that selective αv integrin deletions in PDGFRβ (platelet derived growth factor receptor beta) expressing pericytes identifies a targetable pathway regulating fibrosis in skeletal muscle. We report that PDGFRβ-Cre inactivates genes in murine skeletal muscle pericytes with high efficiency. Deletion of the αv integrin subunit in pericytes protected mice from chemical injury induced skeletal muscle fibrosis. Pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated muscle fibrosis, even when administered after fibrosis was established.en
dc.contributor.sponsorWellcome Trusten
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionCorselli M, Crisan M, Murray IR, West CC, Scholes J, Codrea F, et al. Identification of perivascular mesenchymal stromal/stem cells by flow cytometry. Cytometry A 2013;83(8):714-20.en
dc.relation.hasversionChen WC, Park TS, Murray IR, Zimmerlin L, Lazzari L, Huard J, et al. Cellular kinetics of perivascular MSC precursors. Stem Cells Int 2013;2013:983059.en
dc.relation.hasversionMurray IR, West CC, Hardy WR, James AW, Park TS, Nguyen A, et al. Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci 2013.en
dc.relation.hasversionMurray IR, West CC, Hardy WR, James AW, Park TS, Lazzari L, Soo C, Péault B. Natural History of Mesenchymal Stem Cells, from Vessel Walls to Culture Vessels. Cellular and Molecular Life Sciences 2014;71(8):1353-74en
dc.relation.hasversionMurray IR, Corselli M, Petrigliano F, Soo C, Péault B. Recent insights into mesenchymal stem cell identity: implications for orthopaedic applications. Bone and Joint Journal 2014;96-B(3):291-8.en
dc.relation.hasversionWest CC, Murray IR, González ZN, Hindle P, Hay DC, Stewart KJ, Péault B. Ethical, legal and practical issues of establishing an adipose stem cell bank for research. J Plast Reconstr Aesthet Surg. 2014 Jun;67(6):745-751.en
dc.subjectperivascular stem cellen
dc.subjectosteogenesisen
dc.subjectfibrosisen
dc.subjectpericyteen
dc.titlePerivascular stem cells at the crossroads of tissue regeneration and pathologyen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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