Oligodendrocyte Progenitor Cell Response to White Matter Stroke

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Project Summary/Abstract White matter stroke is a progressive vascular disease that leads to neurological deficits and can cause dementia. It produces an area of cell death and axonal disruption (the “infarct”) and induces a response of reactive astrocytes and oligodendrocyte precursors cells. In 70% of clinical studies, white matter strokes expand from preexisting lesions into adjacent white matter (the “peri-infarct” region) further damaging and disrupting neuronal connections, causing substantial disability. Currently, what is largely known about white matter repair is derived from studies in non-stroke injuries of white matter such as multiple sclerosis (MS). Limited remyelination occurs in MS through an oligodendrocyte progenitor cell (OPC) response in which OPCs proliferate, differentiate into oligodendrocytes, and remyelinate axons. OPCs proliferate in the peri-infarct region in white matter stroke, but unlike in MS, they do not appear to mature into myelinating oligodendrocytes. This study will utilize a recently developed mouse model of diffuse white matter stroke that produces progressive damage from the small blood vessels in the corpus callosum. This model produces a larger lesion and more closely mimics advanced, chronic stages of human white matter stroke. In aim 1, I will map the OPC response and myelination events after white matter stroke and determine cell fate outcomes of OPCs using novel viral and transgenic approaches. In aim 2, I will determine the role of OPC differentiation induced by candidate genes in white matter repair in vivo. These genes were identified to be highly altered in stroke-induced OPCs as well as to promote OPC differentiation in vitro. The outcome of this work will be to identify novel molecular targets for neural repair and functional recovery in white matter stroke.