The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index; 19 of the 29 sources its claims cite were checked for support.
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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Claims the paper makes
19 of 29 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > Increased M2 densities during efficient remyelination
What the sources say
- Supportedcites [4] Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012). source
The citation is attached to the statement that young–old pairing restores remyelination in the older animal, not to the citing paper’s Fig. 6 finding about M2-cell density. The Results section reports significantly improved remyelination in heterochronic-old animals compared with isochronic-old controls. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > M2 depletion inhibits oligodendrocyte differentiation
What the sources say
- Supportedcites [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
The Results (Axin2 protein stabilization promotes OLP differentiation; page unavailable) identify Caspr-positive paranodes as an indicator of node-of-Ranvier density in an assay of myelination. The citing authors present the M2-depletion result and Ankyrin-G staining as their own observations, not findings attributed to this source. (LLM, conf=0.88)
- Supportedcites [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
The citation attaches to the statement that nodes of Ranvier indicate compact myelin, not to the citing authors’ observation of fewer nodes after M2 depletion. In “CXCL13 and endothelin 2 promote myelination,” the source links compact-myelin formation to paranodal Caspr localization at nodes of Ranvier and confirms compact myelin by electron microscopy. The Discussion’s Fig. 2 caption likewise describes node formation as confirmation of myelination. (LLM, conf=0.91)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Discussion
What the sources say
- Supportedcites [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
The Abstract states that maturing progenitors were only rarely present in chronic multiple sclerosis lesions and identifies a differentiation block as a major determinant of remyelination failure. The Discussion likewise reports that progenitors remain in chronic lesions but do not mature into oligodendrocytes. (LLM, conf=0.94)
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In the paper
“and Arg-1+ M2 cells (to 8 ± 8 and 40 ± 13 % of wildtype controls at 3 and 10 dpl, respectively).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > An M1 to M2 switch at the initiation of remyelination
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“M2 densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger animal”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > An M1 to M2 switch at the initiation of remyelination
What the sources say
- Not checked — no full text of the sourcecites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and in MS lesions that normally show remyelination”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > An M1 to M2 switch at the initiation of remyelination
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At 21 dpl, there was a reduction in Arg-1+ M2 cells compared to 10 dpl (Fig. 1b, c).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > An M1 to M2 switch at the initiation of remyelination
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, by 10 dpl there were more Arg-1+ CD68+ M2 cells than iNOS+ CD68+ M1 cells (Fig. 1b, c).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > An M1 to M2 switch at the initiation of remyelination
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- Probably not a substantial claim. 19
- It may state two separate claims as one. 10
Every source the paper cites for this claim was checked and supports it.
In the paper
“In contrast, M1 ‘classically activated’ phenotypes are associated with enhanced antigen presentation properties and secretion of pro-inflammatory cytokines and reactive oxygen/nitrogen species9.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Abstract
What the sources say
- Supportedcites [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 says classically activated macrophages produce oxygen and nitrogen radicals and secrete inflammatory cytokines. The Results section on antigen presentation reports that they up-regulate MHC Class II and CD86 and induce T-cell activation, supporting enhanced antigen-presenting properties; it also notes that Type II-activated macrophages showed still higher expression. (LLM, conf=0.92)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“which secrete anti-inflammatory cytokines/growth factors9.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Abstract
What the sources say
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“they also exhibit regenerative properties through the phagocytosis of myelin debris3, 4 and secretion of growth/neurotrophic factors5.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Abstract
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [4] Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012). source
This source is cited for myelin-debris phagocytosis, not for growth/neurotrophic-factor secretion, which has a separate citation. The Results section reports that young macrophages enhance remyelination by clearing inhibitory myelin debris; the Discussion likewise identifies their greater debris-clearance capacity as central to this effect. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Abstract
What the sources say
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [8] Deonarine, K. et al. Gene expression profiling of cutaneous wound healing. J. Transl. Med. 5, 11 (2007). sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Discussion
What the sources say
- Supportedcites [8] Deonarine, K. et al. Gene expression profiling of cutaneous wound healing. J. Transl. Med. 5, 11 (2007). source
The Results (‘Comparison of markers of M1 and M2 macrophages’) report that early wound-healing expression included 11 M1 and seven M2 markers, while later expression included nine M2 and one M1 marker. The citation to this paper attaches to the cutaneous wound-healing clause, not the demyelination comparison. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [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
- Supportedcites [37] Olah, M. et al. Identification of a microglia phenotype supportive of remyelination. Glia 60, 306–321 (2012). source
Citation 37 attaches to the cuprizone-induced demyelination clause, not the separate claims about wound healing or immune-mediated demyelination. In the Discussion (page unavailable), the authors report no evidence for distinct demyelination- and remyelination-associated microglial phenotypes. The Microglia Phenotype section likewise reports that both M1- and M2-associated markers increased during demyelination and remyelination, supporting the absence of an observed M1-to-M2 switch in this model. (LLM, conf=0.93)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
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In the paper
“the receptor which is recruited by ligand-bound Acvr2 and which is required for subsequent functional downstream signalling33.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > M2-derived activinA drives oligodendrocyte differentiation
What the sources say
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Partly supported
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In the paper
“Additionally, TGFβ isoforms have been shown to induce myelin protein expression42, 43.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Discussion
What the sources say
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
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)
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > RNA extraction, reverse transcription, and quantitative real-time polymerase chain reaction array (qRT-PCR)
What the sources say
- Partly supportedcites [18] Huang, J.K. et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci. 14, 45–53 (2011). sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
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In the paper
“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.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Discussion
What the sources say
- Supportedcites [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
The Results section (‘Rho family GTPases regulate OPC morphologic differentiation’) reports that dominant-negative Cdc42 or Rac1 inhibited oligodendrocyte morphologic differentiation. The Discussion reports that activated Rac and Cdc42 promoted more highly differentiated cells. This supports the Rac/Cdc42 portion for which this paper is cited in the multi-citation sentence; the activin-receptor framing is the citing authors’ own finding. (LLM, conf=0.90)
- Supportedcites [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
The Introduction and the section ‘Rac1 is required for proper axon ensheathment and myelination’ identify Cdc42 and Rac1 as important for CNS myelination. This supports the part of the multi-citation sentence for which this paper is offered: that Rac/Cdc42 signaling has been implicated in myelination. (LLM, conf=0.90)
- Supportedcites [40] Flores, A.I. et al. Constitutively active Akt induces enhanced myelination in the CNS. J. Neurosci. 28, 7174–7183 (2008). source
For the Akt component of this multi-citation sentence, the Introduction reports that constitutively active Akt enhanced oligodendrocyte maturation and increased CNS myelin production in transgenic mice. The copy does not provide a page number. (LLM, conf=0.92)
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The rapid depolarization of microglia in the absence of polarizing factors (data not shown) required these to be present during conditioning of media”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Microglia polarization
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > Increased M2 densities during efficient remyelination
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Results > M2-derived activinA drives oligodendrocyte differentiation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Contaminating astrocytes were < 7% of the culture in all polarization states (data not shown).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Microglia polarization
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“All manual cell counts were performed in a blinded manner.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Quantification and statistical analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each condition was performed in quadruplicate wells and the experiment was repeated with 3 independent OPC samples and 3 conditioned media samples.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Transfilter microchemotaxis assays
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Multiple Sclerosis Tissue
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“3-5 independent supernatant sets were used.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Microglia polarization
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“successful polarization under these growth conditions was confirmed (data not shown).”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Microglia and OPC Culture
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical methods were used to predetermine sample sizes but these were similar to those generally employed in the field.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Quantification and statistical analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All assays represent a minimum of 3 independent experiments treated with conditioned media from at least 3 microglial preparations.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Microglia and OPC Culture
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“whereas glatiramer acetate induces a peripheral M2 phenotype48”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Discussion
What the sources say
- Not checked — no full text of the sourcecites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the CNS-permeable therapy FTY720 decreases peripheral M1 and M2 polarization in rodents47”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > Discussion
What the sources say
- Not checked — no full text of the sourcecites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Antibody isotype controls (Sigma) added to sections at the same final concentration as the respective primary antibodies showed little or no non-specific staining.”
§ M2 microglia/macrophages drive oligodendrocyte differentiation during CNS remyelination > ONLINE METHODS > Immunohistochemistry
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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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Remyelination alters the pattern of myelin in the cerebral cortex
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Microglia and inflammation: conspiracy, controversy or control?
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The Dynamic Inflammatory Tissue Microenvironment: Signality and Disease Therapy by Biomaterials
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“For instance, the protein activin-A that guides differentiation of oligodendrocytes during remyelination of the central nervous system (CNS) is a critical macrophage-derived proreparative factor, and inhibition of M2-derived activin-A protein blocks the differentiation of oligodendrocytes during remyelination in cultu…”
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The Molecular Basis for Remyelination Failure in Multiple Sclerosis
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Immune modulation of hair follicle regeneration
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Oligodendrocytes and Microglia: Key Players in Myelin Development, Damage and Repair
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Anti-inflammatory Microglia/Macrophages As a Potential Therapeutic Target in Brain Metastasis
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Metadata
- 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)
- ORCID
- 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
- Semantic Scholar
- 15842749de36d7c3a388eaecb4b8ac95eadf69d4
- Cited by
- 1,777
- References
- 48
- Citations by year
- 2026: 108 · 2025: 111 · 2024: 147 · 2023: 145 · 2022: 171 · 2021: 175 · 2020: 155 · 2019: 141 · 2018: 150 · 2017: 139 · 2016: 129 · 2015: 111 · 2014: 80 · 2013: 14
- FWCI
- 66.06
- 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) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Wellcome Trust (079249, 089000)
- Topics
- Health Sciences › Medicine › Clinical Neurology › 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, central nervous system regeneration, microglia
- MeSH terms
- Adult, Aged, Aged, 80 and over, Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Central Nervous System, Demyelinating Diseases, Clodronic Acid, Female, Humans, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Myelin Proteins, Oligodendroglia, Regeneration, Culture Media, Conditioned, Rats, Sprague-Dawley, Microglia, Cadmium Chloride, Mice, Rats, In Vitro Techniques
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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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