生理衰老和炎症诱导的细胞衰老可能导致多发性硬化症的少突胶质细胞功能障碍

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-05-09 DOI:10.1007/s00401-024-02733-x
Farina Windener, Laureen Grewing, Christian Thomas, Marie-France Dorion, Marie Otteken, Lara Kular, Maja Jagodic, Jack Antel, Stefanie Albrecht, Tanja Kuhlmann
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摘要

衰老会影响中枢神经系统的所有细胞类型,并在中枢神经系统疾病中扮演重要角色。然而,人们对驱动这些年龄相关变化的潜在分子机制及其对疾病的影响还知之甚少。衰老脑白质以及多发性硬化症等疾病的特点是髓鞘和副髓鞘的细微异常,这表明中枢神经系统的髓鞘维持细胞少突胶质细胞在衰老和某些疾病中失去了保持适当髓鞘结构和潜在功能的能力。在这里,我们利用来自年轻人、成年人和老年人供体的直接转化少突胶质细胞(dchiOL)来研究与年龄相关的变化。所有三个年龄组的 dchiOL 都以类似的方式分化为 O4 + 未成熟少突胶质细胞,但 MBP + 成熟 dchiOL 的比例随着供体年龄的增加而下降。这与老龄 dchiOL 中 ROS 生成增加和细胞衰老标志物(如 CDKN1A、CDKN2A)上调有关。通过比较成年和老年供体的 dchiOL 转录组图谱,发现了 1324 个受不同调控的基因,这些基因与供体成纤维细胞的转录组图谱或已发表的直接转化人类神经元或原始啮齿类动物少突胶质细胞系细胞的转录组图谱重叠有限。对 dchiOL 和人类白质组织样本进行的甲基组分析表明,在中枢神经系统白质和 dchiOL 中,时间年龄和表观遗传年龄是相关的,并确定了年龄特异性表观遗传特征。此外,我们还观察到,与健康人相比,多发性硬化症(MS)患者有髓鞘、外观正常的白质表观遗传学老化加速。利用促炎性小胶质细胞的上清液可在体外诱导年轻的 dchiOL 分化受损和细胞衰老标记上调。总之,我们的数据表明,生理衰老和炎症诱导的细胞衰老是多发性硬化等炎症性脱髓鞘疾病少突胶质细胞病理学的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Physiological aging and inflammation-induced cellular senescence may contribute to oligodendroglial dysfunction in MS

Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as CDKN1A, CDKN2A in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors’ fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS.

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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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