Deciphering oligodendrocyte lineage heterogeneity in development and disease

Oligodendrocytes are the myelinating glia of the central nervous system (CNS). By forming lipid-rich myelin membranes that spirally enwrap axonal segments, oligodendrocytes ensure rapid saltatory impulse propagation, structural integrity, and metabolic and trophic support to the nerves. Oligodendrocyte lineage (OLG)(1) arises from oligodendrocyte precursor cells (OPCs), which emerge from radial glia during early embryonic development in an intricate, spatiotemporally defined fashion. As highly migratory, OPCs rapidly populate the brain and the spinal cord and begin transitioning to differentiation-committed oligodendrocyte precursors (COPs). Shortly after birth, myelin synthesis occurs with the newly-formed and myelin-forming oligodendrocytes (NFOLs and MFOLs), which finally differentiate into mature oligodendrocytes (MOLs), completing the lineage trajectory. These populations possess unique transcriptional signatures reflecting their lineage differentiation state. Moreover, MOLs, in particular, comprise several transcriptionally distinct cell clusters, the functional significance of which remains unclear.

In multiple sclerosis (MS), myelinating oligodendrocytes become the primary targets of chronic CNS inflammation. Consequently, the accumulating myelin damage materializes in the form of multifocal lesions, the pathological hallmarks of MS. In parallel, OLG respond to pathological environments by promoting myelin repair but also by expressing genes involved in complement formation, interferon response, and major histocompatibility complex (MHC) I and II, among others. Thus, their transcriptional heterogeneity(2) expands, and the emergence of the disease-associated (DA) states suggests that OLG might not be just passive targets of the immune system but potentially active players in immunomodulation. Nevertheless, when and where the DA states emerge, how they affect the remyelination, and whether they carry protective or detrimental functions in the context of MS remains to be determined.

This thesis aimed to bridge the gap between the transcriptional diversity of OLG and its significance in health and disease. The work can be divided into three central topics: 1) Deciphering OLG heterogeneity in development and health (Papers I-II, i, iii); 2) Adaptations of spatial transcriptomics tools to investigate physiological and pathological phenomena (Papers II-IV, ii-iv); and 3) Elucidating the dynamics and potential roles of OLG heterogeneity in pathologies (Papers I, IV, and v).

(1) Oligodendrocyte lineage cells, i.e., oligodendroglia (OLG).

(2) The terms heterogeneity and diversity are used interchangeably in this thesis.

List of scientific papers

I. Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury. Elisa M. Floriddia#, T‰nia LourenŤo, Shupei Zhang, David van Bruggen, Markus M. Hilscher, Petra Kukanja, Jo‹o P. GonŤalves dos Santos, Mźge Altőnkšk, Chika Yokota, Enric Llorens-Bobadilla, Sara B. Mulinyawe, M‡rio Gr‹os, Lu O. Sun, Jonas FrisŽn, Mats Nilsson, GonŤalo Castelo-Branco#. Nature Communications. 2020;11(1):5860. #Correspondence.
https://doi.org/10.1038/s41467-020-19453-x

II. Spatial and temporal heterogeneity in the lineage progression of fine oligodendrocyte subtypes. Markus M. Hilscher#, Christoffer Mattsson Langseth, Petra Kukanja, Chika Yokota, Mats Nilsson* and GonŤalo Castelo-Branco*#. BMC Biology. 2022;20(1):122. *Equal contribution. #Correspondence.
https://doi.org/10.1186/s12915-022-01325-z

III. Spatial epigenomeĐtranscriptome co-profiling of mammalian tissues. Di Zhang*, Yanxiang Deng*#, Petra Kukanja, Eneritz Agirre, Marek Bartosovic, Mingze Dong, Cong Ma, Sai Ma, Graham Su, Shuozhen Bao, Yang Liu, Yang Xiao, Gorazd B. Rosoklija, Andrew J. Dwork, J. John Mann, Kam W. Leong, Maura Boldrini, Liya Wang, Maximilian Haeussler, Benjamin J. Raphael, Yuval Kluger, GonŤalo Castelo-Branco# and Rong Fan#. Nature. 2023;616(7955):113-122. #Correspondence.
https://doi.org/10.1038/s41586-023-05795-1

IV. Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology. Petra Kukanja*#, Christoffer Mattsson Langseth*#, Leslie A. Rubio Rodr’guez-Kirby, Eneritz Agirre, Chao Zheng, Amitha Raman, Chika Yokota, Christophe Avenel, Katarina Tiklov‡, AndrŽ O. Guerreiro-Cacais, Tomas Olsson, Markus M. Hilscher, Mats Nilsson# and GonŤalo Castelo-Branco#. Cell. 2024;187(8):1990-2009.e19. *Equal contribution. #Correspondence.
https://doi.org/10.1016/j.cell.2024.02.030