Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia

Taylor, Dave; Pirianov, Grisha; Holland, Samantha J.; McGinnity, Colm J.; Norman, Adele; Reali, Camilla; Diemel, Lara T.; Gverić, Djordje; Yeung, Davy; Mehmet, Huseyin

doi:10.1002/jnr.22335

Cited by 98 publications

(75 citation statements)

References 74 publications

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“…Given the substantial plasticity that may be retained by myeloid cells, even after activation, we previously validated the polarization properties of our human myeloid cells, including the MDMs and microglia used in our current experiments (11,19). In rodents, supernatants collected from LPS-activated microglia (M1) were shown to attenuate proliferation of OPCs through a TNF-a/IL-6-dependent mechanism; no effect on OPC survival was observed (43). Interestingly, the same supernatants enhanced survival of mature oligodendrocytes.…”

Section: Discussionmentioning

confidence: 90%

Direct and Indirect Effects of Immune and Central Nervous System–Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation

Moore

Cui

Warsi

et al. 2015

The Journal of Immunology

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In multiple sclerosis, successful remyelination within the injured CNS is largely dependent on the survival and differentiation of oligodendrocyte progenitor cells. During inflammatory injury, oligodendrocytes and oligodendrocyte progenitor cells within lesion sites are exposed to secreted products derived from both infiltrating immune cell subsets and CNS-resident cells. Such products may be considered either proinflammatory or anti-inflammatory and have the potential to contribute to both injury and repair processes. Within the CNS, astrocytes also contribute significantly to oligodendrocyte biology during development and following inflammatory injury. The overall objective of the current study was to determine how functionally distinct proinflammatory and anti-inflammatory human immune cell subsets, implicated in multiple sclerosis, can directly and/or indirectly (via astrocytes) impact human oligodendrocyte progenitor cell survival and differentiation. Proinflammatory T cell (Th1/Th17) and M1-polarized myeloid cell supernatants had a direct cytotoxic effect on human A2B5+ neural progenitors, resulting in decreased O4+ and GalC+ oligodendrocyte lineage cells. Astrocyte-conditioned media collected from astrocytes pre-exposed to the same proinflammatory supernatants also resulted in decreased oligodendrocyte progenitor cell differentiation without an apparent increase in cell death and was mediated through astrocyte-derived CXCL10, yet this decrease in differentiation was not observed in the more differentiated oligodendrocytes. Th2 and M2 macrophage or microglia supernatants had neither a direct nor an indirect impact on oligodendrocyte progenitor cell differentiation. We conclude that proinflammatory immune cell responses can directly and indirectly (through astrocytes) impact the fate of immature oligodendrocyte-lineage cells, with oligodendrocyte progenitor cells more vulnerable to injury compared with mature oligodendrocytes.

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Section: Discussionmentioning

confidence: 90%

Direct and Indirect Effects of Immune and Central Nervous System–Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation

Moore

Cui

Warsi

et al. 2015

The Journal of Immunology

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“…Interestingly, the effects of growth factors on NG21 cells may also depend on the developmental stage and/or location of cells within the CNS (Mason and Goldman, 2002;Pfeiffer et al, 1993). Most pathological conditions also induce local production of certain cytokines and chemokines ) that together with blood derived factors can influence proliferation of NG21 cells (Kerstetter et al, 2009;Rhodes et al, 2006;Taylor et al, 2010).…”

Section: Change Of Cell Cycle Properties After Injurymentioning

confidence: 97%

Progenitors in the adult cerebral cortex: Cell cycle properties and regulation by physiological stimuli and injury

Simon

Götz

Dimou

2011

Glia

280

384

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The adult brain parenchyma contains a widespread population of progenitors generating different cells of the oligodendrocyte lineage such as NG2+ cells and some mature oligodendrocytes. However, it is still largely unknown how proliferation and lineage decisions of these progenitors are regulated. Here, we first characterized the cell cycle length, proliferative fraction, and progeny of dividing cells in the adult cerebral cortex and then compared these proliferation characteristics after two distinct stimuli, invasive acute brain injury and increased physiological activity by voluntary physical exercise. Our data show that adult parenchymal progenitors have a very long cell cycle due to an extended G1 phase, many of them can divide at least twice and only a limited proportion of the progeny differentiates into mature oligodendrocytes. After stab wound injury, however, many of these progenitors re-enter the cell cycle very fast, suggesting that the normally long G1 phase is subject to regulation and can be abruptly shortened. In striking contrast, voluntary physical exercise shows the opposite effect with increased exit of the cell cycle followed by an enhanced and fast differentiation into mature oligodendrocytes. Taken together, our data demonstrate that the endogenous population of adult brain parenchymal progenitors is subject to profound modulation by environmental stimuli in both directions, either faster proliferation or faster differentiation.

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“…It is unclear, however, whether HAf may also function as a DAMP in chronic WMI to disrupt myelination via a tolerance-like mechanism. OPCs express TLRs, but their stimulation does not promote proinflammatory cytokine release (9). Although, IκK/NF-κB signaling is the main proinflammatory pathway associated with TLR activation, it does not regulate developmental myelination or remyelination (10).…”

Section: Introductionmentioning

confidence: 99%

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

Srivastava¹,

Diba²,

Dean³

et al. 2018

Journal of Clinical Investigation

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ers by interactions of FoxO3 with the chromatin-remodeling factor Brg1 and the TF Olig2, which are involved in control of OPC differentiation (14-16). Hence, central myelination failure is regulated by a noncanonical TLR4/AKT/FoxO3 signaling pathway utilized by bHAf to induce a tolerance-like state that selectively constrains OPC maturation and myelination. ResultsNeonatal hypoxic-ischemic WMI promotes MDa HA depolymerization. To investigate the status of MDa HA in chronic neonatal WMI, we employed our preterm-equivalent rat hypoxia-ischemia (H-I) model, which generates myelination failure and replicates key features of human WMI ( Figure 1A) (17). MDa HA turnover in the ECM after H-I was visualized with a biotinylated HA-binding protein (HABP) and costained with glial fibrillary acidic protein (GFAP) as a marker of WMI. Unlike in age-matched uninpro-myelination signal (13). This tolerance-like action of bHAf was mediated through TLR4 but not via CD44 or TLR2. As in TLR4-mediated IT, bHAf 's influence on myelination was reversible when MDa HA depolymerization was attenuated or bHAf was removed. AKT desensitization was similarly reversible in vivo in neonatal WMI. Moreover, bHAf actions were mediated via a noncanonical TRIF-dependent pathway, also involved in IT, rather than the canonical MyD88 arm of TLR4 signaling. AKT desensitization resulted in maturation-dependent activation of the FoxO3 transcription factor (TF), which selectively constrained preOL maturation in a bHAf-dependent fashion. A role for activated FoxO3 in human myelination failure was supported by selective localization of nuclear FoxO3 to OPCs in human preterm WMI and multiple sclerosis (MS) plaques. bHAf-mediated OPC maturation arrest appears to be regulated at the FoxO3 and myelin basic protein (MBP) promot- (Contralateral). Only the lesion group had a significant reduction in HA recovery. (E) Incubation of MDa HA with the lesion lysate generated HAf below ~650 kDa. Lesion-lysate activity was sensitive to heat inactivation but insensitive to deferoxamine (50 μM). B and C: control n = 2; H-I n = 4 animals for each age group (P4 and P14). D: n = 6 (H-I), n = 5 (control), and n = 4 (hypoxia) animals (P7). E: n = 4 separate experiments on 4 different animals at P4 after H-I at P3; one representative experiment is shown. *P < 0.05 by ANOVA. Mean ± SD. Scale bars: 300 μm (B and C). The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 0 2 7 jci.orgVolume 128 Number 5 May 2018 with MBP-labeled oligodendrocytes (Supplemental Figure 2A). To confirm de novo progressive myelin generation, we undertook ultrastructural studies that identified axons wrapped with multilamellar myelin sheaths ( Figure 2B). In contrast to vehicle-treated slices, which displayed robust myelination of the corpus callosum, slices incubated with MDa HA until 21 days in vitro (DIV21) displayed a pronounced reduction in myelinated axons ( Figure 2C). Myelination failure was not related to decreased OPC survival, since MDa HA treatment did not enhance OPC degeneratio...

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Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia

Cited by 98 publications

References 74 publications

Direct and Indirect Effects of Immune and Central Nervous System–Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation

Direct and Indirect Effects of Immune and Central Nervous System–Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation

Progenitors in the adult cerebral cortex: Cell cycle properties and regulation by physiological stimuli and injury

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

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