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Cell states along oligodendrocyte development and disease

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posted on 2024-09-02, 18:00 authored by David van BruggenDavid van Bruggen

The brain, one of the most complex organs in the body, where an immense diversity of cell states emerges from simple structure, where function arises from sets of regulatory principles and pattern persist where individual cells do not. Revealing the regulatory underpinnings of the brain, from unspecified cell states to diversity, is paramount for achieving a thorough understanding of the development process and generating insight into the disease states of the brain. This thesis is an exploration into how canonical regulatory factors and elements, such as transcription factors and genes, lock a regulatory system in a multi-outcome network with limited possible states.

The work in this thesis focuses on the oligodendrocyte lineage, a glial cell known for it’s supportive role in the central nervous system, where it facilitates electrical transmission through the enscheathment of axons. Oligodendrocytes (OLs) lie at the heart of multiple sclerosis (MS), a disease where an immune response is mounted against myelin. As a response, oligodendrocyte precursor cells (OPCs) move towards lesions and remyelinate axons, however, this mechanism fails in later stages of the disease. Thus, an understanding to how OPCs develop is vital to amelioration of the altered oligodendrocyte population. In Paper I we reveal a previously underestimated heterogeneity within the oligodendrocyte lineage in mouse. We show that OL maturation is an ongoing process, albeit, decreasing in frequency with age. Furthermore, complex wheel training in mice revealed that the OLs respond to this challenge through an increase in differentiation. Paper II investigates the cellular response in the experimental autoimmune encephalomyelitis (EAE) disease mouse model of MS, where we find a tailored response by the resident OL population, changed from its normal transcriptional program, expressing a spectrum of genes related to survival, immunological stimulation, phagocytosis, and active differentiation. Furthermore, we provide evidence that OLs can elicit responses from T cells. In Paper III we explore the different waves of OPC generation in the developing mouse brain at embryonic day 13.5 and postnatal day 7. We show that recently Pdgfra expressing cells at the E13.5 time point exhibit a multitude of patterning genes, and we show the emergence of a possible OPC progenitor through the inclusion of a bridging E17.5 time point population. This pre-OPC population is biased towards expressing glial and OL lineage specifying genes such as Olig1, Olig2, Ptprz1, and Bcan. Furthermore, lineage tracing of OPC developmental waves, shows no transcriptional differences, leading us to conclude that OPCs are generally naïve to the time or region of specification. In Paper IV we show that we are able to detect OPC formation in the developing human forebrain. We detect OPCs at the earliest sampled time point post conception week 8. We attempt to recover the path of OPC formation, and investigate the regulatory dynamics in the specification of OPCs.

List of scientific papers

I. Sueli Marques, Amit Zeisel, Simone Codeluppi, David van Bruggen, Ana Mendanha Falcão, Lin Xiao, Huiliang Li, Martin Häring, Hannah Hochgerner, Roman A Romanov, Daniel Gyllborg, Ana B Muñoz-Manchado, Gioele La Manno, Peter Lönnerberg, Elisa M Floriddia, Fatemah Rezayee, Patrik Ernfors, Ernest Arenas, Jens Hjerling-Leffler, Tibor Harkany, William D Richardson, Sten Linnarsson, Gonçalo Castelo-Branco. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science. 2016, Vol. 352 Issue 6291, Page 1326-1329.
https://doi.org/10.1126/science.aaf6463

II. Ana Mendanha Falcão, David van Bruggen, Sueli Marques, Mandy Meijer, Sarah Jäkel, Eneritz Agirre, Samudyata, Elisa M. Floriddia, Darya Vanichkina, Charles ffrench-Constant, Anna Williams, André Ortlieb Guerreiro-Cacais, Gonçalo Castelo-Branco. Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nature Medicine. 2018, Vol. 24, Page 1837-1844.
https://doi.org/10.1038/s41591-018-0236-y

III. Sueli Marques, David van Bruggen, Darya Pavlovna Vanichkina, Elisa Mariagrazia Floriddia, Hermany Munguba, Leif Väremo, Stefania Giacomello, Ana Mendanha Falcão, Mandy Meijer, Åsa Kristina Björklund, Jens Hjerling-Leffler, Ryan James Taft, Gonçalo Castelo-Branco. Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development. Developmental Cell. 2018, Vol. 46, Page 504-517.
https://doi.org/10.1016/j.devcel.2018.07.005

IV. David van Bruggen, Erik Sundström, Gonçalo Castelo-Branco. Single cell transcriptomics reveals cell-states along human neural developmental landscape. [Manuscript]

History

Defence date

2021-01-15

Department

  • Department of Medical Biochemistry and Biophysics

Publisher/Institution

Karolinska Institutet

Main supervisor

Castelo-Branco, Gonçalo

Co-supervisors

Linnarsson, Sten; Daub, Carsten Oliver

Publication year

2020

Thesis type

  • Doctoral thesis

ISBN

978-91-8016-103-9

Number of supporting papers

4

Language

  • eng

Original publication date

2020-12-23

Author name in thesis

van Bruggen, David

Original department name

Department of Medical Biochemistry and Biophysics

Place of publication

Stockholm

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