Notch inhibition rescues TNF-α mediated block in multiciliated ependymal cell differentiation: Implications for hydrocephalus therapy

Abstract

ABSTRACTHydrocephalus is a prevalent condition among newborns leading to substantial neurocognitive and motor impairment. Novel therapies are needed to supplant invasive surgeries, but identifying targetable cells and pathways remains a hurdle to devising alternative pharmacological options. Multiciliated ependymal cells (MECs) promote cerebrospinal fluid flow within brain ventricles, and their dysfunction is associated with various forms of hydrocephalus. Here we show that an acute exposure to TNF-α strongly impairs the conversion of ependymal cell radial glial progenitors (ecRGPs) into MECs. Inhibition of MEC differentiation was correlated with elevated expression levels of notch pathway effectors normally downregulated prior to the transition of ecRGPs into MECs. TNF-α inhibitedMulticilingene upregulation along with downstream genes critical for centriole amplification and multicilia formation, resulting in cells with greatly diminished basal bodies and multicilia. Treatment with notch inhibitor DBZ, either in parallel with TNF-α or sequentially days later, rescued MEC differentiation and expression of genes required for multicilia formation. These results provide a rationale for how TNFα can impair MEC development, and they offer a targetable pathway to the treatment of some forms of hydrocephalus.