Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia.
In the premature infant, hypoxic-ischemic damage to the cerebral white matter [periventricular leukomalacia (PVL)] is a common and leading cause of brain injury that often results in chronic neurologic disability from cerebral palsy. The cellular basis for the propensity of white matter injury to occur in the developing brain and the greater resistance of the adult white matter to similar injury remains unknown. By using a neonatal rat model of hypoxic-ischemic injury, we found that the mechanism of perinatal white matter injury involved maturation-dependent vulnerability in the oligodendroctye (OL) lineage. The timing of appearance of late OL progenitors was the major developmental factor that accounted for the susceptibility of the neonatal white matter to injury. Late OL progenitors were the major OL lineage stage killed by apoptosis, whereas early OL progenitors and more mature OLs were highly resistant. The density of pyknotic late OL progenitors was significantly increased in the ischemic hemisphere (67 +/- 31 cells/mm2) versus the control hemisphere (2.2 +/- 0.4 cells/mm2; mean +/- SEM; p = 0.05), which resulted in the death of 72 +/- 6% of this OL stage. Surviving late OL progenitors displayed a reactive response in which an increase in cell density was accompanied by accelerated maturation to a P27/kip1-positive oligodendrocyte. Because we showed recently that late OL progenitors populate human cerebral white matter during the high risk period for PVL (Back et al., 2001), maturation-dependent vulnerability of OL progenitors to hypoxia-ischemia may underlie the selective vulnerability to PVL of the white matter in the premature infant.
Back
Stephen A
SA
Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon 97201, USA. backs@ohsu.edu
Han
Byung Hee
BH
Luo
Ning Ling
NL
Chricton
Charlene A
CA
Xanthoudakis
Steve
S
Tam
John
J
Arvin
Kara L
KL
Holtzman
David M
DM
D000818:Animals; D000831:Animals, Newborn; D001273:Atmosphere Exposure Chambers; D001921:Brain / Q000098:blood supply / Q000473:pathology*; D002339:Carotid Arteries / Q000502:physiology; D002452:Cell Count; D016923:Cell Death; D002455:Cell Division; D019070:Cell Lineage; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000473:pathology; D005911:Gliosis / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D008026:Ligation; D009836:Oligodendroglia / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000473:pathology*