Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury

Ann Neurol. 2008 Apr;63(4):520-30. doi: 10.1002/ana.21359.


Objective: Abnormal myelination is a major pathological sequela of chronic periventricular white matter injury in survivors of premature birth. We tested the hypothesis that myelination failure in chronic hypoxia-ischemia-induced periventricular white matter injury is related to persistent depletion of the oligodendrocyte (OL) precursor pool required to generate mature myelinating OLs.

Methods: A neonatal rat model of hypoxia-ischemia was used where acute degeneration of late OL progenitors (preOLs) occurs via a mostly caspase-independent mechanism. The fate of OL lineage cells in chronic cerebral lesions was defined with OL lineage-specific markers.

Results: Acute caspase-3-independent preOL degeneration from hypoxia-ischemia was significantly augmented by delayed preOL death that was caspase-3-dependent. Degeneration of preOLs was offset by a robust regenerative response that resulted in a several-fold expansion in the pool of surviving preOLs in chronic lesions. However, these preOLs displayed persistent maturation arrest with failure to differentiate and generate myelin. When preOL-rich chronic lesions sustained recurrent hypoxia-ischemia at a time in development when white matter is normally resistant to injury, an approximately 10-fold increase in caspase-dependent preOL degeneration occurred relative to lesions caused by a single episode of hypoxia-ischemia.

Interpretation: The mechanism of myelination failure in chronic white matter lesions is related to a combination of delayed preOL degeneration and preOL maturation arrest. The persistence of a susceptible population of preOLs renders chronic white matter lesions markedly more vulnerable to recurrent hypoxia-ischemia. These data suggest that preOL maturation arrest may predispose to more severe white matter injury in preterm survivors that sustain recurrent hypoxia-ischemia.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation* / physiology
  • Cell Lineage* / physiology
  • Cell Proliferation*
  • Chronic Disease
  • Demyelinating Diseases / pathology
  • Demyelinating Diseases / physiopathology
  • Hypoxia-Ischemia, Brain / pathology
  • Hypoxia-Ischemia, Brain / physiopathology
  • Nerve Fibers, Myelinated / pathology*
  • Nerve Fibers, Myelinated / physiology
  • Oligodendroglia / cytology*
  • Oligodendroglia / pathology*
  • Oligodendroglia / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Stem Cells / pathology