Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury.
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.


CONCLUSIONS
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.
Segovia
Kristen N
KN
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
McClure
Melissa
M
Moravec
Matthew
M
Luo
Ning Ling
NL
Wan
Ying
Y
Gong
Xi
X
Riddle
Art
A
Craig
Andrew
A
Struve
Jaime
J
Sherman
Larry S
LS
Back
Stephen A
SA
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D049109:Cell Proliferation; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000473:pathology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000473:pathology* / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology* / Q000473:pathology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000473:pathology