The Ties That Bind: Glial Transplantation in White Matter Ischemia and Vascular Dementia

Abstract

White matter injury is a progressive vascular disease that leads to neurological deficits and vascular dementia. It comprises up to 30% of all diagnosed strokes, though up to ten times as many events go undiagnosed in early stages. There are several pathologies that can lead to white matter injury. While some studies suggest that white matter injury starts as small infarcts in deep penetrating blood vessels in the brain, others point to the breakdown of endothelial function or the blood-brain barrier as the primary cause of the disease. Whether due to local endothelial or BBB dysfunction, or to local small infarcts (or a combination), white matter injury progresses, accumulates, and expands from preexisting lesions into adjacent white matter to produce motor and cognitive deficits that present as vascular dementia in the elderly. Vascular dementia is the second leading cause of dementia, and white matter injury-attributed vascular dementia represents 40% of all diagnosed dementias and aggravates Alzheimer's pathology. Despite the advances in the last 15 years, there are few animal models of progressive subcortical white matter injury or vascular dementia. This review will discuss recent progress in animal modeling of white matter injury and the emerging principles to enhance glial function as a means of promoting repair and recovery.

Keywords: Animal models; Glial-based therapies; Vascular dementia; White matter injury.

Fig. 1

Overview of white matter injury progression in humans. White matter injury is initiated by vascular dysfunction, and it damages primarily the gliovascular unit, followed by axonal degeneration and demyelination. White matter lesions accumulate over time to produce motor and cognitive decline that presents as vascular dementia in elderly

Fig. 2

Overview of the oligodendrocyte differentiation blockage due to white matter injury. White matter injury increases oligodendrocyte progenitor cell division and migration but inhibits oligodendrocyte differentiation

Fig. 3

Overview of hiPSC-GEP transplant-induced white matter repair. hiPSC-GEP transplant after white matter injury enhances oligodendrocyte differentiation and promotes remyelination that leads to motor and cognitive improvement in a model of white matter injury in mice