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

作者：Farina Windener, Laureen Grewing, Christian Thomas, Marie‐France Dorion, Marie Otteken, Lara Kular, Maja Jagodic, Jack P. Antel, Stefanie Albrecht, Tanja Kuhlmann · 发表于：Acta Neuropathologica · 年份：2024 · DOI：10.1007/s00401-024-02733-x · 被引用次数：32 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Multiple Sclerosis Research Studies、Tryptophan and brain disorders

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 a...