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Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia
Stephen A Back1, Byung Hee Han, Ning Ling Luo
1Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon 97201, USA. backs@ohsu.edu
Insights
Hypoxic-ischemic injury selectively harms late oligodendrocyte progenitors in neonatal brains, leading to periventricular leukomalacia (PVL). This maturation-dependent vulnerability explains why premature infants are susceptible to PVL and cerebral palsy.
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- Periventricular leukomalacia (PVL) is a common cause of neurologic disability in premature infants.
- The cellular mechanisms underlying white matter injury susceptibility in developing brains remain unclear.
Purpose of the Study:
- To investigate the cellular basis of hypoxic-ischemic white matter injury in the neonatal brain.
- To identify the specific oligodendrocyte lineage stage vulnerable to injury.
Main Methods:
- Utilized a neonatal rat model of hypoxic-ischemic injury.
- Analyzed oligodendrocyte progenitor cell populations and their response to injury via apoptosis and maturation markers.
Main Results:
- Late oligodendrocyte progenitors demonstrated a maturation-dependent vulnerability to hypoxic-ischemic injury.
- Apoptosis significantly increased in late oligodendrocyte progenitors in the ischemic hemisphere.
- Surviving late oligodendrocyte progenitors accelerated maturation.
Conclusions:
- The susceptibility of neonatal white matter to hypoxic-ischemic injury is linked to the vulnerability of late oligodendrocyte progenitors.
- This vulnerability may explain the selective susceptibility to PVL in premature infants.
Abstract:
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.