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 Cen_US
dc.contributor.committeeMemberGrande-Allen, Janeen_US
dc.contributor.committeeMemberLwigale, Peter Yen_US
dc.contributor.committeeMemberMcNew, James Aen_US
dc.contributor.committeeMemberStern, Michealen_US
dc.creatorSpurlin, James Wen_US
dc.date.accessioned2016-01-27T17:25:37Zen_US
dc.date.available2016-01-27T17:25:37Zen_US
dc.date.created2016-05en_US
dc.date.issued2015-12-16en_US
dc.date.submittedMay 2016en_US
dc.date.updated2016-01-27T17:25:37Zen_US
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.en_US
dc.format.mimetypeapplication/pdfen_US
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>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/88164en_US
dc.language.isoengen_US
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.en_US
dc.subjectcorneaen_US
dc.subjectwound healingen_US
dc.subjectorganogenesisen_US
dc.subjectregenerationen_US
dc.subjectdevelopmenten_US
dc.subjectembryonic manipulationsen_US
dc.subjectTGF-betaen_US
dc.subjectmyofibroblastsen_US
dc.subjectBMPen_US
dc.subjectECMen_US
dc.titleA novel paradigm for non-fibrotic regeneration of the cornea: The role of TGF-beta superfamily during embryonic cornea regenerationen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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