Multiple Sclerosis: remyelination and oligodendroglial cell death

 

Multiple sclerosis (MS) is the most frequent demyelinating disease of young adults. Worldwide it affects approximately one million people with major personal and socio-economic consequences. Pathologically, MS is a chronic inflammatory disease that leads to focal loss of myelin and oligodendrocytes. Our research focuses on mechanisms that modulate oligodendroglial cell death, differentiation and myelination. Our aim is to contribute to the identification of new treatment strategies promoting remyelination.

Figure 1: MS lesions are typically located within the white matter (A). MS lesions can be found in cerebrum, brainstem (as shown in B), cerebellum or spinal cord. The normal appearing white matter shows a blue colour while the demyelinated areas are pale. Oligodendrocytes, the myelin maintaining cell population, can be cultured in vitro. These cells have a small cell body and multiple branched processes (C).

 

In current projects we analyze the mechanisms underlying oligodendroglial migration as well as the functional role of selected signalling cascades on oligodendroglial differentiation and remyelination. To address our research questions we study MS tissue sections, primary rodent cell cultures, organotypic cerebellar slices and different demyelinating animal models.

Figure 2: Cerebellar slices were cultured for 12 days in vitro resulting in multiple myelinated axons (A). The formation of nodes of Ranvier is indicated by Caspr staining (B). Electronmicroscopic analyses enable us to visualize the black appearing myelin sheets wrapping the axons of healthy adult mice (C) and demyelinated axons after loss of myelin (D).

To translate our results from the mouse to the human system we developed a protocol to generate oligodendrocytes from human induced pluripotent stem cells (iPSC). Using this protocol we study the phenotype of oligodendrocytes from patients with different neurological diseases and further dissect molecular pathways regulating oligodendroglial cell death, differentiation and migration.

Figure 3: Within two to four weeks numerous O4 positive oligodendrocytes are generated from iPSC derived neural progenitor cells (A). The cells differentiate into MBP positive mature oligodendrocytes (B). Oligodendrocytes were generated from iPSC from patients with frontotemporal dementia caused by mutations in MAPT (N279K). iPSC derived oligodendrocytes carrying this mutation (MAPT1/MAP2) display a higher susceptibility to oxidative stress induced cell death compared to gene corrected control cell lines (MAPT 1 GC/MAPT 2GC) or oligodendrocytes derived from iPSC from a healthy individual (control) (C).

 
Our projects are funded by DFG, the Hertie-Foundation, IZKF Münster and IMF Münster.

Selected publications

  1. Ehrlich M, Mozafari S, Glatza M, Starost L, Velychko S, Hallmann AL, Cui QL, Schambach A, Kim KP, Bachelin C, Marteyn A, Hargus G, Johnson RM, Antel J, Sterneckert J, Zaehres H, Schöler HR, Baron-Van Evercooren A, Kuhlmann T. Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors. PNAS 2017:114: E2243-E2252. doi: 10.1073/pnas.1614412114
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  3. Kuhlmann T, Ludwin S, Prat A, Antel J, Brück W, Lassmann H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017 133:13-24.
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  5. Preisner A*, Albrecht S*, Cui Q, Hucke S, Ghelman J, Hartmann C, Taketo MM, Antel J, Klotz L, Kuhlmann T. Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination. Acta Neuropathol. 2015; 130: 247-61.* equal contribution
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  7. Ehrlich M*, Hallmann AL*, Reinhardt P, Araúzo-Bravo MJ, Korr S, Röpke A, Psathaki OE, Ehling P, Meuth SG, Oblak AL, Murrell JR, Ghetti B, Zaehres H, Schöler HR, Sterneckert J#, Kuhlmann T#, Hargus G#. Distinc neurodegenerative changes in an induced pluripotent Stem Cell Model of frontotemporal dementia linked to mutant TAU protein. Stem Cell Reports 2015; 5: 83-96 * and # equal contribution.
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  9. Haines JD, Herbin O, de la Hera B, Vidaurre OG, Moy GA, Sun Q, Fung HYJ, Albrecht S, Alexandropoulos K, McCauley D, Chook YM, Kuhlmann T, Kidd GJ, Shacham S, Casaccia P. Selective inhibitors of nuclear export avert progression in preclinical models of inflammatory demyelination. Nat Neurosci 2015.
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  11. Hargus G,*, Ehrlich M,*, Arauzo-Bravo MJ, Hallmann AL, Hemmer K, Reinhardt P, Kim KP, Adachi K, Santourlidis S, Ghanjati F, Kim JB, Sterneckert J, Schwamborn J, Schöler HR, Kuhlmann T#, Zaehres H#. Neural induction of human iPS cells reveals origin-dependent neural cell identities in vitro and after transplantation into the adult rodent brain. Cell Reports 2014; 8: 1697-703. *and # equal contribution.
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  13. Hagemeier K*, Lürbke A*, Hucke S, Albrecht S, Preisner A, Klassen E, Hoffmann E, Brück W, Klotz L, Kuhlmann T. Puma, but not Noxa is essential for oligodendroglial cell death. Glia 2013; 61: 1712-23. * equal contribution
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  15. Pedre X, Mastronardi F, Bruck W, López-Rodas G, Kuhlmann T*, Casaccia P*. Changed histone acetylation patterns in NAWM and early MS lesions. J Neurosci. 2011; 31: 3435-3445. *Equal contribution
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  17. Goldschmidt T, Antel J, König F, Brück W*, Kuhlmann T*. The remyelination capacity of the MS brain decreases with disease chronicity. Neurology 2009, 72: 1914-21. * shared authorship
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  19. Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J, Brück W.. Maturation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic MS. Brain 2008, 131: 1749 -58

Contact: Tanja Kuhlmann (Email)