Do all oligodendrogenic stem cells age at the same rate?

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

In the brain the fibres of nerve cells are protected by insulating sheaths called myelin. Myelin is made by a specialized cell called an oligodendrocyte. During ageing, brain myelin is lost without being replaced contributing to age-related decline in brain function. In addition, the ability of the tissue to cope with diseases in which myelin is lost (such as in multiple sclerosis) is especially compromised in the elderly. Two main types of adult brain stem cells are responsible for making new oligodendrocytes and restoring myelin throughout life. One is widely distributed throughout the CNS (parenchymal stem cells) while the other is confined to a specific region deep within the brain (niche stem cells). Parenchymal stem cells are born during infancy and previous research has shown that are adversely affected by age. In contrast, niche stem cells are constantly born, even in the aged brain. This suggests that the adverse effects of age will have a greater impact in parenchymal versus niche stem cells. In this project we will conduct a series of experiments to address this fundamental question, establish why the machinery of myelin maintenance and regeneration becomes less efficient with ageing and provide pointers to how to alleviate the effects of ageing on brain function.

Technical Summary

Loss of myelin sheaths from CNS axons is a prominent histological finding in the aging 'healthy' and diseased brain. This is related to the age-associated decline in the ability of the CNS to generate new cells to replace lost myelin. The main source of replacement cells is the oligodendrocyte progenitor cells (OPCs) that are widely distributed throughout the CNS. These cells are generated during the perinatal period and although capable of self-renewal nevertheless undergo age-associated changes, with an increasing fraction of them becoming senescent. This reduces myelin maintenance in the aged brain. Recently, neural stem cells located in the subependymal zone have been identified as an additional source of OPCs and ultimately new (re)myelinating oligodendrocytes in the brain. Since these niche-derived OPCs are generated from stem cells we hypothesise that they will be less adversely affected than the adult parenchymal OPCs. In this project, we will use transgenic mice (crossing Rosa26-EYFP and GFAP-CreErt2 mouse lines) to specifically label subependymal zone stem cells and their progeny, including OPCs. Based on this technology and using a battery of in vivo and in vitro assays, we will compare the properties (cell cycle kinetics, migration potential, remyelination potential) of the constantly generated niche-derived and potentially young OPCs with the more numerous peri-natally generated ageing OPCs. Importantly, the comparison between young and aged progenitors of the same lineage performed in the context of both the young and aged brain will allow the dissection of cell-intrinsic and extrinsic factors implicated in the age-related changes in the properties of OPCs. This project will advance our knowledge on the oligodendrogenic potential of adult neurogenic areas and will identify molecular pathways involved in the effects of ageing in the overall brain oligodendrogenic machinery.

Planned Impact

One of the main features of ageing is the gradual decline in brain function (referred to as dementia), leading to deterioration of cognitive abilities (memory loss, confusion) and the presentation of multiple neurological symptoms. An estimated 750,000 people are affected by dementia in the UK (24 million world wide) and the prediction is that there will be over 940,000 people living with dementia by 2021 with the number reaching 1.7 million by 2050 (more than 80 million world-wide). Moreover, the economic burden of dementia in the UK is estimated to reach £27 billion per annum by 2018 while delaying the onset of dementia by five years would halve the number of deaths from the condition, saving 30,000 lives a year and significantly reduce the cost to society. Alzheimer's disease is the most common type of dementia, affecting 62 per cent of those diagnosed and becoming so prevalent that it afflicts more than 50% of the population over the age of 85 with age itself being the most important risk factor. Other types of dementia include; vascular dementia affecting 17 per cent of those diagnosed and mixed dementia affecting 10 per cent of those diagnosed. Accumulating experimental and clinical evidence reveals that the age-related loss of myelin (the membranous sheath that surrounds, protects and supports the function of nerve axons), caused by the increased rate of destruction of myelin sheaths and the decreased potential of the aged brain to replace it, underlines dementia either manifested as Alzheimer's disease or as vascular dementia. Therefore, discoveries in the biology of the cells that form myelin (called oligodendrocytes) and on the cells that regenerate myelin (oligodendrocyte precursors) are expected to have significant implications in the treatment and prevention of dementia, hence the improvement of health and wellbeing in the elderly population. The results that will be generated by this project will allow the identification of the properties of oligodendrocyte precursors that are affected by aging (both as a result of the aging of the cells and of the aging of the surrounding brain tissue) and of targets for strategies aiming in alleviating or reversing age-related effects. Furthermore, because oligodendrocyte precursors are a type of stem cell, the results of the project will contribute in the wider understanding of the effects of aging on stem cells, hence benefiting other areas of age-related deterioration of health, such as muscle preservation and regeneration and hematopoiesis.

Publications

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De La Fuente AG (2020) Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing. in Molecular & cellular proteomics : MCP

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Kazanis I (2017) Stem Cell Reports in Subependymal zone derived oligodendroblasts respond in a fast and transient mode to focal demyelination but fail to generate myelin in young and aged mice

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Kazanis I (2013) Neurogenesis in the adult mammalian brain: how much do we need, how much do we have? in Current topics in behavioral neurosciences

 
Description In this project we have discovered that CNS progenitors derived from the sub-ventricular zone (SVZ) are highly responsive to white matter injury in the vicinity of the SVZ, but in contrast to locally derived adult progenitors, they rarely differentiate into new myelin sheath forming oligodendrocytes.
Exploitation Route Redirect translationally oriented research on remyelination to focus on parenchymal progenitor cells rather than stem cell-derived progenitors.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description White matter meeting (Trondheim) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact This was a symposium in which a number of international clinical and basic science experts shared their expertise on current issues in the field of "white matter biology". It was attended by approximately 60-100 medical students as part of their PhD course.

Networking with peers has started to develop.
Year(s) Of Engagement Activity 2014
URL http://nansenneuro.net/news/secretariat-news/50458-finally-an-appreciation-of-white-matter.html