Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants
Article first published online: 24 JAN 2012
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 71, Issue 1, pages 93–109, January 2012
How to Cite
Buser, J. R., Maire, J., Riddle, A., Gong, X., Nguyen, T., Nelson, K., Luo, N. L., Ren, J., Struve, J., Sherman, L. S., Miller, S. P., Chau, V., Hendson, G., Ballabh, P., Grafe, M. R. and Back, S. A. (2012), Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann Neurol., 71: 93–109. doi: 10.1002/ana.22627
- Issue published online: 24 JAN 2012
- Article first published online: 24 JAN 2012
- Accepted manuscript online: 12 SEP 2011 08:28AM EST
- Manuscript Accepted: 16 AUG 2011
- Manuscript Revised: 11 AUG 2011
- Manuscript Received: 7 JUL 2011
- National Institutes of Neurological Diseases and Stroke. Grant Numbers: 1RO1NS054044, R37NS045737-06S1/06S2, 1F30NS066704
- Bugher Award from the American Heart Association
- March of Dimes Birth Defects Foundation
- Canada Research Chair in Neonatal Neuroscience
- Michael Smith Foundation for Health Research Scholar award
- Canadian Institutes of Health Research Clinician Scientist award
- NIH. Grant Number: R01NS071263
The major form of magnetic resonance imaging–defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested preoligodendrocyte (preOL) maturation in reactive astrocyte-rich lesions.
A retrospective autopsy series (1983–2000) was selected for cases with diffuse WMI and analyzed relative to prospectively collected contemporary cases (2003–2010). Controls were age- and region-matched to address regional variation in preOL maturation. Successive oligodendrocyte stages were analyzed with lineage-specific markers. Microscopic necrosis was quantified with microglial markers. Axon injury markers defined the burden of axonopathy. Extracellular matrix remodeling was defined by detection of hyaluronic acid (HA), an inhibitor of preOL maturation, and the HA receptor, CD44.
In the contemporary case series, diffuse WMI was accompanied by a significant reduction in the burden of microscopic necrosis and axonopathy. Diffuse astrogliosis extended into the lesion surround with elevated HA and astrocyte-expressed CD44. The total population of OL lineage stages was significantly increased in lesions. This increase coincided with significant expansion of the preOL pool.
Although these data confirm that microscopic necrosis occurs in contemporary cases, the markedly decreased burden supports that it does not contribute substantially to myelination failure. The primary mechanism of myelination failure involves a disrupted cellular response whereby preOLs fail to differentiate in diffuse astrogliotic lesions. PreOL maturation arrest converts chronic WMI to a more immature state related to the burden of astrogliosis. ANN NEUROL 2012;71:93–109