The Role of Endothelin and Notch Signaling in Demyelinating Brain Injury and Disease

Multiple Sclerosis (MS) and diffuse white matter injury (DWMI) are two common white matter disabilities that affect adults and newborns, respectively. The therapeutic options for MS and DWMI are very limited, and the mechanisms underlying disease pathogenesis are still not completely understood. One potential remedy for both MS and DWMI is to enhance endogenous myelination and remyelination processes that are carried out by a pool of progenitors in the brain called oligodendrocyte progenitor cells (OPCs). Our lab has identified two signaling pathways which might play a role in OPC maturation, myelination and remyelination. We have shown that endothelin-1 (ET-1) is released following demyelinating injury in adult mice, and that epidermal growth factor (EGF) signaling regulates developmental myelination. However, we have not investigated the effect of these two signaling pathways on white matter repair in neonatal and adult tissue following injury.;MS is predominantly an adult autoimmune disease that targets mature oligodendrocytes (OLs) and the myelin they produce. Autoimmune attacks lead to OL death and focal demyelinated lesions throughout the CNS. OPCs have the ability to repair these lesions, in a process called remyelination. However, remyelination failure is frequently found in MS tissue and is a major obstacle to recovery. The OPC potential to differentiate and remyelinate can be prevented by inhibitory signals present in the pathological MS lesion environment. Identification of these signals is essential to promote OPC differentiation and lesion repair. To dissect the signals that regulate the remyelination process, we used the lysolecithin (LPC) model of toxin-induced demyelination in mice. We have previously found that the signaling molecule ET-1 is released at high levels in LPC lesions, but its role in remyelination has not been studied. Using this model and staining of human MS tissue, we found that ET-1 is highly expressed in reactive astrocytes of demyelinated lesions. Using both gain- and loss-of-function approaches in mice, we demonstrate that ET-1 drastically reduces the rate of remyelination. We also discovered that ET-1 acts mechanistically by promoting Notch activation in OPCs during remyelination through induction of Jagged1 expression in reactive astrocytes. Pharmacological inhibition of ET signaling prevented Notch activation in demyelinated lesions, and accelerated remyelination. These findings reveal that ET-1 is a negative regulator of OPC differentiation and remyelination, and is potentially a novel therapeutic target to promote lesion repair and remyelination in MS tissue.;DWMI is a common finding in very preterm infants (<32 weeks gestation) and results in chronic neurodevelopmental impairments. DWMI is caused by poor oxygen exchange by underdeveloped lungs in the premature infant. Whereas in MS the loss of OLs initiates a regenerative response, DWMI delays the initial generation of myelin during developmental myelination. This leads to diffuse WM damage and hypomyelination. Myelin deficits in DWMI are caused by delays in OPC maturation, and in a previous study we demonstrated that the epidermal growth factor receptor (EGFR) plays an important role in OPC development. Here, we examined whether enhanced EGFR signaling promotes myelin recovery in the developing brain. To recapitulate the hallmarks of human DWMI, we used a well-established model of chronic hypoxia in mice. Chronic hypoxia led to delays in WM development, OL death, and delays in OPC maturation. Injury also increased Notch activation in the WM which contributed to delayed OPC maturation. Intranasal delivery of HB-EGF immediately after injury prevented these myelin deficits and led to accelerated functional recovery. HB-EGF also reduced Notch activation in OPCs, and prevented upregulation of Delta1 and NICD. This study found that the administration of HB-EGF through a non-invasive route can be used to stimulate OPC development and could be a clinically relevant therapeutic intervention for premature infants with WM injury. (Abstract shortened by UMI.).