White Matter Stroke Induces a Unique Oligo-Astrocyte Niche That Inhibits Recovery.

Subcortical white matter stroke is a common stroke subtype. White matter stroke stimulates adjacent oligodendrocyte progenitor cells (OPCs) to divide and migrate to the lesion, but stroke OPCs have only a limited differentiation into mature oligodendrocytes. To understand the molecular systems that are active in OPC responses in white matter stroke, OPCs were virally labeled and laser-captured in the region of partial damage adjacent to the infarct in male mice. RNAseq indicates two distinct OPC transcriptomes associated with the proliferative and limited-regeneration phases of OPCs after stroke. Molecular pathways related to nuclear receptor activation, ECM turnover, and lipid biosynthesis are activated during proliferative OPC phases after stroke; inflammatory and growth factor signaling is activated in the later stage of limited OPC differentiation. Within ECM proteins, Matrilin-2 is induced early after stroke and then rapidly downregulated. Prediction of upstream regulators of the OPC stroke transcriptome identifies several candidate molecules, including Inhibin A-a negative regulator of Matrilin-2. Inhibin A is induced in reactive astrocytes after stroke, including in humans. In functional assays, Matrilin-2 induces OPC differentiation, and Inhibin A inhibits OPC Matrilin-2 expression and inhibits OPC differentiation. In vivo, Matrilin-2 promotes motor recovery after white matter stroke, and promotes OPC differentiation and ultrastructural evidence of remyelination. These studies show that white matter stroke induces an initial proliferative and reparative response in OPCs, but this is blocked by a local cellular niche where reactive astrocytes secrete Inhibin A, downregulating Matrilin-2 and blocking myelin repair and recovery.SIGNIFICANCE STATEMENT Stroke in the cerebral white matter of the brain is common. The biology of damage and recovery in this stroke subtype are not well defined. These studies use cell-specific RNA sequencing and gain-of-function studies to show that white matter stroke induces a glial signaling niche, present in both humans and mice, between reactive astrocytes and oligodendrocyte progenitor cells. Astrocyte secretion of Inhibin A and downregulation of oligodendrocyte precursor production of Matrilin-2 limit OPC differentiation, tissue repair, and recovery in this disease.

Mechanisms of demyelination and remyelination in the young and aged brain following white matter stroke.

Subcortical white matter stroke (WMS) accounts for 25% of all incidences of stroke and results in severe motor and cognitive disability. WMS stands as the second leading cause of dementia and is immensely prevalent in older adults. In a startlingly statistic, a majority of human beings will present WMS by 80 years of age. Early ischemic lesions produced by WMS are asymptomatic and termed "silent strokes". WMS is, however, progressive with both the size of the lesions and their distribution, increasing as patients age. Pathological analyses in both postmortem human tissue samples and mouse models of WMS demonstrate myelin degeneration as a chief hallmark of WMS. This suggests that the development of rehabilitative strategies in human WMS will necessitate an understanding of the pathophysiology of demyelination and remyelination following ischemic injury. This review will address our current understanding of WMS from human imaging studies, the development of rodent models of WMS, the mechanistic underpinning of myelin degeneration following WMS as well as remyelination dynamics in the adult brain.

Subcortical White Matter Stroke in the Mouse: Inducing Injury and Tracking Cellular Proliferation.

Here, we describe a method for inducing subcortical white matter stroke in mice, as well as tracking cellular proliferation through drinking water administration of EdU and ex vivo labeling.

Stroke in CNS white matter: Models and mechanisms.

White matter stroke (WMS) is a debilitating disorder, which is characterized by the formation of ischemic lesions along subcortical white matter tracts of the central nervous system. Initial infarction during the early stages of the disease is often asymptomatic and is thus considered a form of silent stroke. However, over time lesions accumulate, resulting in severe cognitive and motor decline of which there are no known therapies. Functional imaging and post mortem analysis of patients demonstrates a loss of oligodendrocytes and the subsequent damage of myelin as a primary hallmark of WMS lesions. Though the adult mammalian brain maintains the capacity to regenerate adult oligodendrocytes, this process is blocked in the infarcted white matter thereby preventing remyelination. Recent evidence suggests that activation of neural circuits via motor training or direct stimulation drives oligodendrogenesis and de novo myelin synthesis, opening a potential avenue for therapy in WMS.