Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury

Autor: Jaime Struve, Ning Ling Luo, Larry S. Sherman, Ying Wan, Art Riddle, Andrew Craig, Matthew Moravec, Kristen N. Segovia, Xi Gong, Stephen A. Back, Melissa M. McClure
Rok vydání: 2008
Předmět:
Zdroj: Annals of Neurology. 63:520-530
ISSN: 1531-8249
0364-5134
DOI: 10.1002/ana.21359
Popis: Human periventricular white matter injury (PWMI) is the major form of brain injury and leading cause of cerebral palsy in survivors of premature birth. With advances in neonatal care, a changing spectrum of chronic PWMI has emerged. Whereas focal cystic necrotic lesions (periventricular leukomalacia; PVL) previously predominated,1, 2 recent neuroimaging studies support that focal or diffuse noncystic myelination disturbances and cerebral gray matter atrophy are now the major lesions associated with chronic PWMI.3–6 The critically-ill preterm neonate appears to be particularly susceptible to ischemic white matter injury related to developmentally-regulated susceptibility of preOLs to oxidative stress.2,7 PreOLs are pre-myelinating, mitotically-active late oligodendrocyte (OL) progenitors that generate mature myelinating OLs.7 The high-risk period for PWMI coincides with selective vulnerability of preOLs to oxidative stress.8–11 Early human PWMI lesions display a pronounced but not complete reduction in preOL density,8 which suggests a mechanism for subsequent myelination failure in chronic PWMI. However, the fate of the residual pool of preOLs is unknown. Prior studies have not determined if myelination disturbances are related to persistent depletion of preOLs.12–17 We hypothesized that myelination failure in chronic PWMI is related to acute degeneration of preOLs from hypoxia-ischemia (H–I) that depletes the preOL pool available to generate mature OLs. We employed a preterm-equivalent neonatal rat model of H–I where white matter injury is accompanied by pronounced acute preOL degeneration via a mostly caspase-3-independent mechanism and earlier and later OL stages are markedly more resistant.10,18 We analyzed diffuse non-cystic white matter lesions that resemble those now common in human PWMI. Paradoxically, chronic white matter lesions displayed myelination failure that coincided with reactive astrogliosis and robust regeneration of preOLs. Expansion of the preOL pool occurred despite delayed preOL death that was caspase-3-mediated. These unexpected findings support an alternative explanation for myelination failure in chronic non-cystic PWMI that is related to a persistent arrest of OL maturation at pre-myelinating stages. PreOL maturation arrest may have deleterious consequences for preterm survivors that sustain recurrent hypoxia-ischemia. We demonstrate that persistence of preOLs beyond their normal developmental window markedly increases white matter susceptibility to injury in response to recurrent hypoxia-ischemia.
Databáze: OpenAIRE
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