Do adult human oligodendrocytes remyelinate poorly and can we change this to better treat progressive multiple sclerosis?

成人少突胶质细胞髓鞘再生能力是否较差？我们能否改变这一点以更好地治疗进行性多发性硬化症？

• 批准号: MR/T015594/1
• 负责人: Anna Williams
• 金额: $ 66.03万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT015594%2F1
• 关键词: Do; adult; human; oligodendrocytes; remyelinate

Multiple sclerosis (MS) is a common chronic disease of the brain and spinal cord, often starting in young adulthood, which frequently causes disability. Although the early stages of the disease can now be controlled with medication, in the later stages, there are no treatments to either slow, stop or reverse disability. One focus of research to help the later 'progressive' phase of MS is to encourage repair of the myelin sheath that covers the nerves. This is damaged in MS and when replaced can protect nerves from dying. The cells that carry out repair of this myelin sheath are called oligodendrocytes, which are present in brains of people with MS, but these cells struggle to repair the myelin sheaths. Researchers have now developed drugs that might help oligodendrocytes to repair myelin sheaths but in trials in people they only showed a very small effect. This project will investigate ways to improve this effect.Firstly, we now know that rat oligodendrocytes are worse at repairing myelin as they get older, and most drugs are tested in the lab on very young oligodendrocytes. We found that these drugs currently being tested in clinical trials do not help adult brain oligodendrocytes repair myelin. However, these drugs become effective again if they are first treated with another drug called metformin. Secondly, we recently found that there are different types of human oligodendrocytes, which are different from in rat oligodendrocytes, and some of these types might be better at repairing myelin than others.In this project, we will test whether adult human oligodendrocytes also become worse at repairing myelin with age, and can be rejuvenated to respond better to the pro-repair drugs with metformin. To do this we need to be able to grow adult human oligodendrocytes in a dish. We will obtain some from human brain biopsies, but also we will try and make 'aged' cells from stem cells (which normally represent very young cells) by using genetic tricks. We will also see whether we can use this method of rejuvenation in combination with drugs to help encourage the formation of the best type of oligodendrocytes for myelin repair.This project will find out whether we can better test MS therapies on relevant adult human cells, to improve their response to drugs helping myelin repair. Some of these pro-repair drugs and metformin are being considered for use in 'The Efficient Clinical Trials Platform' to be launched by the MS Society UK in 2020, and so this project will help select some of these current drugs and provide a relevant testing platform for other drugs. This means we will better at finding drugs that are more likely to work in MS and can test them in MS patients quickly.

多发性硬化症（MS）是一种常见的脑和脊髓慢性疾病，通常始于年轻的成年期，经常导致残疾。虽然疾病的早期阶段现在可以通过药物控制，但在后期阶段，没有治疗方法可以减缓，停止或逆转残疾。研究的一个重点是帮助MS的后期“进行性”阶段，以鼓励修复覆盖神经的髓鞘。这在MS中被损坏，当被替换时可以保护神经免于死亡。进行髓鞘修复的细胞被称为少突胶质细胞，它们存在于MS患者的大脑中，但这些细胞难以修复髓鞘。研究人员现在已经开发出可能帮助少突胶质细胞修复髓鞘的药物，但在人体试验中，它们只显示出非常小的效果。本项目将研究改善这种效果的方法。首先，我们现在知道，随着年龄的增长，大鼠少突胶质细胞修复髓鞘的能力越来越差，大多数药物都是在实验室中对非常年轻的少突胶质细胞进行测试的。我们发现这些目前正在临床试验中测试的药物并不能帮助成年大脑少突胶质细胞修复髓鞘。然而，这些药物再次变得有效，如果他们首先与另一种药物称为二甲双胍治疗。第二，我们最近发现人类少突胶质细胞有不同的类型，与大鼠少突胶质细胞不同，其中一些类型可能比其他类型更擅长修复髓鞘。在这个项目中，我们将测试成年人少突胶质细胞是否也随着年龄的增长而修复髓鞘变差，并且可以恢复活力，对二甲双胍的促修复药物有更好的反应。要做到这一点，我们需要能够在培养皿中培养成人少突胶质细胞。我们将从人脑活检中获得一些，但我们也将尝试通过使用遗传技巧从干细胞（通常代表非常年轻的细胞）中制造“衰老”细胞。我们还将看看我们是否可以使用这种返老还童的方法与药物相结合，以帮助促进髓鞘修复的最佳类型的少突胶质细胞的形成。该项目将发现我们是否可以更好地测试MS疗法对相关的成人细胞，以改善他们对帮助髓鞘修复的药物的反应。其中一些促修复药物和二甲双胍正在考虑用于MS Society UK将于2020年推出的“高效临床试验平台”，因此该项目将有助于选择其中一些现有药物，并为其他药物提供相关的测试平台。这意味着我们将更好地找到更有可能在MS中起作用的药物，并可以在MS患者中快速进行测试。

项目成果

The antimicrobial peptide cathelicidin is critical for the development of Th17 responses in severe inflammatory disease

• DOI: 10.1101/2022.01.27.477976
• 发表时间: 2022-01
• 期刊: bioRxiv
• 作者: K. Smith;Danielle Minns;B. McHugh;Rebecca K. Holloway;R. O’Connor;Anna C. Williams;L. Melrose;Rhoanne C. McPherson;V. Miron;D. Davidson;E. Findlay

Oligodendroglia heterogeneity in the human central nervous system.

• DOI: 10.1007/s00401-021-02390-4
• 发表时间: 2022-03
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Seeker LA;Williams A
• 通讯作者: Williams A

AimSeg: a machine-learning-aided tool for axon, inner tongue and myelin segmentation

AimSeg：用于轴突、内舌和髓磷脂分割的机器学习辅助工具

• DOI: 10.1101/2023.01.02.522533
• 发表时间: 2023
• 作者: Rondelli A

Oligodendroglial Heterogeneity in Neuropsychiatric Disease.

• DOI: 10.3390/life11020125
• 发表时间: 2021-02-06
• 期刊: Life (Basel, Switzerland)
• 作者: Bøstrand SMK;Williams A
• 通讯作者: Williams A

New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination

• DOI: 10.1101/2020.05.22.110551
• 发表时间: 2020-05
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Sarah A. Neely;Jill M Williamson;Anna Klingseisen;Lida Zoupi;J. Early;Anna C. Williams;D. Lyons