Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury

Kristen N. Segovia, Melissa McClure, Matthew Moravec, Ling Luo Ning, Ying Wan, Xi Gong, Art Riddle, Andrew Craig, Jaime Struve, Larry S. Sherman, Stephen A. Back

Research output: Contribution to journalArticlepeer-review

278 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)520-530
Number of pages11
JournalAnnals of Neurology
Issue number4
StatePublished - Apr 2008

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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