Metabolic control of neural stem cell function in a patient-derived model of multiple sclerosis

Multiple sclerosis (MS), the most prevalent inflammatory autoimmune disorder affecting the central nervous system (CNS), results in the deterioration of myelin sheaths and neuronal injury. For reasons that remain unclear, the majority of patients eventually enter a disease stage termed progressive MS (PMS), which is characterised by a substantial failure of the main endogenous brain repair mechanism seen in the early stages of the disease. During this period, patients experience a gradual accrual of neurological deficits, which are largely attributable to neuronal loss. There are limited treatment options for this phase of the disease. Notably, progression of the disease is associated with aging, with recent studies implicating cellular senescence (CS), particularly in the stem cell compartment of the PMS brain, as a probable contributor to disease progression by creating a hostile environment. Given the intricate interplay between cellular metabolism and CS, there is growing interest in exploring metabolic pathways as potential targets for therapeutic intervention in PMS to correct dysfunctional senescence-associated phenotypes that may be contributing to neuronal loss. My research aims to investigate the role of neural stem cell (NSC) metabolism in driving pathological changes in the PMS brain. Most MS models do not account for ageing, by either utilising middle-aged animals or employing reprogramming technologies which lead to cellular rejuvenation (e.g., induced pluripotent stem cells [iPSCs]). In the present study I am utilizing an innovative *in vitro* disease model employing human induced neural stem cells (iNSCs), which retain the epigenetic age of the somatic cells by bypassing the pluripotency stage in the reprogramming process. I conducted comprehensive phenotypic and multi-omics analyses of iNSCs generated from healthy controls and people with PMS. This investigation unveiled a distinct senescent gene expression profile in PMS iNSCs, primarily associated with inflammatory signalling, heightened metabolic activity, and the secretion of senescence-associated secretory phenotype (SASP) factors. PMS-derived iNSCs exhibited elevated synthesis of fatty acids and cholesterol, leading to the accumulation of cholesteryl ester-enriched lipid droplets. Furthermore, the lipogenic state mediated by HMG-CoA reductase activity triggered SASP release in PMS iNSCs via transcriptional regulation by cholesterol-dependent transcription factors. Notably, SASP from PMS iNSCs induced neurotoxicity, which could be mitigated through pharmacological intervention targeting HMG-CoA reductase using simvastatin (SV), a cholesterol-lowering drug. These findings highlight an intrinsic disease-linked, cholesterol-related, hypermetabolic phenotype in PMS iNSCs, culminating in neurotoxic signalling, which can be pharmacologically rescued, and establish iNSCs as a viable tool to study disease mechanisms in PMS.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Ionescu, Rosana-Bristena

Advisor dc:contributor.advisor

• Pluchino, Stefano

• cellular senescence
• cholesterol metabolism
• disease modelling
• lipid droplets
• multi-omics
• multiple sclerosis
• neural stem cells
• Neuroimmunology
• neurotoxicity
• SASP

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1f263d98-ec6d-4e53-a010-d9f9144e151a/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.111968

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/373610