A novel paradigm for non-fibrotic regeneration of the cornea: The role of TGF-beta superfamily during embryonic cornea regeneration

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dc.contributor.advisorFarach-Carson, Mary C
dc.contributor.committeeMemberGrande-Allen, Jane
dc.contributor.committeeMemberLwigale, Peter Y
dc.contributor.committeeMemberMcNew, James A
dc.contributor.committeeMemberStern, Micheal
dc.creatorSpurlin, James W
dc.date.accessioned2016-01-27T17:25:37Z
dc.date.available2016-01-27T17:25:37Z
dc.date.created2016-05
dc.date.issued2015-12-16
dc.date.submittedMay 2016
dc.date.updated2016-01-27T17:25:37Z
dc.description.abstractDamage to the cornea results in fibrotic scarring, leading to the loss of tissue transparency and reduced visual acuity. In fact, corneal opacity is the world’s third leading cause of blindness. Other than transplantation of the affected tissue, there is no treatment to prevent corneal scarring. For these reasons, there is a need to develop anti-fibrotic therapies to promote corneal regeneration after injury. Embryonic tissue has a remarkable regenerative capacity. However, prior to this study, it was not known if the embryonic cornea possessed the ability to regenerate. I hypothesized wounded embryonic corneas wound exhibit non-fibrotic regeneration, and could be used to elucidate novel mechanisms of cornea regeneration. I developed a multistep microdissection method that allows access to the embryonic cornea and several other tissues undergoing organogenesis. Utilizing this methodology, I found embryonic corneal wounds induce a transient population of scar-forming myofibroblast, and ultimately regenerate scar-free. Immunohistological analysis of wounded embryonic corneas revealed transient change in expression of ECM components, which is restored to normal levels in the healed corneas. Furthermore, I showed that Sema3A mRNA is elevated and innervation of wounded embryonic corneas is inhibited during healing, but regenerated corneas are fully innervated. These findings contribute to the understanding of the events that orchestrate scar-free regeneration of wounded corneas. Since embryonic corneas possess an intrinsic regenerative capacity, the embryonic wound healing model serves as a great tool to study regulatory mechanisms that facilitate non-fibrotic healing. Because scar associated myofibroblasts are inherently transient in the embryonic cornea wound, I sought to determine mechanistic regulation of this cell population during cornea regeneration. I hypothesized the embryonic cornea wound would exhibit unique regulation of myofibroblast inductive growth factor, TGF-beta, during regeneration. Through studying gene expression profiles in the embryonic cornea wound healing model, I determined the spatiotemporal distribution of TGF-beta transcripts and the subsequent activation of the myofibroblast population. Moreover, I identified the expression of candidate TGF-beta antagonists when myofibroblasts are found to exit the regenerating cornea. My data shows BMP3 as a novel antagonist to TGF-beta mediated myofibroblast differentiation in isolated embryonic corneal cells. Interestingly, TGF-beta mediated accumulation of focal adhesion appears to be attenuated by BMP3, implicating the role of cellular adhesion in promoting the myofibroblast phenotype. Collectively, this work demonstrates the utility of the embryonic cornea wound healing model to identify novel mechanisms of scar-free cornea regeneration. Additionally, this novel mechanism of BMP3 antagonism on TGF-beta mediated fibrotic response suggests targeting aspects of cellular adhesion signaling may provide viable therapeutics to mitigate corneal fibrosis.
dc.format.mimetypeapplication/pdf
dc.identifier.citationSpurlin, James W. "A novel paradigm for non-fibrotic regeneration of the cornea: The role of TGF-beta superfamily during embryonic cornea regeneration." (2015) Diss., Rice University. <a href="https://hdl.handle.net/1911/88164">https://hdl.handle.net/1911/88164</a>.
dc.identifier.urihttps://hdl.handle.net/1911/88164
dc.language.isoeng
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.
dc.subjectcornea
dc.subjectwound healing
dc.subjectorganogenesis
dc.subjectregeneration
dc.subjectdevelopment
dc.subjectembryonic manipulations
dc.subjectTGF-beta
dc.subjectmyofibroblasts
dc.subjectBMP
dc.subjectECM
dc.titleA novel paradigm for non-fibrotic regeneration of the cornea: The role of TGF-beta superfamily during embryonic cornea regeneration
dc.typeThesis
dc.type.materialText
thesis.degree.departmentBiochemistry and Cell Biology
thesis.degree.disciplineNatural Sciences
thesis.degree.grantorRice University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
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