Assessing whether human oligodendrocytes go senescent: a cell culture and transcriptomic interrogation of human white matter

Abstract

White matter (WM) atrophy is an early sign of Alzheimer's Disease pathophysiology. However, our understanding of the main cell type that comprises white matter, the oligodendrocyte (OL), is far less understood than other neural cell types. Senescence is a phenotype associated with aging where damaging stimuli cause permanent cell cycle arrest. To date, it is unclear whether OLs become senescent or not. Understanding OL functions in both WM and gray matter (GM), and whether OLs become senescent, will help incorporate these cells into the complex physiology of the human brain. We developed human OLs from induced-pluripotent stem cells and found little evidence of senescence after exposure to typical senescence-inducing agents. Next, we generated a single nucleus RNA sequencing dataset on human WM, using spatial transcriptomics provide further information. We integrated our WM OLs to an overlapping dataset on GM and identified that GM OLs are producing more machinery for synapse formation and neurotransmitter cycling, while WM OLs are producing more immune and autophagy transcripts. Further, we identified a unique OL phenotype in high AD pathology donors with elevated transcripts related to cytokine production, cytoplasmic chaperone proteins, DNA damage repair, and ferritin accumulation. Together, we have identified a possible senescent OL phenotype and generated a highly valuable resource for further studies.