title: Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice.
abstract: White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis. In these areas of only partial damage, local white matter progenitors respond to injury, as oligodendrocyte progenitors (OPCs) proliferate. However, OPCs fail to mature into oligodendrocytes (OLs) even in regions of demyelination with intact axons and instead divert into an astrocytic fate. Local axonal sprouting occurs, producing an increase in unmyelinated fibers in the corpus callosum. The OPC maturation block after white matter stroke is in part mediated via Nogo receptor 1 (NgR1) signaling. In both aged and young adult mice, stroke induces NgR1 ligands and down-regulates NgR1 inhibitors during the peak OPC maturation block. Nogo ligands are also induced adjacent to human white matter stroke in humans. A Nogo signaling blockade with an NgR1 antagonist administered after stroke reduces the OPC astrocytic transformation and improves poststroke oligodendrogenesis in mice. Notably, increased white matter repair in aged mice is translated into significant poststroke motor recovery, even when NgR1 blockade is provided during the chronic time points of injury. These data provide a perspective on the role of NgR1 ligand function in OPC fate in the context of a specific and common type of stroke and show that it is amenable to systemic intervention to promote recovery.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Elif G
authors.initials: EG
authors.lastname: Sozmen
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Shira
authors.initials: S
authors.lastname: Rosenzweig
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Llorente
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: David J
authors.initials: DJ
authors.lastname: DiTullio
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Michal
authors.initials: M
authors.lastname: Machnicki
authors.affiliation: Department of Neuropathology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Lief A
authors.initials: LA
authors.lastname: Havton
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109.
authors.forename: Roman J
authors.initials: RJ
authors.lastname: Giger
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Hinman
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; scarmichael@mednet.ucla.edu.
authors.forename: S Thomas
authors.identifier: 0000-0002-1169-9203
authors.initials: ST
authors.lastname: Carmichael
mesh_terms: D000375:Aging; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000473:pathology; D002454:Cell Differentiation; D003711:Demyelinating Diseases; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000737:chemistry*; D000070816:Nogo Receptor 1 / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology; D000074586:Remyelination; D013234:Stem Cells / Q000166:cytology; D020521:Stroke / Q000503:physiopathology*; D000071939:Stroke Rehabilitation; D066127:White Matter / Q000378:metabolism* / Q000473:pathology
chemical_list: D008024:Ligands; D000070816:Nogo Receptor 1; C486580:RTN4R protein, human; C419790:Rtn4r protein, mouse
keywords: astrocyte; oligodendrocyte; oligodendrocyte progenitor cell; repair; subventricular zone