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

被引:646
作者
Kuhlmann, T. [1 ,2 ]
Miron, V. [3 ]
Cuo, Q. [3 ]
Wegner, C. [2 ]
Antel, J. [3 ]
Brueck, W. [2 ,4 ]
机构
[1] Univ Hosp, Inst Neuropathol, D-48149 Munster, Germany
[2] Univ Med Ctr Gottingen, Dept Neuropathol, Gottingen, Germany
[3] McGill Univ, Montreal Neurol Inst, Neuroimmunol Unit, Montreal, PQ, Canada
[4] Univ Med Ctr Gottingen & Gemeinnutzige Hertie Sti, Inst Multiple Sclerosis Res, Gottingen, Germany
关键词
oligodendroglial progenitors; multiple sclerosis; Olig2; Nkx2.2;
D O I
10.1093/brain/awn096
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:1749 / 1758
页数:10
相关论文
共 57 条
[1]  
Allen IV, 1991, MCALPINES MULTIPLE S, P341
[2]   TNFα promotes proliferation of oligodendrocyte progenitors and remyelination [J].
Arnett, HA ;
Mason, J ;
Marino, M ;
Suzuki, K ;
Matsushima, GK ;
Ting, JPY .
NATURE NEUROSCIENCE, 2001, 4 (11) :1116-1122
[3]   bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS [J].
Arnett, HA ;
Fancy, SPJ ;
Alberta, JA ;
Zhao, C ;
Plant, SR ;
Kaing, S ;
Raine, CS ;
Rowitch, DH ;
Franklin, RJM ;
Stiles, CD .
SCIENCE, 2004, 306 (5704) :2111-2115
[4]   Remyelinated lesions in multiple sclerosis -: Magnetic resonance image appearance [J].
Barkhof, F ;
Brück, W ;
De Groot, CJA ;
Bergers, E ;
Hulshof, S ;
Geurts, J ;
Polman, CH ;
van der Valk, P .
ARCHIVES OF NEUROLOGY, 2003, 60 (08) :1073-1081
[5]   Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion [J].
Barnett, MH ;
Prineas, JW .
ANNALS OF NEUROLOGY, 2004, 55 (04) :458-468
[6]   Efficient central nervous system remyelination requires T cells [J].
Bieber, AJ ;
Kerr, S ;
Rodriguez, M .
ANNALS OF NEUROLOGY, 2003, 53 (05) :680-684
[7]  
Blaschuk KL, 2000, DEVELOPMENT, V127, P1961
[8]   MONOCYTE-MACROPHAGE DIFFERENTIATION IN EARLY MULTIPLE-SCLEROSIS LESIONS [J].
BRUCK, W ;
PORADA, P ;
POSER, S ;
RIECKMANN, P ;
HANEFELD, F ;
KRETZSCHMAR, HA ;
LASSMANN, H .
ANNALS OF NEUROLOGY, 1995, 38 (05) :788-796
[9]   OLIGODENDROCYTES IN THE EARLY COURSE OF MULTIPLE-SCLEROSIS [J].
BRUCK, W ;
SCHMIED, M ;
SUCHANEK, G ;
BRUCK, Y ;
BREITSCHOPF, H ;
POSER, S ;
PIDDLESDEN, S ;
LASSMANN, H .
ANNALS OF NEUROLOGY, 1994, 35 (01) :65-73
[10]   Synantocytes: New functions for novel NG2 expressing glia [J].
Butt, AM ;
Kiff, J ;
Hubbard, P ;
Berry, M .
JOURNAL OF NEUROCYTOLOGY, 2002, 31 (6-7) :551-565