The pathological potential of ependymal cells in mild traumatic brain injury

Abstract

Mild traumatic brain injury (mTBI) is a common neurological condition affecting millions of individuals worldwide. Although the pathology of mTBI is not fully understood, ependymal cells present a promising approach for studying the pathogenesis of mTBI. Previous studies have revealed that DNA damage in the form of γH2AX accumulates in ependymal cells following mTBI, with evidence of widespread cellular senescence in the brain. Ependymal ciliary dysfunction has also been observed, leading to altered cerebrospinal fluid homeostasis. Even though ependymal cells have not been extensively studied in the context of mTBI, these observations reflect the pathological potential of ependymal cells that may underlie the neuropathological and clinical presentations of mTBI. This mini review explores the molecular and structural alterations that have been reported in ependymal cells following mTBI, as well as the potential pathological mechanisms mediated by ependymal cells that may contribute to overall dysfunction of the brain post-mTBI. Specifically, we address the topics of DNA damage-induced cellular senescence, dysregulation of cerebrospinal fluid homeostasis, and the consequences of impaired ependymal cell barriers. Moreover, we highlight potential ependymal cell-based therapies for the treatment of mTBI, with a focus on neurogenesis, ependymal cell repair, and modulation of senescence signaling pathways. Further insight and research in this field will help to establish the role of ependymal cells in the pathogenesis of mTBI and may lead to improved treatments that leverage ependymal cells to target the origins of mTBI pathology.

Keywords: DNA damage; brain barriers; cellular senescence; cerebrospinal fluid; ependymal cells; mild traumatic brain injury; neural stem cells.

FIGURE 1

Potential pathological mechanisms of ependymal cells in the pathogenesis of mTBI. Following mTBI, ependymal cells display DNA damage in the form of γH2AX. Persistent DNA damage that is not effectively repaired through DNA repair mechanisms may trigger a state of ependymal senescence, which is accompanied by the secretion of pro-inflammatory SASP factors into the CSF. The morphological and structural changes driven by senescence may lead to ependymal cellular dysfunction and thus, impaired ependymal barrier functionality. One likely outcome of compromised ependymal barrier function is dysregulation of CSF composition, circulation, and waste-removal processes. A state of ependymal dysfunction likely increases the brain’s risk of developing further neuropathologies and disease, specifically neurodegenerative diseases like Alzheimer’s disease, chronic traumatic encephalopathy, and Parkinson’s disease. These mechanisms reveal aspects of ependymal cell pathobiology that can be targeted to treat mTBI, such as modulation of senescence signaling pathways, enhanced neurogenesis through NSC-ependymal cell crosstalk, and regeneration or repair of the ependymal cell lining. Solid arrows represent observed outcomes. Dashed arrows represent hypothesized outcomes.