Late oligodendrocyte progenitors coincide with the developmental window ofvulnerability for human perinatal white matter injury

Hypoxic-ischemic injury to the periventricular cerebral white matter [periv entricular leukomalacia (PVL)] results in cerebral palsy and is the leading cause of brain injury in premature infants. The principal feature of PVL i s a chronic disturbance of myelination and suggests that oligodendrocyte (O L) lineage progression is disrupted by ischemic injury. We determined the O L lineage stages at risk for injury during the developmental window of vuln erability for PVL (23-32 weeks, postconceptional age). In 26 normal control autopsy human brains, OL lineage progression was defined in parietal white matter, a region of predilection for PVL. Three successive OL stages, the late OL progenitor, the immature OL, and the mature OL, were characterized between 18 and 41 weeks with anti-NG2 proteoglycan, O4, O1, and anti-myelin basic protein (anti-MBP) antibodies. NG2+O4+ late OL progenitors were the predominant stage throughout the latter half of gestation. Between 18 and 2 7 weeks, O4+O1+ immature OLs were a minor population (9.9 +/- 2.1% of total OLs; n = 9). Between 28 and 41 weeks, an increase in immature OLs to 30.9 +/- 2.1% of total OLs (n = 9) was accompanied by a progressive increase in MBP+ myelin sheaths that were restricted to the periventricular white matte r. The developmental window of high risk for PVL thus precedes the onset of myelination and identifies the late OL progenitor as the major potential t arget. Moreover, the decline in incidence of PVL at similar to 32 weeks coi ncides with the onset of myelination in the periventricular white matter an d suggests that the risk for PVL is related to the presence of late OL prog enitors in the periventricular white matter.