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Brain Advance Access originally published online on May 30, 2008
Brain 2008 131(7):1749-1758; doi:10.1093/brain/awn096
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis

T. Kuhlmann1,2, V. Miron3, Q. Cuo3, C. Wegner2, J. Antel3 and W. Brück2,4

1Institute of Neuropathology, University Hospital Münster, Münster, Germany, 2Department of Neuropathology, University Medical Centre Göttingen, 3Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Canada and 4Institute for Multiple Sclerosis Research, University Medical Centre Göttingen and Gemeinnützige Hertie-Stiftung, Göttingen, Germany

Correspondence to: Tanja Kuhlmann, Institute of Neuropathology, University Hospital Münster, Münster, Domagkstr. 19, 48149 Münster, Germany E-mail: tanjakuhlmann{at}gmx.de

Impaired function/differentiation of progenitor cells might provide an explanation for the limited remyelination observed in the majority of chronic multiple sclerosis lesions. Here, we establish that in the normal adult human CNS, the transcription factors Nkx2.2 and Olig2 are strongly expressed in progenitor cells while mature oligodendrocytes are characterized by low levels of Olig2 or Nkx2.2. In vitro studies confirmed the expression of Olig2 in oligodendroglial progenitor cells and mature oligodendrocytes while astrocytes, microglial cells and neurons were negative for Olig2. In early multiple sclerosis lesions, we found Olig2-positive progenitor cells throughout all lesion stages and in periplaque white matter (PPWM). The number of progenitors in PPWM was significantly increased compared with the white matter from controls. In chronic multiple sclerosis lesions progenitor cells were still present, however, in significantly lower numbers than in early multiple sclerosis lesions. A subpopulation of progenitor cells in early multiple sclerosis lesions and PPWM but not in control cases co-expressed NogoA, a marker of mature oligodendrocytes. The co-expression of these two markers suggested that these cells were maturing oligodendrocytes recently recruited from the progenitor pool. In contrast, in chronic multiple sclerosis lesions maturing progenitors were only rarely present. In summary, we provide evidence that a differentiation block of oligodendroglial progenitors is a major determinant of remyelination failure in chronic multiple sclerosis lesions.

Key Words: oligodendroglial progenitors; multiple sclerosis; Olig2; Nkx2.2

Abbreviations: OPCs, oligodendroglial progenitor cells; PPWM, periplaque white matter

Received December 5, 2007. Revised April 15, 2008. Accepted April 25, 2008.


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