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dc.contributor.advisorRambukkana, Anura
dc.contributor.advisorTomlinson, Simon
dc.contributor.authorHess, Samuel Joseph
dc.date.accessioned2017-12-18T11:50:40Z
dc.date.available2017-12-18T11:50:40Z
dc.date.issued2016-11-29
dc.identifier.urihttp://hdl.handle.net/1842/25778
dc.description.abstractTerminally differentiated Schwann cells (SCs), the glial cells in the adult peripheral nerves, display a remarkable plasticity by adopting a de-differentiated phenotype following injury and becoming specialised to repair-type cells for promoting nerve regeneration. Adult SC plasticity is also hijacked by leprosy-causing Mycobacterium leprae during peripheral nerve infection, which make SCs susceptible to reprogramming and generation of progenitor/stem-like cells for bacterial advantage. Interestingly, de-differentiated SCs generated during nerve injury and infection reactivated stem cell transcription factor Sox2, which is essential for maintaining pluripotency in embryonic stem cells (ESCs). In this study we address what role Sox2 plays and how it is involved in adult SC plasticity. We identified that Sox2 binds to a network of gene targets in de-differentiated adult SCs across the mouse genome. This Sox2 target network is distinct from Sox2 target genes in core ESC pluripotency, and appears to be modulated by SC microenvironmental changes and pathological conditions, as nerve crush injury and infection-induced reprogramming expanded Sox2 binding to target genes. In vivo knockdown by shRNA of Sox2 in wild type adult nerves demonstrated reduction in SC de-differentiation. Mutant mice defective in natural nerve degeneration, de-differentiation and regeneration (Wallerian degeneration slow mice; Wlds) not only show impaired Sox2 binding to its target genes but also a delay in Sox2 and target gene expression after nerve crush injury. Together, these in vivo data reveal an impact of Sox2 and its target network on SC plasticity. Furthermore, altered expression of many of these target genes after Sox2 knockdown in wild type adult Schwann cells in vitro and in vivo as well as in injured Wlds nerves suggests a functional role of a Sox2 target network in nerve injury-repair processes. This includes Sox2 target genes such as Megf10, Btc, Atf3 and Nestin. By acting on these genes Sox2 may coordinate relevant gene functions ranging from phagocytosis/clearance, proliferation, transcription and cytoskeletal dynamics. Thus, this study proposes a novel concept of how reactivation of an embryonic stem cell regulator like Sox2 in adult tissues coordinates a gene network regulating Schwann cell plasticity and multiple biological functions facilitating the nerve injury-repair process. These findings may aid in developing strategies towards promoting nerve regeneration, or designing treatments for neuropathies in which deregulation of Schwann cell de-differentiation contributes to pathogenesis.en
dc.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionHess, Samuel, and Anura Rambukkana. “Bacterial-Induced Cell Reprogramming to Stem Cell-like Cells: New Premise in Host-Pathogen Interactions.” Current Opinion in Microbiology 23 (February 2015): 179–88. doi:10.1016/j.mib.2014.11.021.en
dc.subjectSox2en
dc.subjectplasticityen
dc.subjectSchwann cellen
dc.titleSox2 target network in regulating adult Schwann cell plasticity: new insights into peripheral nerve regeneration and pathologyen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31en
dcterms.accessRightsRestricted Accessen


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