Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants

Abstract

Objective The major form of MRI-defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested pre-oligodendrocyte (preOL) maturation in reactive astrocyte-rich lesions. Methods A retrospective autopsy series (1983–2000) was selected for cases with diffuse WMI and analyzed relative to prospectively-collected contemporary cases (2003–2010). Controls were age and region-matched to address regional variation in preOL maturation. Successive oligodendrocyte stages were analyzed with lineage-specific markers. Microscopic necrosis was quantified with microglial markers. Axon injury markers defined the burden of axonopathy. Extracellular matrix remodelling was defined by detection of hyaluronic acid (HA), an inhibitor of preOL maturation, and the HA receptor, CD44. Results In the contemporary case series, diffuse WMI was accompanied by a significant reduction in the burden of microscopic necrosis and axonopathy. Diffuse astrogliosis extended into the lesion surround with elevated HA and astrocyte-expressed CD44. The total population of OL lineage stages was significantly increased in lesions. This increase coincided with significant expansion of the preOL pool. Interpretation Although these data confirm that microscopic necrosis occurs in contemporary cases, the markedly decreased burden supports that it does not contribute substantially to myelination failure. The primary mechanism of myelination failure involves a disrupted cellular response whereby preOLs fail to differentiate in diffuse astrogliotic lesions. Pre-oligodendrocyte maturation arrest converts chronic WMI to a more immature state related to the burden of astrogliosis.

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

“…Thus, this focal hypointense signal abnormality corresponded to small discrete regions of focal microscopic necrosis that were detected at submillimeter resolution. Both the incidence and lesion burden of these small necrotic foci of WMI were quite similar to that observed in human WMI [54]. Although these lesions are readily detected by histopathology, they are not readily detected by MRI at lower field strength.…”

“…This shortcoming, for example, limits the relevance of rodent hypoxia-ischemia models for the study of myelination disturbances associated with chronic human WMI. Necrotic injury to cerebral gray matter contributes substantially to neuro-axonal degeneration as a cause of dysmyelination, which is not a prominent feature of WMI in either fetal sheep [53] or contemporary human cases of WMI [54]. The basis for this difference in susceptibility to gray matter injury in rodents relative to sheep and humans is likely to be multifactorial.…”

“…We used quantitative electron microscopy studies in our preterm fetal sheep model of global cerebral ischemia to define the extent of axonal degeneration in MRI-defined diffuse WMI [53]. During the chronic phase of WMI from this same fetal sheep preparation [46] and human [54], microscopic foci of necrosis were observed that were rich in microglia, but lacked astrocytes or axons. However, no significant axonal degeneration, axonal loss or shift in the distribution of axon calibers was observed by quantitative electron microscopy studies in preterm fetal sheep [53].…”

Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

“…This pattern is consistent with the seminal findings of Back and colleagues 26 of maturational arrest of oligodendrocytes in the neonatal rat after hypoxia-ischemia, and in premature infants with diffuse white matter injury. 27 Ethanol is widely used as a vehicle for numerous studies, such as those using melatonin as a putative neuroprotective agent. 11 It is an allosteric modulator of the inhibitory GABA receptor, increasing opening frequency and chloride flux, 28 and increases GABAergic neurotransmission both indirectly and through GABA release from presynaptic terminals in many brain regions.…”

Microglia activation in the extremely preterm human brain

“…Back and colleagues (35,36) have more recently suggested that higher field strengths would be more sensitive in detecting histophathologically defined diffuse white matter injury, which may not be evident on conventional MRI. Although magnetic field strengths of 1.5T and 3T are more clinically relevant, high-field-strength MRI may be required for future postmortem studies to diagnose more subtle forms of white matter injury for comparative histological studies as seen in our cohort of preterm hemorrhage brains.…”