Engineering hiPSCs to enhance neural progenitor transplantation in degenerative cervical myelopathy
type: CreativeWork
description: Neural progenitor cell transplantation has been widely explored in traumatic spinal cord injury (SCI) but has yet to be evaluated as a treatment for degenerative cervical myelopathy (DCM), a non-traumatic form of spinal cord injury. Importantly, the extent of astrogliosis and extracellular matrix remodelling that could limit or enhance neural progenitor cell (NPC) graft efficacy in DCM is unknown. The first aim of this project was to examine changes in the extracellular matrix in DCM. Immunohistochemistry of post-mortem patient tissue and a mouse model of DCM indicated astrogliosis and chondroitin sulfate proteoglycan accumulation, which could inhibit NPC integration. Meanwhile, bulk-transcriptomics from human post-mortem tissue revealed no upregulation of astrogliosis- or fibrosis-related genes in DCM. Second, the extent of endogenous remodelling of perineuronal extracellular matrix structures that could enable functional connectivity of NPC grafts – and which may underlie compensatory plasticity in DCM – is unknown. Immunohistochemical analysis of perineuronal nets (PNN) in murine models of DCM showed no significant changes in the number of PNN-positive neurons. Additionally, transcriptomic analysis of PNN-related gene expression from human tissue similarly showed no significant changes in DCM. Therefore, while diffuse astrogliosis and ECM deposition occurs in DCM, endogenous PNN remodelling may not underlie compensatory plasticity. Next, given the importance of PNNs in regulating synaptic plasticity, elucidating mechanisms of their development and remodeling through in-vitro models of human neurons would be useful. No such systems have been reported thus far and it remains unclear whether forward reprogrammed hiPSC-derived glutamatergic and GABAergic neurons contain PNNs. The second aim of this thesis was to determine the extent of PNN formation in forward reprogrammed neurons. Both NGN2 (glutamatergic) and ASCL1/DLX2 (GABAergic) lines displayed punctate, immatur…
abstract: Neural progenitor cell transplantation has been widely explored in traumatic spinal cord injury (SCI) but has yet to be evaluated as a treatment for degenerative cervical myelopathy (DCM), a non-traumatic form of spinal cord injury. Importantly, the extent of astrogliosis and extracellular matrix remodelling that could limit or enhance neural progenitor cell (NPC) graft efficacy in DCM is unknown. The first aim of this project was to examine changes in the extracellular matrix in DCM. Immunohistochemistry of post-mortem patient tissue and a mouse model of DCM indicated astrogliosis and chondroitin sulfate proteoglycan accumulation, which could inhibit NPC integration. Meanwhile, bulk-transcriptomics from human post-mortem tissue revealed no upregulation of astrogliosis- or fibrosis-related genes in DCM. Second, the extent of endogenous remodelling of perineuronal extracellular matrix structures that could enable functional connectivity of NPC grafts – and which may underlie compensatory plasticity in DCM – is unknown. Immunohistochemical analysis of perineuronal nets (PNN) in murine models of DCM showed no significant changes in the number of PNN-positive neurons. Additionally, transcriptomic analysis of PNN-related gene expression from human tissue similarly showed no significant changes in DCM. Therefore, while diffuse astrogliosis and ECM deposition occurs in DCM, endogenous PNN remodelling may not underlie compensatory plasticity. Next, given the importance of PNNs in regulating synaptic plasticity, elucidating mechanisms of their development and remodeling through in-vitro models of human neurons would be useful. No such systems have been reported thus far and it remains unclear whether forward reprogrammed hiPSC-derived glutamatergic and GABAergic neurons contain PNNs. The second aim of this thesis was to determine the extent of PNN formation in forward reprogrammed neurons. Both NGN2 (glutamatergic) and ASCL1/DLX2 (GABAergic) lines displayed punctate, immatur…
author: Poulin, Noah
language: eng
keywords: Degenerative Cervical Myelopathy, Spinal cord injury
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c0b23286-3685-425c-973e-ba16b8bd2b1b/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2024-01-01
date modified: 2026-07-22T22:24:31Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.107280