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Elucidating interactions between the dermal fibroblast phenotype, inflammatory signals and extra-cellular matrix components

Sandulache, Vlad Constantin (2006) Elucidating interactions between the dermal fibroblast phenotype, inflammatory signals and extra-cellular matrix components. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The study of dermal wound healing has long been used to elucidate the cellular and molecular processes guiding the connective tissue response to injury. Of particular interest are the mechanisms by which soluble mediators, including inflammatory signals, guide fibroblast activity within the wound bed. This thesis addresses the role of prostaglandin E2 (PGE2) in the regulation of fibroblast activities relevant to restoration of tissue structure and function. Although PGE2 has been previously shown to play an important role in various wound healing steps, its precise contribution to the overall outcome of dermal repair is unclear. Using three well defined human dermal fibroblast phenotypes this study demonstrates that while PGE2 signaling during dermal repair triggers pro-inflammatory cascades, its effects on fibroblast activities are putatively anti-fibrotic. Specifically, exogenous PGE2 decreases the migratory and contractile potential of dermal fibroblasts through destabilization of the actin cytoskeleton and inhibits endogenous collagen synthesis. While PGE2 effects on fibroblast activity are largely conserved across phenotypes, fetal fibroblasts maintain a quantitatively diminished response to PGE2-induced alterations of cytoskeletal dynamics.Upon further analysis, this effect was shown to be representative of a larger intrinsic fibroblast phenotype. Fetal dermal fibroblasts were shown to maintain elevated rates of migration and contraction, as part of a generalized hyperactive dynamic state. Surprisingly, this phenotype was found to be sufficiently robust so as to persist despite changes in substrate and environmental constraints. In light of this finding, one additional approach was used to ascertain the robustness of the fetal fibroblast. Transplantation of fetal dermal fibroblasts into an adult wound environment was used to assess whether the intrinsic fetal fibroblast phenotype can survive the multitude of events comprising adult wound healing. While results are preliminary, this approach does present a useful tool for future studies aimed at elucidating the precise fetal fibroblast phenotype and its contribution to overall wound healing response.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sandulache, Vlad
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWells, Alan H.wellsa@upmc.eduAHW6
Committee MemberHackam, David
Committee MemberHebda, Patricia
Committee MemberMonga, Satdarshan P.S.smonga@pitt.eduSMONGA
Committee MemberStrom, Stephenstrom@pitt.eduSTROM
Date: 27 April 2006
Date Type: Completion
Defense Date: 2 March 2006
Approval Date: 27 April 2006
Submission Date: 9 March 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: collagen; fibroblast; matrix; migration; prostaglandinE2; wound healing
Other ID:, etd-03092006-110541
Date Deposited: 10 Nov 2011 19:32
Last Modified: 19 Dec 2016 14:35


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