Oligodendrocytes (OL) have been for decades considered a passive, homogenous population of cells that provide support to neurons, and show a limited response to pathological stimuli. This view has been dramatically changed by the introduction of powerful transcriptomic methods that have uncovered a broad spectrum of OL populations that co-exist within the healthy central nervous system (CNS) and also across a variety of diseases. Specifically, single-cell and single-nucleus RNA-sequencing (scRNA-seq, snRNA-seq) have been used to reveal OL variations in maturation, myelination and immune status. The newly discovered immunomodulatory role suggests that OL may serve as targets for future therapies. In this review, we summarize the current understanding of OL heterogeneity in mammalian CNS as revealed by scRNA-seq and snRNA-seq. We provide a list of key studies that identify consensus marker genes defining the currently known OL populations. This resource can be used to standardize analysis of OL related datasets and improve their interpretation, ultimately leading to a better understanding of OL functions in health and disease.

Department of Biochemistry and Microbiology Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Czechia

Department of Cellular Neurophysiology Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czechia

Department of Informatics and Chemistry Faculty of Chemical Technology University of Chemistry and Technology Prague Czechia

Faculty of Science Charles University Prague Czechia

Laboratory of Gene Expression Institute of Biotechnology of the Czech Academy of Sciences Vestec Czechia

TATAA Biocenter AB Gothenburg Sweden

Zobrazit více v PubMed

Bakken T. E., Jorstad N. L., Hu Q., Lake B. B., Tian W., Kalmbach B. E., et al. (2021). Comparative cellular analysis of motor cortex in human, marmoset and mouse. Nature 598 111–119. 10.1038/s41586-021-03465-8 PubMed DOI PMC

Bartosovic M., Kabbe M., Castelo-Branco G. (2021). Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues. Nat. Biotechnol. 39 825–835. 10.1038/s41587-021-00869-9 PubMed DOI PMC

BICCN (2021). A multimodal cell census and atlas of the mammalian primary motor cortex. Nature 598 86–102. 10.1038/s41586-021-03950-0 PubMed DOI PMC

Chen W. T., Lu A., Craessaerts K., Pavie B., Sala Frigerio C., Corthout N., et al. (2020). Spatial transcriptomics and in situ sequencing to study alzheimer’s disease. Cell 182:e919. 10.1016/j.cell.2020.06.038 PubMed DOI

Del Rio-Hortega P. (1921). Estudios sobre la neurogia. La glia de escasas rediaciones (oligodendroglia). Bol. Real Soc. Esp. Hist. Nat. 21 63–92.

Del-Aguila J. L., Li Z., Dube U., Mihindukulasuriya K. A., Budde J. P., Fernandez M. V., et al. (2019). A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain. Alzheimers Res. Ther. 11:71. 10.1186/s13195-019-0524-x PubMed DOI PMC

Falcao A. M., van Bruggen D., Marques S., Meijer M., Jakel S., Agirre E., et al. (2018). Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nat. Med. 24 1837–1844. 10.1038/s41591-018-0236-y PubMed DOI PMC

Floriddia E. M., Lourenco T., Zhang S., van Bruggen D., Hilscher M. M., Kukanja P., et al. (2020). Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury. Nat. Commun. 11:5860. 10.1038/s41467-020-19453-x PubMed DOI PMC

Gerrits E., Brouwer N., Kooistra S. M., Woodbury M. E., Vermeiren Y., Lambourne M., et al. (2021). Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer’s disease. Acta Neuropathol. 141 681–696. 10.1007/s00401-021-02263-w PubMed DOI PMC

Grubman A., Chew G., Ouyang J. F., Sun G., Choo X. Y., McLean C., et al. (2019). A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 22 2087–2097. 10.1038/s41593-019-0539-4 PubMed DOI

Habib N., Avraham-Davidi I., Basu A., Burks T., Shekhar K., Hofree M., et al. (2017). Massively parallel single-nucleus RNA-seq with DroNc-seq. Nat. Methods 14 955–958. 10.1038/nmeth.4407 PubMed DOI PMC

Hilscher M. M., Langseth C. M., Kukanja P., Yokota C., Nilsson M., Castelo-Branco G. (2022). Spatial and temporal heterogeneity in the lineage progression of fine oligodendrocyte subtypes. BMC Biol. 20:122. 10.1186/s12915-022-01325-z PubMed DOI PMC

Jakel S., Agirre E., Mendanha Falcao A., van Bruggen D., Lee K. W., Knuesel I., et al. (2019). Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566 543–547. 10.1038/s41586-019-0903-2 PubMed DOI PMC

Kaya T., Mattugini N., Liu L., Ji H., Besson-Girard S., Kaiji S., et al. (2022). T cells induce interferon-responsive oligodendrocytes during white matter aging. bioRxiv [Preprint]. 10.1101/2022.03.26.485917 PubMed DOI PMC

Kenigsbuch M., Bost P., Halevi S., Chang Y., Chen S., Ma Q., et al. (2022). A shared disease-associated oligodendrocyte signature among multiple CNS pathologies. Nature Neurosci. 25 876–886. 10.1038/s41593-022-01104-7 PubMed DOI PMC

Knowles J. K., Xu H., Soane C., Batra A., Saucedo T., Frost E., et al. (2022). Maladaptive myelination promotes generalized epilepsy progression. Nat. Neurosci. 25 596–606. 10.1038/s41593-022-01052-2 PubMed DOI PMC

Lake B. B., Chen S., Sos B. C., Fan J., Kaeser G. E., Yung Y. C., et al. (2018). Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36 70–80. 10.1038/nbt.4038 PubMed DOI PMC

Lau S. F., Cao H., Fu A. K. Y., Ip N. Y. (2020). Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 117 25800–25809. 10.1073/pnas.2008762117 PubMed DOI PMC

Lee S. H., Rezzonico M. G., Friedman B. A., Huntley M. H., Meilandt W. J., Pandey S., et al. (2021). TREM2-independent oligodendrocyte, astrocyte, and T cell responses to tau and amyloid pathology in mouse models of Alzheimer disease. Cell Rep. 37:110158. 10.1016/j.celrep.2021.110158 PubMed DOI

Leng K., Li E., Eser R., Piergies A., Sit R., Tan M., et al. (2021). Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat. Neurosci. 24 276–287. 10.1038/s41593-020-00764-7 PubMed DOI PMC

Marques S., Zeisel A., Codeluppi S., van Bruggen D., Mendanha Falcao A., Xiao L., et al. (2016). Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 352 1326–1329. 10.1126/science.aaf6463 PubMed DOI PMC

Mathys H., Davila-Velderrain J., Peng Z., Gao F., Mohammadi S., Young J. Z., et al. (2019). Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570 332–337. 10.1038/s41586-019-1195-2 PubMed DOI PMC

Meijer M., Agirre E., Kabbe M., van Tuijn C. A., Heskol A., Zheng C., et al. (2022). Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility. Neuron 110:e1113. PubMed PMC

Morabito S., Miyoshi E., Michael N., Shahin S., Martini A. C., Head E., et al. (2021). Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease. Nat. Genet. 53 1143–1155. PubMed PMC

Nagy C., Maitra M., Tanti A., Suderman M., Theroux J. F., Davoli M. A., et al. (2020). Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nat. Neurosci. 23 771–781. 10.1038/s41593-020-0621-y PubMed DOI

Pandey S., Shen K., Lee S. H., Shen Y. A., Wang Y., Otero-Garcia M., et al. (2022). Disease-associated oligodendrocyte responses across neurodegenerative diseases. Cell Rep. 40:111189. 10.1016/j.celrep.2022.111189 PubMed DOI

Pineda S. S., Lee H., Fitzwalter B. E., Mohammadi S., Pregent L. J., Gardashli M. E., et al. (2021). Single-cell profiling of the human primary motor cortex in ALS and FTLD. bioRxiv [Preprint]. 10.1101/2021.07.07.451374 DOI

Qian X., Harris K. D., Hauling T., Nicoloutsopoulos D., Munoz-Manchado A. B., Skene N., et al. (2020). Probabilistic cell typing enables fine mapping of closely related cell types in situ. Nat. Methods 17 101–106. 10.1038/s41592-019-0631-4 PubMed DOI PMC

Russ D. E., Cross R. B. P., Li L., Koch S. C., Matson K. J. E., Yadav A., et al. (2021). A harmonized atlas of mouse spinal cord cell types and their spatial organization. Nat. Commun. 12:5722. 10.1038/s41467-021-25125-1 PubMed DOI PMC

Ruzicka W. B., Mohammadi S., Davila-Velderrain J., Subburaju S., Tso D. R., Hourihan M., et al. (2020). Single-cell dissection of schizophrenia reveals neurodevelopmental-synaptic axis and transcriptional resilience. medRxiv [Preprint]. 10.1101/2020.11.06.20225342 DOI

Sadick J. S., O’Dea M. R., Hasel P., Dykstra T., Faustin A., Liddelow S. A. (2022). Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease. Neuron 110 1788–1805.e1710. 10.1016/j.neuron.2022.03.008 PubMed DOI PMC

Seeker L. A., Williams A. (2022). Oligodendroglia heterogeneity in the human central nervous system. Acta Neuropathol. 143 143–157. 10.1007/s00401-021-02390-4 PubMed DOI PMC

Smajic S., Prada-Medina C. A., Landoulsi Z., Ghelfi J., Delcambre S., Dietrich C., et al. (2022). Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145 964–978. 10.1093/brain/awab446 PubMed DOI PMC

Stuart T., Satija R. (2019). Integrative single-cell analysis. Nat. Rev. Genet. 20 257–272. 10.1038/s41576-019-0093-7 PubMed DOI

Svensson V., da Veiga Beltrame E., Pachter L. (2020). A curated database reveals trends in single-cell transcriptomics. Database 2020:baaa073. 10.1093/database/baaa073 PubMed DOI PMC

Velmeshev D., Schirmer L., Jung D., Haeussler M., Perez Y., Mayer S., et al. (2019). Single-cell genomics identifies cell type-specific molecular changes in autism. Science 364 685–689. 10.1126/science.aav8130 PubMed DOI PMC

Yadav A., Matson K. J. E., Li L., Hua I., Petrescu J., Kang K., et al. (2022). A Cellular Taxonomy of the Adult Human Spinal Cord. bioRxiv [Preprint]. 10.1101/2022.03.25.485808 PubMed DOI PMC

Yao Z., Liu H., Xie F., Fischer S., Adkins R. S., Aldridge A. I., et al. (2021). A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex. Nature 598 103–110. 10.1038/s41586-021-03500-8 PubMed DOI PMC

Zeisel A., Hochgerner H., Lonnerberg P., Johnsson A., Memic F., van der Zwan J., et al. (2018). Molecular Architecture of the Mouse Nervous System. Cell 174:e1022. 10.1016/j.cell.2018.06.021 PubMed DOI PMC

Zeisel A., Munoz-Manchado A. B., Codeluppi S., Lonnerberg P., La Manno G., Jureus A., et al. (2015). Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347 1138–1142. 10.1126/science.aaa1934 PubMed DOI

Zhang M., Eichhorn S. W., Zingg B., Yao Z., Cotter K., Zeng H., et al. (2021). Spatially resolved cell atlas of the mouse primary motor cortex by MERFISH. Nature 598 137–143. 10.1038/s41586-021-03705-x PubMed DOI PMC

Zhou Y., Song W. M., Andhey P. S., Swain A., Levy T., Miller K. R., et al. (2020). Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 26 131–142. 10.1038/s41591-019-0695-9 PubMed DOI PMC