M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination
Open accessAbstract
The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration.
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19 of 29 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured
- Findingown data
Pairing of an old animal with a young animal (Y/O) led to increased densities of M2 microglia/macrophages in the lesions in the older animal relative to O/O pairings.
“Pairing of an old animal with a young animal (Y/O), a manipulation that restores remyelination efficiency in the older animal4, led to increased densities of M2 microglia/macrophages in the lesions in the older animal relative to those seen in the O/O pairings (Fig. 6b, c).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012). source
- Findingown data
M2 depletion decreased the number of nodes of Ranvier, shown by reduced paranodal Caspr localization flanking nodal Ankyrin-G.
“Second, we demonstrated a decrease in the number of nodes of Ranvier normally indicative of compact myelin27, 28 by showing reduced paranodal Caspr localization (flanking nodal Ankyrin-G) (Fig. 5g, h).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [27] Fancy, S.P. et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat. Neurosci. 14, 1009–1016 (2011). source
- cites [28] Yuen, T.J. et al. Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. Brain 136, 1035–1047 (2013). source
- Premisecitation
A block in oligodendrocyte differentiation is a feature of chronic MS lesions.
“Our results showing that M2 cells are required for oligodendrocyte differentiation are of particular interest given that a block in oligodendrocyte differentiation is a feature of chronic MS lesions46.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [46] Kuhlmann, T. et al. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131, 1749–1758 (2008). source
- Findingown data
The absence of peripherally-derived macrophages in CCR2−/− lesions led to a reduction in total numbers of Arg-1+ M2 cells to 8 ± 8 and 40 ± 13 % of wildtype controls at 3 and 10 dpl, respectively.
“and Arg-1+ M2 cells (to 8 ± 8 and 40 ± 13 % of wildtype controls at 3 and 10 dpl, respectively).”
Quote in the paperSubstantial claim - Findingown data
M2 densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger animal.
“M2 densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger animal”
Quote in the paperSubstantial claim
- Findingown data
The same switch from an M1 to M2 response during remyelination was observed in another model of demyelination induced by injection of ethidium bromide into the rat caudal cerebellar peduncles (CCP).
“We also observed the same switch from an M1 to M2 response during remyelination in another model of demyelination induced by injection of ethidium bromide into the rat caudal cerebellar peduncles (CCP) (Supplementary Fig. 2 online)14.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Woodruff, R.H. & Franklin, R.J.M. The expression of myelin protein mRNAs during remyelination of lysolecithin-induced demyelination. Neuropathol. Appl. Neurobiol. 25, 226–235 (1999). source
- Findingown data
M2 densities were increased in MS lesions that normally show remyelination.
“and in MS lesions that normally show remyelination”
Quote in the paperSubstantial claim - Findingown data
The transition from M1 to M2 polarization still occurred within the microglia population in CCR2−/− mice, with the majority of CD68+ cells being iNOS+ at 3 dpl and Arg-1+ at 10 dpl.
“The transition from M1 to M2 polarization still occurred as before within the microglia population in CCR2−/− mice, with the majority of CD68+ cells being iNOS+ at 3 dpl and Arg-1+ at 10 dpl (Fig. 2b, c).”
Quote in the paperSubstantial claim - Findingown data
At 21 dpl, there was a reduction in Arg-1+ M2 cells compared to 10 dpl.
“At 21 dpl, there was a reduction in Arg-1+ M2 cells compared to 10 dpl (Fig. 1b, c).”
Quote in the paperSubstantial claim - Findingown data
By 10 dpl there were more Arg-1+ CD68+ M2 cells than iNOS+ CD68+ M1 cells.
“However, by 10 dpl there were more Arg-1+ CD68+ M2 cells than iNOS+ CD68+ M1 cells (Fig. 1b, c).”
Quote in the paperSubstantial claim - Findingown data
Oligodendrocyte differentiation was enhanced in vitro with M2 conditioned media.
“Oligodendrocyte differentiation was enhanced in vitro with M2 conditioned media”
Quote in the paperSubstantial claim - Findingown data
The iNOS+ M1 population was composed of 39 ± 3 % (3 dpl) and 46 ± 14 % GFP+ macrophages (10 dpl).
“The iNOS+ M1 population was composed of 39 ± 3 % (3 dpl) and 46 ± 14 % GFP+ macrophages (10 dpl)”
Quote in the paperSubstantial claim - Findingown data
The polarization switch during remyelination was confirmed using additional markers for M1 (TNFα and CD16/32) and M2 phenotypes (MR and IGF-1).
“The polarization switch during remyelination was confirmed using additional markers for M1 (tumor necrosis factor (TNF)α and CD16/32) and M2 phenotypes (mannose receptor (MR) and insulin-like growth factor (IGF)-1) (Supplementary Fig. 1 online).”
Quote in the paperNot a substantial claim - Findingown data
A switch from an M1- to M2-dominant response occurred within microglia and peripherally-derived macrophages as remyelination started.
“Here we show that a switch from an M1- to M2-dominant response occurred within microglia and peripherally-derived macrophages as remyelination started.”
Quote in the paperSubstantial claim - Findingown data
At 3 dpl, substantially more CD68+ microglia/macrophages expressed the M1 marker iNOS than the M2 marker Arg-1.
“At 3 dpl, substantially more CD68+ microglia/macrophages expressed the M1 marker inducible nitric oxide synthase (iNOS) than the M2 marker arginase-1 (Arg-1) (Fig. 1b, c).”
Quote in the paperSubstantial claim - Findingown data
Only a low percentage of CD68+ microglia/macrophages remained unpolarized (iNOS- and Arg-1-) throughout remyelination.
“Only a low percentage of CD68+ microglia/macrophages remained unpolarized (iNOS- and Arg-1-) throughout remyelination (Fig. 1c).”
Quote in the paperNot a substantial claim - Findingown data
Oligodendrocyte differentiation was impaired in vivo following intra-lesional M2 depletion.
“and impaired in vivo following intra-lesional M2 depletion”
Quote in the paperSubstantial claim - Findingown data
Blocking M2-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures.
“Blocking M2-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures.”
Quote in the paperSubstantial claim - Findingown data
The absence of peripherally-derived macrophages in CCR2−/− lesions led to a reduction in total numbers of iNOS+ M1 cells to 37 ± 10 and 33 ± 7 % of wildtype control at 3 and 10 dpl, respectively.
“However, the absence of peripherally-derived macrophages in CCR2−/− lesions did lead to a reduction in total numbers of iNOS+ M1 cells (to 37 ± 10 and 33 ± 7 % of wildtype control at 3 and 10 dpl, respectively)”
Quote in the paperSubstantial claim - Findingown data
Both GFP+ iNOS+ M1 macrophages and GFP+ Arg-1+ M2 macrophages were present at 3 and 10 dpl.
“Both GFP+ iNOS+ M1 macrophages and GFP+ Arg-1+ M2 macrophages were present at 3 and 10 dpl (Fig. 2e, f).”
Quote in the paperSubstantial claim - Findingown data
The Arg-1+ M2 population was composed of 63 ± 12 % (3 dpl) and 68 ± 23 % GFP+ macrophages (10 dpl).
“whereas the Arg-1+ M2 population was composed of 63 ± 12 % (3 dpl) and 68 ± 23 % GFP+ macrophages (10 dpl)”
Quote in the paperSubstantial claim - Findingown data
All MS lesion types showed significantly higher densities of total CD68+ microglia/macrophages compared to controls.
“All lesion types showed significantly higher densities of total CD68+ microglia/macrophages and iNOS+ M1 cells compared to controls (Fig. 7d, f).”
Quote in the paperNot a substantial claim - Findingown data
More MR+ M2a and M2c polarized microglia expressed activin-A in vitro in comparison to iNOS+ M1 microglia.
“In keeping with this, we found that more MR+ M2a and M2c polarized microglia expressed activin-A in vitro in comparison to iNOS+ M1 microglia (Fig. 8a).”
Quote in the paperSubstantial claim - Findingown data
Treatment of slices with anti-activin-A antibody alone did not reduce the number of oligodendrocytes relative to IgG control.
“as treatment of slices with anti-activin-A antibody alone did not reduce the number of oligodendrocytes relative to IgG control (Fig. 8h).”
Quote in the paperSubstantial claim - Findingown data
Conditioned media derived from both M1 and M2 microglia increased OPC proliferation.
“Conditioned media derived from both M1 and M2 microglia increased OPC proliferation (evidenced by increased total OPC numbers, cell cycle activity, and 5-bromo-2-deoxyuridine (BrdU) incorporation (Supplementary Fig. 5a-d online))”
Quote in the paperNot a substantial claim - Findingown data
Activin-A was sufficient to enhance oligodendrocyte differentiation in cultured OPCs.
“To test the effect of activin-A on oligodendrocyte differentiation, we exposed cultured OPCs to activin-A and found it was sufficient to enhance oligodendrocyte differentiation (Fig. 8d).”
Quote in the paperSubstantial claim - Findingown data
Conditioned media derived from both M1 and M2 microglia increased chemotaxic migration of OPCs.
“and also increased chemotaxic migration (Supplementary Fig. 5e online).”
Quote in the paperNot a substantial claim - Findingown data
Significantly elevated numbers of M2 cells were seen only in acute active MS lesions and within the rim of chronic active MS lesions.
“While a few remyelinated lesions showed increased densities of MR+ M2 cells compared to controls, significantly elevated numbers of M2 cells were seen only in acute active lesions and within the rim of chronic active lesions (Fig. 7e, f, g), both areas of recent damage where ongoing remyelination would be expected.”
Quote in the paperSubstantial claim- Rests on an assumption: M2 cell densities in MS lesions indicate areas of ongoing remyelination.
- Findingown data
Activin-A immunoreactivity was reduced upon M2 depletion with MCLs.
“and was reduced upon M2 depletion with MCLs (Fig. 8b).”
Quote in the paperSubstantial claim - Findingown data
Densities of CD16/32+ M1 microglia/macrophages were substantially higher in O/O pairings than Y/Y pairings.
“In contrast, densities of CD16/32+ M1 microglia/macrophages were substantially higher in O/O pairings than Y/Y pairings and not significantly reduced by Y/O pairing (Fig. 6d).”
Quote in the paperSubstantial claim - Findingown data
NG2+ OPCs within remyelinating lesions expressed both Acvr2A and Acvr2B.
“Examination of expression of receptors that directly bind activin-A, Acvr2A and Acvr2B, showed that NG2+ OPCs within remyelinating lesions expressed both subtypes (Fig. 8c).”
Quote in the paperSubstantial claim - Findingown data
M1 depletion reduced the density of PCNA+ Nkx2.2+ proliferating OPCs at 3 dpl compared to control.
“M1 depletion reduced the density of proliferating cell nuclear antigen (PCNA)+ Nkx2.2+ proliferating OPCs at 3dpl compared to control (Fig. 4d)”
Quote in the paperNot a substantial claim - Findingown data
Y/O pairing did not significantly reduce densities of CD16/32+ M1 microglia/macrophages.
“In contrast, densities of CD16/32+ M1 microglia/macrophages were substantially higher in O/O pairings than Y/Y pairings and not significantly reduced by Y/O pairing (Fig. 6d).”
Quote in the paperSubstantial claim - Findingown data
Activin-A immunoreactivity was more evident in association with MR+ M2 cells at 10 dpl compared to iNOS+ M1 cells at 3 dpl.
“we examined expression in lesions and found that activin-A immunoreactivity was more evident in association with MR+ M2 cells at 10 dpl compared to iNOS+ M1 cells at 3 dpl, and was reduced upon M2 depletion with MCLs (Fig. 8b).”
Quote in the paperSubstantial claim - Findingown data
GdCl3 injection did not significantly affect M2 cell numbers.
“GdCl3 injection did not significantly affect M2 cell numbers (Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
Following lysolecithin-induced demyelination, cerebellar slices treated with M2 CM during the initiation of remyelination showed increased numbers of CC1+ MBP+ mature oligodendrocytes.
“Following lysolecithin-induced demyelination, slices treated with M2 CM during the initiation of remyelination showed increased numbers of CC1+ MBP+ mature oligodendrocytes, which was considerably reduced with anti-activin-A blocking IgG supplementation (Fig. 8g, h).”
Quote in the paperSubstantial claim- Rests on an assumption: The ex vivo organotypic cerebellar slice culture model reflects in vivo remyelination sufficiently to test the role of activin-A in M2-driven oligodendrocyte differentiation.
- Findingown data
Supplementing cultures with M2 conditioned media and an activin-A blocking antibody reduced oligodendrocyte differentiation (MBP+ cells).
“To confirm a role for activin-A in the differentiation-promoting effect of M2 microglia, we supplemented cultures with M2 conditioned media and an activin-A blocking antibody and observed reduced oligodendrocyte differentiation (MBP+ cells) (Fig. 8e).”
Quote in the paperSubstantial claim - Findingown data
Only M2 conditioned media prevented OPC apoptosis in media deprived of serum and growth factors.
“In contrast, only M2 conditioned media prevented OPC apoptosis in media deprived of serum and growth factors (Supplementary Fig. 6 online), conditions that reveal the physiological target-dependent survival mechanisms of newly-formed oligodendrocytes in vivo.”
Quote in the paperSubstantial claim - Findingown data
M1 depletion did not impair OPC migration (as measured by numbers of NG2+ or Nkx2.2+ OPCs).
“However, OPC migration (as measured by numbers of NG2+ or Nkx2.2+ OPCs) and remyelination were not impaired (Supplementary Fig.7g, h online).”
Quote in the paperSubstantial claim - Findingown data
All MS lesion types showed significantly higher densities of iNOS+ M1 cells compared to controls.
“All lesion types showed significantly higher densities of total CD68+ microglia/macrophages and iNOS+ M1 cells compared to controls (Fig. 7d, f).”
Quote in the paperNot a substantial claim - Findingown data
OPCs within remyelinating lesions expressed Acvr1B.
“Importantly, OPCs also expressed Acvr1B, the receptor which is recruited by ligand-bound Acvr2 and which is required for subsequent functional downstream signalling33.”
Quote in the paperSubstantial claim - Findingown data
The increase in CC1+ MBP+ mature oligodendrocytes in slices treated with M2 CM was considerably reduced with anti-activin-A blocking IgG supplementation.
“which was considerably reduced with anti-activin-A blocking IgG supplementation (Fig. 8g, h).”
Quote in the paperSubstantial claim- Rests on an assumption: The ex vivo organotypic cerebellar slice culture model reflects in vivo remyelination sufficiently to test the role of activin-A in M2-driven oligodendrocyte differentiation.
- Findingown data
M1 depletion did not impair remyelination.
“However, OPC migration (as measured by numbers of NG2+ or Nkx2.2+ OPCs) and remyelination were not impaired (Supplementary Fig.7g, h online).”
Quote in the paperSubstantial claim - Findingown data
Densities of M2 microglia/macrophages (MR+ isolectin B4+ and Arg-1+ CD68+) were higher in lesions of young animals paired to another young animal (Y/Y) than in old animals paired to another old animal (O/O).
“Densities of M2 microglia/macrophages (MR+ isolectin B4+ and Arg-1+ CD68+) were higher in the lesions of young animals paired to another young animal (Y/Y) than in old animals paired to another old animal (O/O) (Fig. 6b, c).”
Quote in the paperSubstantial claim - Findingown data
M2 depletion decreased co-localization of MBP and the late myelin marker MOG.
“First, we observed decreased co-localization of MBP and the late myelin marker MOG (Supplementary Fig. 8i online).”
Quote in the paperSubstantial claim - Findingown data
M2 depletion caused an increase in the number and proportion of iNOS+ M1 cells.
“M2 depletion caused an increase in the number and proportion of iNOS+ M1 cells (Fig. 5d and Supplementary Fig. 8g online), supporting previous findings of reciprocal regulation between M1 and M2 polarization and associated cytokines25, 26.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [25] Das, J. et al. A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat. Immunol. 2, 45–50 (2001). source
- cites [26] Jang, E. et al. Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J. 27, 1176–1190 (2012). source
- Findingown data
Only M2 conditioned media increased oligodendrocyte differentiation, assessed by expression of MBP and MOG.
“Additionally, only M2 conditioned media increased oligodendrocyte differentiation, assessed by expression of myelin basic protein (MBP) (Fig. 3a, b) and myelin oligodendrocyte glycoprotein (MOG) (Fig. 3c).”
Quote in the paperSubstantial claim - Findingown data
M2 depletion decreased expression of differentiation markers MAG and MBP at 10 dpl.
“M2 depletion decreased expression of differentiation markers myelin associated glycoprotein (MAG) and MBP at 10 dpl (Fig. 5e, f), indicating a delay in oligodendrocyte differentiation.”
Quote in the paperSubstantial claim - Interpretationown data
M2 polarization is essential for efficient remyelination.
“Our results therefore show that M2 polarization is essential for efficient remyelination”
Quote in the paperSubstantial claim - Interpretationown data
Macrophages contribute equally to both M1 and M2 populations before and during the switch in polarization.
“showing that macrophages contribute equally to both M1 and M2 populations before and during the switch in polarization.”
Quote in the paperSubstantial claim - Interpretationreasoning
Young macrophages that enter the lesion in the old CNS rejuvenate the lesion environment to promote M2 polarization of endogenous populations.
“with the young macrophages that enter the lesion in the old CNS rejuvenating the lesion environment to promote M2 polarization of endogenous populations.”
Quote in the paperSubstantial claim - Interpretationown data
M1 polarization regulates OPC proliferation.
“confirming a role for M1 polarization in regulating OPC proliferation.”
Quote in the paperNot a substantial claim - Interpretationown data
M2-driven oligodendrocyte differentiation during remyelination is mediated via secretion of activin-A.
“Together, these data provide a molecular mechanism for M2-driven oligodendrocyte differentiation during remyelination via secretion of activin-A.”
Quote in the paperSubstantial claim - Interpretationown data
OPCs within remyelinating lesions have the capacity to directly bind and respond to M2-derived activin-A.
“Together, these findings indicate the capacity of OPCs within remyelinating lesions to directly bind and respond to M2-derived activin-A.”
Quote in the paperSubstantial claim - Interpretationown data
M2 depletion delays oligodendrocyte differentiation.
“indicating a delay in oligodendrocyte differentiation.”
Quote in the paperSubstantial claim - Study design and conductown data
MCLs selectively deplete M2 cells in vitro.
“We confirmed selective M2 depletion in vitro (Supplementary Fig. 8a-f online)”
Quote in the paperSubstantial claim - Study design and conductown data
MCLs injected into a lesion at 8 dpl selectively deplete M2 cells in vivo.
“and in vivo when MCLs were injected into a lesion at 8 dpl (Fig. 5b-d and Supplementary Fig. 8g, h online).”
Quote in the paperSubstantial claim - Interpretationown data
Both peripherally-derived macrophages and resident microglia contribute to the switch from M1 to M2 phenotypes observed at the initiation of remyelination.
“We conclude, therefore, that both peripherally-derived macrophages and resident microglia contribute to the switch from M1 to M2 phenotypes that we observed at the initiation of remyelination.”
Quote in the paperSubstantial claim - Interpretationown data
M2 microglia/macrophages are an essential part of an effective remyelination response.
“and that this is an essential part of an effective remyelination response.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The lysolecithin lesion model is the most appropriate to overcome the issue of overlapping de- and remyelination phases, as damage occurs at the time of toxin injection after which only the regenerative process is present.
“Our choice of lesion model is the most appropriate to overcome this issue, as damage occurs at the time of toxin injection after which only the regenerative process is present.”
Quote in the paperSubstantial claim - Interpretationown data
Increasing densities of M2 microglia/macrophages is associated with enhanced remyelination efficiency.
“Thus, increasing densities of M2 microglia/macrophages is associated with enhanced remyelination efficiency.”
Quote in the paperSubstantial claim - Interpretationown data
M2 cells have regenerative capacity in the CNS.
“in this study we have identified the regenerative capacity of M2 cells in the CNS.”
Quote in the paperSubstantial claim - Interpretationown data
M2 microglia/macrophages drive oligodendrocyte differentiation during remyelination.
“Using cell culture, in vivo manipulation of macrophage populations, parabiosis experiments and correlative analysis of human MS lesions, we showed that M2 microglia/macrophages drive oligodendrocyte differentiation during remyelination”
Quote in the paperSubstantial claim - Interpretationreasoning
The failure to observe a switch in different models of remyelination likely reflects the confounding effects of overlapping de- and remyelination phases in these models, and the consequent difficulty in establishing any correlation with the different stages of the regenerative process.
“This failure to observe a switch in different models of remyelination likely reflects the confounding effects of overlapping de- and remyelination phases in these models, and the consequent difficulty in establishing any correlation with the different stages of the regenerative process.”
Quote in the paperSubstantial claim - Interpretationown data
The reduction in oligodendrocyte differentiation by anti-activin-A blocking IgG was due to blocking of activin-A in M2 conditioned media and not endogenous activin-A.
“This was due to blocking of activin-A in M2 conditioned media and not endogenous activin-A, as treatment of slices with anti-activin-A antibody alone did not reduce the number of oligodendrocytes relative to IgG control (Fig. 8h).”
Quote in the paperSubstantial claim - Study design and conductown data
GdCl3 injection at the time of lesioning selectively depletes M1 cells within a lesion in vivo.
“and within a lesion in vivo by injection at the time of lesioning (Fig. 4a-c and Supplementary Fig. 7e, f online).”
Quote in the paperSubstantial claim - Interpretationown data
The great majority of the increased numbers of M2 cells in the older animal of the Y/O pairings derived from the microglia/macrophages of the old animal.
“The great majority of the increased numbers of M2 cells in the older animal of the Y/O pairings must therefore have derived from the microglia/macrophages of the old animal”
Quote in the paperSubstantial claim - Study design and conductown data
GdCl3 (270 μM) selectively depletes M1 cells in vitro.
“We confirmed the ability of GdCl3 (270 μM) to selectively deplete M1 cells in vitro (Supplementary Fig. 7a-c online)”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 19
- May combine two claims. 10
Classified as probably not a substantial claim. May combine two claims.
PremisecitationM1 'classically activated' phenotypes are associated with enhanced antigen presentation properties and secretion of pro-inflammatory cytokines and reactive oxygen/nitrogen species.
“In contrast, M1 ‘classically activated’ phenotypes are associated with enhanced antigen presentation properties and secretion of pro-inflammatory cytokines and reactive oxygen/nitrogen species9.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Edwards, J.P., Zhang, X., Frauwirth, K.A. & Mosser, D.M. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 80, 1298–1307 (2006). source
Classified as probably not a substantial claim.
PremisecitationM2-polarized phenotypes secrete anti-inflammatory cytokines/growth factors.
“which secrete anti-inflammatory cytokines/growth factors9.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Edwards, J.P., Zhang, X., Frauwirth, K.A. & Mosser, D.M. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 80, 1298–1307 (2006). source
The Introduction identifies both type II-activated and alternatively activated macrophages as M2 phenotypes, and the Results report that type II-activated macrophages secrete high levels of the anti-inflammatory cytokine IL-10. But the Results also report that alternatively activated macrophages secreted no detectable IL-10 under the tested conditions; the cited passages do not establish growth-factor secretion. The claim therefore overgeneralizes across M2 phenotypes. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMicroglia/macrophages exhibit regenerative properties through the phagocytosis of myelin debris and secretion of growth/neurotrophic factors.
“they also exhibit regenerative properties through the phagocytosis of myelin debris3, 4 and secretion of growth/neurotrophic factors5.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [3] Kotter, M.R., Li, W.W., Zhao, C. & Franklin, R.J.M. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci. 26, 328–332 (2006). source
- cites [4] Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012). source
- cites [5] Kotter, M.R., Zhao, C., van, R.N. & Franklin, R.J.M. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol. Dis. 18, 166–175 (2005). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRegenerative properties of microglia/macrophages following injury to muscle and skin are associated with alternative or deactivation to M2-polarized phenotypes (M2a and M2c, respectively).
“Regenerative properties of microglia/macrophages following injury to muscle6, 7 and skin8 are associated with alternative or deactivation to M2-polarized phenotypes (M2a and M2c, respectively), which secrete anti-inflammatory cytokines/growth factors9.”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [6] Ruffell, D. et al. A CREB-C/EBPbeta cascade induces M2 macrophage–specific gene expression and promotes muscle injury repair. Proc. Natl. Acad. Sci. USA 106, 17475–17480 (2009). source
The Discussion (page unavailable) links muscle regeneration to macrophages acquiring an anti-inflammatory M2 phenotype, and the paper reports impaired muscle repair when M2-specific gene expression is disrupted. It does not identify the muscle-associated phenotype specifically as M2a. The skin/M2c portion is attached to a different citation in the citing sentence, so it is not assessed against this source. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [7] Dayan, V. et al. Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res. Cardiol. 106, 1299–1310 (2011). source
- cites [8] Deonarine, K. et al. Gene expression profiling of cutaneous wound healing. J. Transl. Med. 5, 11 (2007). source
For the skin-injury portion cited to this paper, the Results (Comparison of markers of M1 and M2 macrophages; page not provided) report predominantly M2 markers later in cutaneous wound healing. The Discussion links M2 macrophages to tissue repair and angiogenesis, but does not identify the skin-associated phenotype as M2c or establish that a shift to M2 causes regeneration. The muscle-injury citations are separate from this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [9] Edwards, J.P., Zhang, X., Frauwirth, K.A. & Mosser, D.M. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 80, 1298–1307 (2006). source
The Introduction (page unavailable) says type II-activated macrophages secrete IL-10, making them anti-inflammatory. That supports the anti-inflammatory cytokine portion of the statement cited to this paper, but the cited passages do not establish secretion of growth factors or that both named M2 phenotypes secrete them. The muscle- and skin-injury portions carry different citations. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationA switch from M1- to M2-associated gene expression has been reported during cutaneous wound healing but has not been observed in studies of immune-mediated and toxin (cuprizone)-induced demyelination.
“A switch from M1- to M2-associated gene expression has been reported during cutaneous wound healing8 but has not been observed in studies of immune-mediated36 and toxin (cuprizone)-induced demyelination37.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [8] Deonarine, K. et al. Gene expression profiling of cutaneous wound healing. J. Transl. Med. 5, 11 (2007). source
- cites [36] Mikita, J. et al. Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult. Scler. 17, 2–15 (2011). source
- cites [37] Olah, M. et al. Identification of a microglia phenotype supportive of remyelination. Glia 60, 306–321 (2012). source
Classified as probably not a substantial claim.
PremisecitationAcvr1B is required for subsequent functional downstream signalling following recruitment by ligand-bound Acvr2.
“the receptor which is recruited by ligand-bound Acvr2 and which is required for subsequent functional downstream signalling33.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [33] Attisano, L., Wrana, J.L., Montalvo, E. & Massague, J. Activation of signaling by the activin receptor complex. Mol. Cell Biol. 16, 1066–1073 (1996). source
The Abstract says ligand-bound ActR-IIB associates with ActR-IB, and that ActR-IB acts as a downstream transducer whose GS-domain mutations abrogate signal propagation. This supports the recruitment and signalling mechanism, but the studied type II receptor is ActR-IIB, not the specifically named Acvr2. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTGFβ isoforms induce myelin protein expression.
“Additionally, TGFβ isoforms have been shown to induce myelin protein expression42, 43.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [42] Diemel, L.T., Jackson, S.J. & Cuzner, M.L. Role for TGF-beta1, FGF-2 and PDGF-AA in a myelination of CNS aggregate cultures enriched with macrophages. J. Neurosci. Res. 74, 858–867 (2003). source
- cites [43] McKinnon, R.D., Piras, G., Ida, J.A. Jr. & Dubois-Dalcq, M. A role for TGF-beta in oligodendrocyte differentiation. J. Cell Biol. 121, 1397–1407 (1993). source
The Results report that recombinant TGF-β1 increased the proportion of cultured O-2A cells expressing galactocerebroside, a marker of oligodendrocyte differentiation (Fig. 8). Galactocerebroside is not a protein, and the passages do not show that TGF-β isoforms induce myelin protein expression. The isoform-expression Results (p. 1399) identify TGF-β2 and TGF-β3 in oligodendrocytes but do not test their effect on myelin proteins. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationM1 and M2-associated genes were significantly upregulated in a microarray screen of a remyelinating lesion of the rat caudal cerebellar peduncles in vivo.
“A custom qPCR array plate (SABiosciences) was designed to include primers for M1 and M2-associated genes that were detected as being significantly upregulated in a microarray screen of a remyelinating lesion of the rat caudal cerebellar peduncles in vivo18.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Huang, J.K. et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci. 14, 45–53 (2011). source
The Results section, “Increased Rxrg transcripts in CNS remyelinating lesions” (page unavailable), reports a microarray screen of rat caudal cerebellar peduncle lesions and identifies significantly differentially expressed genes, including inflammation-associated genes expressed more highly at 5 days post-lesion. Our copy does not identify those genes as M1- or M2-associated or establish that the genes selected for the citing paper’s qPCR plate were significantly upregulated. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSignalling pathways downstream of activin receptor activation include Rac/Cdc42 GTPases, Akt, and mTOR, all of which have been previously implicated in positively regulating oligodendrocyte differentiation and/or myelination.
“In accordance with our finding, signalling pathways downstream of activin receptor activation include Rac/Cdc42 GTPases, Akt, and mammalian target of rapamycin (mTOR), all of which have been previously implicated in positively regulating oligodendrocyte differentiation and/or myelination38-41.”
Quote in the paperNot a substantial claim4 of 4 sources checked- cites [38] Liang, X., Draghi, N.A. & Resh, M.D. Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes. J. Neurosci. 24, 7140–7149 (2004). source
- cites [39] Thurnherr, T. et al. Cdc42 and Rac1 signaling are both required for and act synergistically in the correct formation of myelin sheaths in the CNS. J. Neurosci. 26, 10110–10119 (2006). source
- cites [40] Flores, A.I. et al. Constitutively active Akt induces enhanced myelination in the CNS. J. Neurosci. 28, 7174–7183 (2008). source
- cites [41] Guardiola-Diaz, H.M., Ishii, A. & Bansal, R. Erk1/2 MAPK and mTOR signaling sequentially regulates progression through distinct stages of oligodendrocyte differentiation. Glia 60, 476–486 (2012). source
The Discussion (page not supplied) reports that mTOR signaling is required for a late stage of oligodendrocyte differentiation and the onset of myelination, and discusses enhanced myelination with an overactive PI3K/Akt/mTOR pathway. It does not establish that Rac/Cdc42 positively regulate these processes or that the listed pathways act downstream of activin receptor activation. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataMicroglia rapidly depolarize in the absence of polarizing factors, requiring polarizing factors to be present during conditioning of media.
“The rapid depolarization of microglia in the absence of polarizing factors (data not shown) required these to be present during conditioning of media”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataGFP+ iNOS+ CD68+ M1 macrophages and GFP+ Arg-1+ CD68+ M2 macrophages present within the lesion contributed to 3.6 ± 1.6 % of iNOS+ M1 cells and 12.4 ± 5 % of Arg-1+ M2 cells.
“GFP+ iNOS+ CD68+ M1 macrophages and GFP+ Arg-1+ CD68+ M2 macrophages present within the lesion (Fig. 6f) only contributed to 3.6 ± 1.6 % of iNOS+ M1 cells and 12.4 ± 5 % of Arg-1+ M2 cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAcvr2 is expressed by CC1+ oligodendrocytes (Acvr2B+) and CD68+ microglia/macrophages (Acvr2A+, Acvr2B+), but not by GFAP+ astrocytes or NF+ axons.
“Assessment of activin-A binding capacity of other cell types within lesions indicates that Acvr2 is expressed by CC1+ oligodendrocytes (Acvr2B+) and CD68+ microglia/macrophages (Acvr2A+, Acvr2B+), but not by GFAP+ astrocytes or NF+ axons (Supplementary Fig. 9 online).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataContaminating astrocytes were less than 7% of the culture in all microglia polarization states.
“Contaminating astrocytes were < 7% of the culture in all polarization states (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll manual cell counts were performed in a blinded manner.
“All manual cell counts were performed in a blinded manner.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataEach transfilter microchemotaxis condition was performed in quadruplicate wells and repeated with 3 independent OPC samples and 3 conditioned media samples.
“Each condition was performed in quadruplicate wells and the experiment was repeated with 3 independent OPC samples and 3 conditioned media samples.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataDiagnosis of MS was confirmed by neuropathological means and clinical history.
“Diagnosis of MS was confirmed by neuropathological means by Dr F. Roncaroli (Consultant Neuropathologist, Imperial College London) and clinical history was provided by Dr R. Nicholas (Consultant Neurologist, Imperial College London)”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataELISAs used 3-5 independent supernatant sets.
“3-5 independent supernatant sets were used.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductown dataMicroglia polarization under serum-free growth conditions was successful.
“successful polarization under these growth conditions was confirmed (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenNo statistical methods were used to predetermine sample sizes, but sample sizes were similar to those generally employed in the field.
“No statistical methods were used to predetermine sample sizes but these were similar to those generally employed in the field.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAll assays represent a minimum of 3 independent experiments treated with conditioned media from at least 3 microglial preparations.
“All assays represent a minimum of 3 independent experiments treated with conditioned media from at least 3 microglial preparations.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlatiramer acetate induces a peripheral M2 phenotype.
“whereas glatiramer acetate induces a peripheral M2 phenotype48”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Weber, M.S. et al. Type II monocytes modulate T cell–mediated central nervous system autoimmune disease. Nat. Med. 13, 935–943 (2007). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe CNS-permeable therapy FTY720 decreases peripheral M1 and M2 polarization in rodents.
“the CNS-permeable therapy FTY720 decreases peripheral M1 and M2 polarization in rodents47”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Schaier, M. et al. Role of FTY720 on M1 and M2 macrophages, lymphocytes, and chemokines in 5/6 nephrectomized rats. Am. J. Physiol. Renal Physiol. 297, F769–F780 (2009). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAntibody isotype controls added to sections at the same final concentration as the respective primary antibodies showed little or no non-specific staining.
“Antibody isotype controls (Sigma) added to sections at the same final concentration as the respective primary antibodies showed little or no non-specific staining.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Remyelination can occur efficiently following CNS demyelination.
“Remyelination, the formation of myelin sheaths around demyelinated axons by newly differentiated oligodendrocytes, can occur efficiently following central nervous system (CNS) demyelination.”
The paper relies on this without support.
Microglia/macrophages are a major component of the innate immune response in CNS remyelination.
“A major component of this regenerative process is a robust innate immune response consisting of peripherally-derived macrophages and their CNS-resident counterparts, microglia.”
The paper relies on this without support.
M2 cell densities in MS lesions indicate areas of ongoing remyelination.
“both areas of recent damage where ongoing remyelination would be expected.”
The paper relies on this without support.
The ex vivo organotypic cerebellar slice culture model reflects in vivo remyelination sufficiently to test the role of activin-A in M2-driven oligodendrocyte differentiation.
“we investigated the role of activin-A in M2-driven oligodendrocyte differentiation during remyelination in intact CNS using ex vivo organotypic cerebellar slice cultures”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the lysolecithin-induced model of demyelination, Miron et al. (2013) identified a subset of microglia present during the remyelination stage that expressed ARG1 + IGF1 + CD206+; these microglia likely secrete factors that promote OPC differentiation as their conditioned media promoted OPC differentiation in vitro, and their selective depletion in vivo impaired remyelination.
“For example, using the lysolecithin‐induced model of demyelination, Miron et al. (2013) identified a subset of microglia present during the remyelination stage that expressed ARG1 + IGF1 + CD206+; these microglia likely secrete factors that promote OPC differentiation as their conditioned media promoted OPC differentiation in vitro, and their selective depletion in vivo impaired remyelination.”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Miron et al. 2013
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMultiple sclerosis, ALS, and spinal cord injury are associated with chronic activation of resident immune cells, microglia.
“These disorders (e.g. multiple sclerosis, ALS, spinal cord injury) are associated with chronic activation of resident immune cells, microglia2–4.”
From Central nervous system regeneration is driven by microglia necroptosis and repopulation (2019) · cites this paper as [3]
The Results section (“Increased M2 densities during efficient remyelination”; page unavailable) reports elevated microglia/macrophage and M1-cell densities in MS lesions, including chronic lesions, supporting the MS portion of the claim. The Discussion mentions studies of neuronal injury, and the references list ALS and injured-spinal-cord studies, but this paper does not establish chronic microglial activation in ALS or spinal cord injury. (LLM, conf=0.86)
Experimental — accuracy not yet measuredResolution of pro-inflammatory microglia activation via a transition to a pro-regenerative microglia state initiates remyelination.
“Resolution of pro-inflammatory microglia activation (iNOS+ TNFα+ CCL2+) via a transition to a pro-regenerative microglia state (Arg-1+ CD206+ IGF-1+) initiates remyelination3.”
From Central nervous system regeneration is driven by microglia necroptosis and repopulation (2019) · cites this paper as [3]
The Results section, “An M1 to M2 switch at the initiation of remyelination” (page unavailable), reports an M1-to-M2 shift as remyelination begins and identifies iNOS and TNFα as M1 markers and Arg-1, mannose receptor, and IGF-1 as M2 markers. The Discussion says M2 microglia/macrophages drive oligodendrocyte differentiation. The copy does not identify CCL2 as a marker of the pro-inflammatory state, and it describes the switch as occurring at the initiation of remyelination rather than establishing that the switch itself initiates it. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRemyelination is impaired when the transition from pro-inflammatory to pro-regenerative microglia is prevented by depletion of pro-regenerative microglia, or when it fails, identified by prolonged pro-inflammatory microglia presence in aged mice and chronic human brain lesions.
“Remyelination is impaired when this transition is prevented (by depletion of pro-regenerative microglia), or when it fails, identified by prolonged pro-inflammatory microglia presence in aged mice and chronic human brain lesions3.”
From Central nervous system regeneration is driven by microglia necroptosis and repopulation (2019) · cites this paper as [3]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe differentiation of local oligodendrocyte progenitor cells into actively myelinating oligodendrocytes is stimulated by innate immune cells.
“Recent data have indicated that the differentiation of local oligodendrocyte progenitor cells into actively myelinating oligodendrocytes is stimulated by innate immune cells.64-67”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [64]
In the lysolecithin model of white matter demyelination, microglia can secrete pro-regenerative factors during recovery time points that enable OPC differentiation and oligodendrocyte regeneration.
“In the lysolecithin model of white matter demyelination, microglia can secrete pro‐regenerative factors during recovery time points that enable OPC differentiation and oligodendrocyte regeneration (Miron et al. 2013).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Miron et al. 2013
Previous studies of white matter demyelination models showed that reactive microglia can support oligodendrocyte regeneration.
“Our finding that cortical reactive microglia impair oligodendrocyte differentiation post‐cuprizone is unexpected, as previous studies of white matter demyelination models showed that reactive microglia can support oligodendrocyte regeneration (Baaklini et al. 2023; Miron et al. 2013).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Miron et al. 2013
White matter microglia can adopt pro-regenerative reactive states.
“Together, these studies indicate that white matter microglia can adopt pro‐regenerative reactive states.”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Miron et al. 2013
Microglia have been previously shown to promote remyelination independent of debris clearance.
“Whether this prolonged inflammatory response is beneficial for remyelination remains unclear, but microglia have been previously shown to promote remyelination independent of debris clearance55–57.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [57]
Microglia have a dynamic role in physiological and injury-induced remyelination.
“microglia play a dynamic role in physiological and injury-induced remyelination (Miron et al., 2013)”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Miron et al., 2013
In vitro, conditioned media derived from microglia in an induced pro-inflammatory M1-like state reduces survival of oligodendrocytes, whereas conditioned media from microglia in an induced anti-inflammatory M2-like state promotes remyelination.
“In vitro, conditioned media derived from microglia in an induced pro-inflammatory ‘M1-like’ state reduces survival of oligodendrocytes in vitro, whereas conditioned media from microglia in an induced anti-inflammatory ‘M2-like’ state promotes remyelination [111,113].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [113]
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Defective cholesterol clearance limits remyelination in the aged central nervous system
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“It has been shown that microglia/macrophages exhibit a more M1-like phenotype during OPC recruitment and that there is a switch toward a M2 phenotype to allow OPC maturation (Boven et al., 2006; Miron et al., 2013).”
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Self-citationThe impact of microglial activation on blood-brain barrier in brain diseases
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Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
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Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology
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TMEM119 marks a subset of microglia in the human brain
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“Microglia regenerative expression profile involves genes related to phagocytosis, breakdown of myelin debris, as well as secretion of regenerative factors and tissue remodeling [36, 49] that can drive OPC differentiation [29, 32].”
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The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review
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“Other reports suggest, however, that myeloid cells can aid recovery by promoting remyelination (Miron et al., 2013), secreting neuroprotective mediators (Butovsky et al., 2006), and promoting phagocytosis of growth-inhibitory myelin debris (Piccio et al., 2007).”
Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions
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Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis
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“For example, anti-inflammatory compounds such as activin-A, and activation of retinoid X receptor g (RXR-g ) have been shown to promote remyelination, and may therefore also promote myelination during development (Huang et al., 2011; Miron et al., 2013) (Table 1).”
Microglia and the brain: Complementary partners in development and disease
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Multiple Sclerosis: Immunopathology and Treatment Update
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- Authors
- Miron, V. E., Boyd, A., Zhao, J.-W., Yuen, T. J., Ruckh, J. M., Shadrach, J. L., van Wijngaarden, P., Wagers, A. J., Williams, A., Franklin, R. J. M., & ffrench-Constant, C.
- Affiliations
- MRC Centre for Regenerative Medicine (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Howard Hughes Medical Institute (US)
- Venue
- Nature Neuroscience
- Published
- 2013-07-21
- Volume
- 16
- Issue
- 9
- Pages
- 1211-1218
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3977045
- OpenAlex
- W1977213877
- Cited by
- 1,788
- References
- 48
- Citations by year
- 2026: 85 · 2025: 110 · 2024: 147 · 2023: 144 · 2022: 169 · 2021: 176 · 2020: 153 · 2019: 141 · 2018: 146 · 2017: 133 · 2016: 124 · 2015: 112 · 2014: 81 · 2013: 14
- FWCI
- 73.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- M2 microglia, macrophage polarization, oligodendrocyte differentiation, activin A, TGF-beta, multiple sclerosis, demyelination, parabiosis
- MeSH terms
- Adult, Aged, Aged, 80 and over, Animals, Animals, Newborn, Cell Differentiation
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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