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

Abstract

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.

Conditional Deletion of Foxg1 Alleviates Demyelination and Facilitates Remyelination via the Wnt Signaling Pathway in Cuprizone-Induced Demyelinated Mice

“…Previous research has demonstrated that Foxg1 may be necessary for maintenance of the NSC pool in the CNS and that genetic inactivity of Foxg1 promotes both gliogenesis and neurogenesis [ 11 ]. NSCs are maintained in a quiescent state in the adult CNS [ 47 ]. Although it has been reported that Foxg1 cKO in nestin-positive NSCs promotes neurogenesis and gliogenesis [ 11 ], it did not markedly change the myelin sheath and behavior in mice fed a normal diet in our study.…”

Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury

“…Astrocyte-derived BDNF promotes not only neuron viability, but also oligodendrogenesis [ 236 ], and induces differentiation of OPCs into mature oligodendrocytes [ 237 ]. Conversely, in an in vivo model of ischemia, Sozmen et al [ 238 ] showed that reactive astrocytes, probably belonging to the A1 subpopulation, blocked proliferation and differentiation of OPCs. This evidence supports the idea that A2-astrocytic phenotype, as opposed to A1, could reduce ischemic damage through an increase in functional oligodendrocytes number.…”

Demyelinating processes in aging and stroke in the central nervous system and the prospect of treatment strategy

“…In addition, astrocytes are also involved in the regulation of OPC differentiation after stroke. Studies have also shown that after stroke, reactive astrocytes secrete inhibin A and inhibit the expression of Matrilin-2 in OPC, which creates a microenvironment that is not conducive to OPC differentiation and remyelination 83 (Figure 1 green dotted square). Moreover, cholesterol is the lipid component that makes up myelin.…”