Fig. 8

Oligodendrocyte and OPC cell states in CSF1R-RD. a–h, Oligodendrocyte cell states. a UMAP plots showing the contributions from CSF1R-RD, healthy control, and AD (left), and from each individual sample (right). b UMAP and bar plots showing the three annotated oligodendrocyte cell states (O1–O3). c Contribution of each oligodendrocyte state per sample. d Contribution of each disease group (CSF1R-RD, AD, healthy) to each oligodendrocyte state cluster. O3 (arrow) represents an CSF1R-RD-associated cell state e Visualization of each oligodendrocyte cluster-defining gene set in UMAP plots. f Dot plot showing top oligodendrocyte state marker genes for each cluster. g Volcano plot depicting DE genes between O3-CSF1R-RD and O1-healthy controls. h Top biological pathways enriched in O3-CSF1R-RD compared with O1-healthy controls. The x-axis represents combined Z scores (magenta: overrepresented in O3; yellow: underrepresented in O3). i–q OPC states. i UMAP plots showing the contributions from CSF1R-RD, healthy control, and AD (left), and from each individual sample (right). j UMAP and bar plots showing the five annotated OPC states (OP0–OP4) k Contribution of each OPC state per sample. l Contribution of each disease group to each OPC state cluster. The OP1 cluster is derived almost exclusively from CSF1R-RD; CSF1R-RD-derived nuclei also contribute to clusters OP1 and OP2 (arrows) m Visualization of each OPC cluster-defining gene set in UMAP plots. n Dot plot showing top OPC marker genes for each cluster. o Volcano plot depicting DE genes between the CSF1R-RD associated cluster OP1 and combined OP2 and OP3 healthy controls (left), and between OP1-CSF1R-RD and OP0-healthy controls. p Top biological pathways enriched in OP1-CSF1R-RD compared with combined OP2 and OP3 healthy controls. The x-axis represents combined Z scores. q Relative expression of genes known to be associated with the differentiation of OPCs into myelin-forming oligodendrocytes for each cluster. OP2 and OP3 represent maturing OPCs. The CSF1R-RD disease associated clusters OP1, OP0 and OP4 show increased expression of negative regulators of OP differentiation and decreased expression of positive regulators of OP differentiation. r Model of CSF1R-RD glial disease pathogenesis. In the healthy brain, activation of CSF1R signaling by the ligands CSF1 (secreted by oligodendrocytes, astrocytes, and OPCs) and IL34 (secreted mainly by neurons) regulates microglia homeostasis and myelin maintenance. In CSF1R-RD, CSF1R dysfunction results in pro-inflammatory and autophagy microglia states, myelin phagocytosis, and arrest in OPC differentiation. GPNMB is a marker for lipid-laden microglia (“pigmented glia”) in ALSP/CSF1R-RD