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Investigating neuroectodermal transdifferentiation: How do CNS progenitors form Schwann cells?


Type

Thesis

Change log

Authors

Chen, Civia 

Abstract

Myelin sheaths provide trophic support to axons, allow rapid nerve impulse conduction and are critical for neuronal function. Under homeostatic conditions, axons of the central nervous system (CNS) are myelinated by oligodendrocytes. However, in response to demyelination, Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), can contribute to CNS remyelination. Although CNS-resident SCs were previously thought to have migrated into the CNS from peripheral sources, lineage tracing studies demonstrated that adult CNS progenitors, oligodendrocyte progenitor cells (OPCs), can produce SCs in vivo. The mechanisms underlying this damage-induced plasticity of OPC fate choice remain incompletely understood. Therefore, in this thesis I sought to understand how changes in the lesion environment alter the differentiation trajectories of individual OPCs, and to determine how these factors affect the transcriptional control of OPC fate choices. Using single-cell RNA-sequencing I identified a subpopulation of OPCs within the demyelinating lesion that co-express SC markers. Within this SC primed group, differential gene analysis revealed a significant upregulation of genes involved in integrin signalling and with bone morphogenetic protein (BMP) activation. I showed that recapitulating the lesion environment by exposing cultured OPCs to vitronectin and BMP4 is sufficient to induce a SC fate within one week of induction. OPC-derived SCs morphologically and transcriptionally resemble primary SCs, and when transplanted into the CNS can survive and myelinate host CNS axons with peripheral type myelin. Subsequently, I found that these external pathways can directly interact with Olig2 and Sox10, which are critical regulators of cell fate in oligodendroglial cells and SCs. I then showed that OPCs can be directly reprogrammed toward a SC fate by manipulating the expression levels of Olig2 and Sox10. To further characterise the molecular changes that accompany the phenotypic conversion, I used single-cell RNA-sequencing to identify the core biological processes required for SC differentiation, and to show that successfully converted OPC-derived SCs express a number of transcriptional hallmarks of peripheral SCs. Together, these findings indicate that injury-related changes in the environment can destabilise oligodendroglial transcription factor networks, which enable alternative OPC fate choices, and reveal deeper insights into the mechanisms underlying OPC cell fate decisions during CNS remyelination.

Description

Date

2022-12-31

Advisors

Arthur-Farraj, Peter
Franklin, Robin

Keywords

Central nervous system, Myelin, oligodendrocyte progenitor cell, remyelination, Schwann cell

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
This work was supported by funding from the UK Multiple Sclerosis Society (MS50), The Adelson Medical Research Foundation and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). C.Z.C. holds a Wellcome PhD studentship.