Remyelination in the CNS: from biology to therapy

Franklin, Robin J.M.; ffrench‐Constant, Charles

doi:10.1038/nrn2480

Cited by 1,319 publications

(1,262 citation statements)

References 248 publications

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“…It is well known that oligodendrocytes can signal to neurons via myelin-axon interactions. 52,53 In addition, oligodendrocytes may support axonal survival through a myelin-independent mechanism since mouse models of oligodendrocyte injury, such as proteolipid protein (plp1)-null mice 54 and Cnp mutant mice, 55 do not show considerable demyelination but induce significant axon loss. 56 Furthermore, oligodendrocytes also metabolically support neuronal axons.…”

Section: Oligodendrocyte-neuron Interactionmentioning

confidence: 99%

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Shindo

Liang

Maki

et al. 2015

J Cereb Blood Flow Metab

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Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

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Section: Oligodendrocyte-neuron Interactionmentioning

confidence: 99%

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Shindo

Liang

Maki

et al. 2015

J Cereb Blood Flow Metab

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“…The origin of endogenous remyelinating cells in the adult CNS has been subject to multiple studies (for more detail see Franklin and Ffrench-Constant [44]). Differentiated postmitotic oligodendrocytes are unable to rebuild myelin sheaths [45][46][47] and remyelination is dependent on cycling cells [47,48].…”

Section: Adult Precursor Cells Can Generate Remyelinating Oligodendromentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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“…Following demyelination oligodendrocyte progenitor cells (OPCs), which are abundant in the adult CNS, migrate toward the lesion where they proliferate and differentiate into myelinating oligodendrocytes (Crawford et al, 2013). Remyelination becomes less efficient in the later stage of MS in part due to a failure of OPC differentiation (Franklin and ffrench‐Constant, 2008; Kuhlmann et al, 2008; Wolswijk, 1998). Failure of remyelination is a major contributor to the accumulation of axonal and neuronal degeneration that characterizes the progressive stage of the disease in which clinical deficits accumulate over time (Bjartmar et al, 2000; De Stefano et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471

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Remyelination in the CNS: from biology to therapy

Cited by 1,319 publications

References 248 publications

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Cell Therapy for Multiple Sclerosis

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

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