Tsg-6 : an inducible mediator of paracrine anti-inflammatory and myeloprotective effects of adipose stem cells

dc.contributor.advisorMarch, Keith Leonard, 1963-
dc.contributor.authorXie, Jie
dc.contributor.otherPetrache, Irina
dc.contributor.otherClauss, Matthias A.
dc.contributor.otherBroxmeyer, Hal E.
dc.date.accessioned2014-01-29T16:39:16Z
dc.date.issued2014-01-29
dc.degree.date2012en_US
dc.degree.disciplineDepartment of Cellular & Integrative Physiologyen
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI).en_US
dc.description.abstractTumor necrosis factor-induced protein 6 (TSG-6) has been shown to mitigate inflammation. Its presence in the secretome of adipose stem / stromal cells (ASC) and its role in activities of ASC have been overlooked. This thesis described for the first time the release of TSG-6 from ASC, and its modulation by endothelial cells. It also revealed that protection of endothelial barrier function was a novel mechanism underlying the anti-inflammatory activity of both ASC and TSG-6. Moreover, TSG-6 was found to inhibit mitogen-activated lymphocyte proliferation, extending the understanding of its pleiotropic effects on major cell populations involved in inflammation. Next, enzyme-linked immunosorbent assays (ELISA) were established to quantify secretion of TSG-6 from human and murine ASC. To study the importance of TSG-6 to specific activities of ASC, TSG-6 was knocked down in human ASC by siRNA. Murine ASC from TSG-6-/- mice were isolated and the down-regulation of TSG-6 was verified by ELISA. The subsequent attempt to determine the efficacy of ASC in ameliorating ischemic limb necrosis and the role of TSG-6, however, was hampered by the highly variable ischemic tissue necrosis in the BALB/c mouse strain. Afterwards in a mouse model of cigarette smoking (CS), in which inflammation also plays an important role, it was observed, for the first time, that 3-day CS exposure caused an acute functional exhaustion and cell cycle arrest of hematopoietic progenitor cells; and that 7-week CS exposure led to marked depletion of phenotypic bone marrow stem and progenitor cells (HSPC). Moreover, a dynamic crosstalk between human ASC and murine host inflammatory signals was described, and specifically TSG-6 was identified as a necessary and sufficient mediator accounting for the activity of the ASC secretome to ameliorate CS-induced myelotoxicity. These results implicate TSG-6 as a key mediator for activities of ASC in mitigation of inflammation and protection of HSPC from the myelotoxicity of cigarette smoke. They also prompt the notion that ASC and TSG-6 might potentially play therapeutic roles in other scenarios involving myelotoxicity.en_US
dc.identifier.urihttps://hdl.handle.net/1805/3876
dc.identifier.urihttp://dx.doi.org/10.7912/C2/2002
dc.language.isoen_USen_US
dc.subjectAdipose stem cell, inflammation, TSG-6, hematopoiesis, smokingen_US
dc.subject.lcshStem cells -- Research -- Analysisen_US
dc.subject.lcshEpithelial cells -- Researchen_US
dc.subject.lcshMesenchymal stem cellsen_US
dc.subject.lcshHematopoiesis -- Regulationen_US
dc.subject.lcshCell interactionen_US
dc.subject.lcshAdipose tissues -- Tumorsen_US
dc.subject.lcshInflammationen_US
dc.subject.lcshLymphocyte transformationen_US
dc.subject.lcshMitogen-activated protein kinasesen_US
dc.subject.lcshTumor necrosis factor -- Receptors -- Researchen_US
dc.subject.lcshSmoking -- Health aspects -- Researchen_US
dc.subject.lcshCellular control mechanismsen_US
dc.subject.lcshCellular signal transduction -- Researchen_US
dc.subject.lcshBone marrow -- Blood-vessels -- Researchen_US
dc.titleTsg-6 : an inducible mediator of paracrine anti-inflammatory and myeloprotective effects of adipose stem cellsen_US
dc.typeThesisen
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