Oligodendrocyte-Encoded HIF Function Couples Postnatal Myelination and White Matter Angiogenesis

Abstract

Summary Myelin sheaths provide critical functional and trophic support for axons in white matter tracts of the brain. Oligodendrocyte precursor cells (OPCs) have extraordinary metabolic requirements during development as they differentiate to produce multiple myelin segments, implying they must first secure adequate access to blood supply. However, mechanisms that coordinate myelination and angiogenesis are unclear. Here, we show that oxygen tension, mediated by OPC-encoded hypoxia-inducible factor (HIF) function, is an essential regulator of postnatal myelination. Constitutive HIF1/2α stabilization resulted in OPC maturation arrest through autocrine activation of canonical Wnt7a/7b. Surprisingly, such OPCs also show paracrine activity that induces excessive postnatal white matter angiogenesis in vivo, and directly stimulates endothelial cell proliferation in vitro. Conversely, OPC-specific HIF1/2α loss-of-function leads to insufficient angiogenesis in corpus callosum and catastrophic axon loss. These findings indicate that OPC-intrinsic HIF signaling couples postnatal white matter angiogenesis, axon integrity and the onset of myelination in mammalian forebrain.

Neurodevelopmental Outcomes After Neonatal Surgery for Major Noncardiac Anomalies

“…8 Also, impairment in brain growth and maturation has been described, 50,51 with an increased vulnerability to white matter injury. To date, the prevalence of brain lesions in surgical patients with NCCA is unknown.…”

Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease

“…Accumulation of psychosine leads to cytotoxic effects on oligodendroglial cells, triggering apoptotic cell death in vitro and in vivo [28,34,35]. Given the important role played by oligodendrocytes in brain vascularization [36], it is conceivable that the vascular alterations observed in the brain of twitcher mice may represent the outcome of the astrocytic/ neuronal injury, with a consequent deficiency in the production of trophic angioneurins [27] and activation of inflammatory responses [6,25]. Accordingly, at variance with the results of the computational analysis of brain cortex microvasculature, no significant alterations of the three-dimensional CD31…”

A bloody brake on myelin repair

“…In mammals, myelination begins around birth and OPCs are maintained throughout life; myelination in the cortex of the adult brain is thought to contribute to learning and higher brain functions 4 . Orchestrating timely OPC generation, oligodendrocyte differentiation and energy-demanding myelin synthesis under changing metabolic conditions and in phases of physiological lowoxygen levels 5 is a major challenge. Unsurprisingly, OPCs must integrate a plethora of external stimuli to determine when to differentiate.…”

“…Unless cellular debris and blood clots are cleared and vascular blood supply is reinstated, remyelination will fail 5 . Thus, it is plausible that bloodborne signalling proteins, such as coagulation factors deposited at sites of physical damage, are detected by OPCs and act as surrogate markers of ongoing repair of the primary injury.…”