Late Oligodendrocyte Progenitors Coincide with the Developmental Window of Vulnerability for Human Perinatal White Matter Injury

Abstract

Hypoxic-ischemic injury to the periventricular cerebral white matter [periventricular leukomalacia (PVL)] results in cerebral palsy and is the leading cause of brain injury in premature infants. The principal feature of PVL is a chronic disturbance of myelination and suggests that oligodendrocyte (OL) lineage progression is disrupted by ischemic injury. We determined the OL lineage stages at risk for injury during the developmental window of vulnerability 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. NG2ϩO4ϩ late OL progenitors were the predominant stage throughout the latter half of gestation. Between 18 and 27 weeks, O4ϩO1ϩ immature OLs were a minor population (9.9 Ϯ 2.1% of total OLs; n ϭ 9). Between 28 and 41 weeks, an increase in immature OLs to 30.9 Ϯ 2.1% of total OLs (n ϭ 9) was accompanied by a progressive increase in MBPϩ myelin sheaths that were restricted to the periventricular white matter. The developmental window of high risk for PVL thus precedes the onset of myelination and identifies the late OL progenitor as the major potential target. Moreover, the decline in incidence of PVL at ϳ32 weeks coincides with the onset of myelination in the periventricular white matter and suggests that the risk for PVL is related to the presence of late OL progenitors in the periventricular white matter.

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

“…From a practical standpoint, the availability, cost, and ease of breeding the sheep makes it a more practical large animal model than the nonhuman primate. In addition, the size (20-40 weeks) and is based on data previously reported [133]. The progression of the oligodendrocyte lineage in fetal sheep white matter development has been previously described [41,42].…”

NF‐Y‐dependent regulation of glutamate receptor 4 expression and cell survival in cells of the oligodendrocyte lineage

“…This work also highlights the NF‐Y system as an important regulator of OPC survival during excitotoxic injury. OPC are exquisitely vulnerable to hypoxic‐ischemic conditions (Back et al, 2002; Back et al, 2001; Back & Rosenberg, 2014). Therefore, we consider the NF‐Y network as an interesting focus for future work aiming to identify novel therapeutic targets for the protection of OPC during excitotoxic injury.…”

“…In support of this, cultured OPC express high levels of GluA3 and 4 (Hossain et al, 2014; Itoh et al, 2002) which may assemble to form Ca 2+ permeable AMPAR, and GluA4 is the predominant subunit expressed by OPC in the developing white matter of rodents and humans (Talos, Fishman, et al, 2006; Talos, Follett, et al, 2006). Importantly, the timing of GluA4 expression in these systems corresponds with an established window of vulnerability during which OPC are selectively injured by hypoxic‐ischemic conditions (Back et al, 2002; Back et al, 2001; reviewed in Fern, Matute, & Stys, 2014), and GluA4 is highly expressed in neural cells vulnerable to excitotoxic cell death (Page & Everitt, 1995). GluA4 signalling is therefore strongly connected to excitotoxicity.…”

Decreased postural control in adolescents born with extremely low birth weight

“…The subplate neuron layer is a transient structure that is located beneath the cortical plate and peaks in activity between 22 and 36 weeks of gestation (Back et al 2001;Perlman 2003). Removal of subplate neurons profoundly affects cortical development and plasticity (Kanold 2009).…”