Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination
Open accessAbstract
Cortical demyelination is a critical contributor to progressive disease in multiple sclerosis (MS). The barriers to cortical remyelination following demyelination are not fully understood, and there are no remyelinating treatments for MS. We previously took advantage of the spatial and temporal resolution of longitudinal in vivo imaging to study cortical oligodendrocyte regeneration following cuprizone‐induced demyelination and found that oligodendrocyte regeneration was impaired. In this study, we investigated whether cortical reactive microglia disrupt oligodendrocyte regeneration. To do so, we used a combination of in situ RNA and immunofluorescence labeling to characterize cortical microglia reactive states following cuprizone‐mediated demyelination. We then depleted cortical microglia by administering a Csf1r inhibitor during the recovery period from cuprizone and quantified oligodendrocyte recovery. We found that following cortical demyelination, deep cortical microglia change morphology, downregulate homeostatic markers (P2RY12, TMEM119), and upregulate a marker (CD68) associated with activated macrophages. These reactive changes persisted through early recovery post‐cuprizone but resolved by late recovery. Depleting cortical microglia post‐cuprizone restored the baseline density of deep cortical ASPA+ oligodendrocytes at early and late recovery. There were also more deep cortical BCAS1+ differentiating oligodendrocytes at early recovery when microglia were depleted, suggesting that transient deep cortical reactive microglia impair oligodendrocyte differentiation following demyelinating injury. Together, we found that cortical microglia adopt spatially restricted reactive functions after demyelination and deep cortical reactive microglia transiently reduce differentiating oligodendrocytes. A potential therapeutic strategy for progressive MS could involve targeting transiently reactive microglia at the right time and place in cortical lesions to promote oligodendrocyte regeneration.
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TL;DR
In cuprizone-induced cortical demyelination, deep cortical microglia become transiently reactive and impair oligodendrocyte regeneration; depleting microglia with a Csf1r inhibitor during recovery restored deep cortical ASPA+ oligodendrocyte density to baseline and increased early BCAS1+ differentiating oligodendrocytes. These effects were not seen in sham-treated cortex, suggesting a reactive microglia-specific barrier.
Key findings
- Deep cortical microglia adopted a reactive state after cuprizone: increased Iba1+ cell numbers in deep cortex (31.4 ± 1.8 baseline vs. 67.6 ± 9.6 cuprizone, p = 0.0014; 73.89 ± 3.3 early recovery, p = 0.0001), downregulated P2RY12 and TMEM119, and upregulated CD68; this persisted through early recovery and resolved by late recovery, while superficial microglia largely remained homeostatic.
- Deep cortical ASPA+ oligodendrocytes were reduced after cuprizone and at early and late recovery versus baseline (baseline n = 4 vs. cuprizone n = 5, p = 0.0010; vs. early recovery n = 5, p < 0.0001; vs. late recovery n = 6, p = 0.0108), with no significant change in NG2+ OPC number and no compensatory increase in BCAS1+ differentiating oligodendrocytes.
- Post-cuprizone PLX-3397 restored deep cortical ASPA+ oligodendrocyte density to baseline at early and late recovery; full cortical ASPA+ cells were ~3-fold higher at early recovery with PLX-3397 (30.9 ± 6.21 vs. 90.5 ± 11.66, p = 0.0328). Early recovery also had more BCAS1+ cells (17.6 ± 2.03 vs. 30.5 ± 1.68, p = 0.0203), with ~2-fold more in deep cortex and more pre-myelinating BCAS1+ cells (p = 0.0163), but no difference in early-myelinating BCAS1+ or BCAS1+GFP+ cells; only 3.57% ± 1.79 of deep cortical BCAS1+ cells expressed CC3.
- In sham-fed mice, PLX-3397 depleted microglia (full cortex 89.7 ± 2.21 vs. 15.17 ± 5.86, p < 0.0001; deep cortex 31.4 ± 1.81 vs. 5.0 ± 1.83, p < 0.0001) without changing ASPA+ oligodendrocyte numbers or MBP myelin coverage. PLX-5622 was less robust than PLX-3397, and cortical GFAP+ astrocyte numbers were unchanged by microglia depletion.
Methods
- Adult mice of both sexes were used: C57BL/6, Mobp-eGFP, and Cx3Cr1-eGFP mice. Mice received 0.2% w/v cuprizone for 4 weeks, then recovered for 2 weeks (“early”) or 5 weeks (“late”); Csf1r inhibitors PLX-3397 (290 ppm) or PLX-5562/PLX-5622 (1200 ppm) were given during recovery, with sham controls.
- Immunofluorescence and in situ RNA labeling (RNAscope) quantified ASPA+ oligodendrocytes, MBP+ myelin, NG2+ OPCs, BCAS1+ differentiating oligodendrocytes, Iba1+/GFP+ microglia, P2RY12, CD68, TMEM119, GFAP, and CC3. Cortical regions were divided into superficial (0–250 μm), middle (250–500 μm), and deep (500–750 μm) zones relative to the pial surface; blinded observers performed cell counts and morphology classification.
- Statistical comparisons used one-way ANOVA with Tukey correction unless otherwise specified; n represents animals per experiment; data are mean ± SEM, with significance at p < 0.05.
Limitations
- Stated: PLX-3397 did not fully eliminate microglia, and surviving deep cortical microglia in PLX-treated mice could be pro-regenerative; individual Csf1r inhibitors may have unexplored off-target effects on oligodendrocyte lineage cells.
- Stated: the study could not distinguish surviving baseline oligodendrocytes from newly formed oligodendrocytes, and increased ASPA+ cells at early recovery could represent dying, surviving, and newly formed cells; fate-tracing is needed, including to assess delayed clearance. The current immunostaining approach also did not detect subtle changes in oligodendrocyte density within the full cortical region, and no significant myelin density change was found with PLX-3397.
- Evident: findings are from the mouse cuprizone model rather than MS tissue, and despite using both sexes, no sex-disaggregated analyses are reported; PLX-5622 effects were less robust than PLX-3397, with late-recovery ASPA+ numbers not significantly different from baseline.
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Claims the paper makes
37 of 51 cited sources checked · 18 supported · 1 flagged · accuracy not yet measured
- Findingown data
There are no significant changes in OPC number in the deep cortex following cuprizone or recovery.
“Similar to our prior study (Orthmann‐Murphy et al. 2020), we found no significant changes in OPC number in the deep cortex (Figure 1G, also see Figure S1C).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
In Results, under “Layer specific differences in cortical remyelination” (page unavailable), the paper reports no evidence of persistent OPC depletion during recovery in deeper cortical layers (p=0.086). That supports the recovery portion, but the passage does not establish that OPC number was unchanged immediately following cuprizone treatment. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Findingcitation
Even in the presence of Csf1r inhibitor, deep cortical reactive astrocytes persistently upregulate GFAP.
“Similar to our previous findings (Orthmann‐Murphy et al. 2020), even in the presence of Csf1r inhibitor, deep cortical reactive astrocytes persistently upregulate GFAP (Figure S5B).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
The Results section, “Layer specific differences in cortical remyelination” (page unavailable), reports that GFAP expression in deeper cortical astrocytes remained elevated throughout recovery and that the cells retained a reactive morphology. It does not report this finding in the presence of a Csf1r inhibitor, so the inhibitor condition is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Loss and formation of oligodendrocytes overlapped in early recovery.
“Due to the exquisite spatial and temporal resolution of in vivo imaging, we also showed that the loss and formation of oligodendrocytes overlapped in early recovery, a finding that is difficult to appreciate by immunostaining alone.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
- Premisecitation
Depletion of microglia using a Csf1r inhibitor either before or during cuprizone administration led to delayed or reduced demyelination in the corpus callosum.
“Depletion of microglia, using an inhibitor of colony stimulating factor 1 receptor (Csf1r) either before or during cuprizone administration, led to delayed or reduced demyelination in the corpus callosum (Marzan et al. 2021).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Marzan et al. 2021 source
- Premisecitation
Nearly all oligodendrocytes present at 5 weeks recovery were newly formed.
“Nearly all oligodendrocytes present at 5 weeks (“late”) recovery were newly formed.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
- Interpretationreasoning
Many of the early recovery BCAS1+ cells formed in PLX-treated mice become stably incorporated into the late recovery cortex.
“Given that deep cortical ASPA+ oligodendrocytes recovered to baseline levels at late recovery only in PLX‐treated mice, but not cuprizone‐only treated mice (Figure 5), and late recovery oligodendrocytes are predominantly represented by newly formed cells (Orthmann‐Murphy et al. 2020), we suspect that many of these early recovery BCAS1+ cells formed in PLX‐treated mice become stably incorporated in”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
- Premisecitation
In the healthy adult cortex, most differentiating oligodendrocytes do not survive.
“We previously showed in the healthy adult cortex that most differentiating oligodendrocytes do not survive (Hughes et al. 2018).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hughes et al. 2018 source
- Premisecitation
The amoeboid morphology and upregulation of CD68 of deep cortical reactive microglia are reminiscent of the previously characterized early developmental subset of microglia that phagocytose OPCs prior to the onset of myelination in the corpus callosum.
“Their amoeboid morphology and upregulation of CD68 are reminiscent of the previously characterized early developmental subset of microglia that phagocytose OPCs prior to the onset of myelination in the corpus callosum (Irfan et al. 2022).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Irfan et al. 2022 source
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
- Premisecitation
White matter microglia can adopt pro-regenerative reactive states.
“Together, these studies indicate that white matter microglia can adopt pro‐regenerative reactive states.”
Quote in the paperSubstantial claim1 of 2 sources checked - Interpretationcitation
There are likely overlapping pathogenic roles of cortical reactive microglia, especially at early recovery.
“In fact, there are likely overlapping pathogenic roles of cortical reactive microglia, especially at early recovery (Orthmann‐Murphy et al. 2020).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
The Results section on layer-specific cortical remyelination discusses reactive astrocytes during recovery, not reactive microglia. The Discussion on cortical OPC regeneration considers possible effects of inflammation but does not assign overlapping pathogenic roles to microglia, particularly in early recovery. Searches for reactive microglia and early-recovery inflammation found no passage addressing that claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
- Findingown data
At late recovery, the total number of ASPA+ oligodendrocytes in the full cortical region is similar to baseline.
“At late recovery, the total number of ASPA+ oligodendrocytes is similar to baseline (Figures 1B and S1A).”
Quote in the paperNot a substantial claim - Findingown data
The number of deep cortical BCAS1+ oligodendrocytes was similar to baseline at all time points.
“Instead, we found that the number of deep cortical BCAS1+ oligodendrocytes was similar to baseline at all time points (Figures 1H,I and S1D).”
Quote in the paperSubstantial claim - Findingown data
There are no significant changes in the number of superficial ASPA+ oligodendrocytes at any time point.
“We did not detect significant changes in the number of superficial ASPA+ oligodendrocytes at any time point (Figure S1A)”
Quote in the paperSubstantial claim - Findingown data
By late recovery, CD68 expression decreased and appeared similar to baseline across all cortical depths.
“By late recovery, CD68 expression decreased and appeared similar to baseline across all cortical depths.”
Quote in the paperNot a substantial claim - Findingown data
Following cuprizone-induced demyelination, deep cortical microglia change morphology to a reactive state.
“Reactive microglia morphology appeared in deep cortical regions after 4 weeks of cuprizone (Figure 2A,B) and persisted at early recovery.”
Quote in the paperNot a substantial claim - Findingown data
In the deep cortical region, MBP signal becomes patchy at early recovery.
“In the deep cortical region, MBP signal becomes patchy at early recovery (Figure 1D).”
Quote in the paperNot a substantial claim - Findingown data
The increase in Iba1+ cells after cuprizone and through early recovery was primarily due to higher numbers of Iba1+ microglia in the deep cortical region.
“This observed Iba1+ cell increase after cuprizone and through early recovery was primarily due to higher numbers of Iba1+ microglia in the deep cortical region”
Quote in the paperNot a substantial claim - Findingown data
Iba1+ cell numbers approached baseline levels by late recovery.
“Iba1+ cell numbers approached baseline levels by late recovery (89.7 ± 2.21 cells Baseline mice (n = 5) vs. 105.1 ± 5.1 cells Late Recovery mice (n = 5), p = 0.8067).”
Quote in the paperNot a substantial claim - Findingown data
In the deep cortical region, there are fewer ASPA+ oligodendrocytes after cuprizone and at early and late recovery compared to baseline.
“In the deep cortical region, there were fewer ASPA+ oligodendrocytes after cuprizone, and at early and late recovery compared to baseline (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
Deep cortical microglia upregulate CD68 after 4 weeks of cuprizone.
“We found that deep cortical microglia upregulate CD68 after 4 weeks of cuprizone, and only some deep cortical microglia maintained their expression in early recovery (Figure 2G), but the comparison to baseline was not significant (Figure 2H).”
Quote in the paperSubstantial claim - Findingown data
Most superficial cortical microglia did not adopt a reactive morphology at any time-point.
“Contrary to deep cortex, most superficial cortical microglia did not adopt a reactive morphology at any time‐point, but middle region cortical microglia adopted a reactive morphology in a similar temporal pattern as the deep cortical microglia (Figure S2A).”
Quote in the paperNot a substantial claim - Findingown data
Compared to baseline, there are fewer ASPA+ oligodendrocytes after cuprizone supplementation and at early recovery in the full cortical region.
“First, we confirmed that, compared to baseline, there are fewer ASPA+ oligodendrocytes after cuprizone supplementation and at early recovery (Figures 1B and S1A).”
Quote in the paperSubstantial claim - Findingown data
In the middle cortical region, there are significantly fewer ASPA+ oligodendrocytes at early recovery compared to baseline.
“In the middle cortical region, there were also significantly fewer ASPA+ oligodendrocytes at early recovery compared to baseline (Figure S1A).”
Quote in the paperSubstantial claim - Findingown data
Deep cortical microglia downregulate TMEM119 after 4 weeks of cuprizone and through early recovery, but not at late recovery.
“Similar to P2RY12, there were fewer TMEM119+ cells in the deep cortex after 4 weeks of cuprizone and through early recovery (Figure 2E,F), but not at late recovery.”
Quote in the paperNot a substantial claim - Findingown data
After cuprizone, there is a 47.85% ± 6.46% increase in the number of Iba1+ cells throughout the full cortical region, with persistent elevation through early recovery.
“Compared to baseline, after cuprizone we observed a 47.85% ± 6.46% increase in the number of Iba1+ cells throughout the full cortical region, with a persistent elevation through early recovery”
Quote in the paperNot a substantial claim - Findingown data
Depleting cortical microglia post-cuprizone with a Csf1r inhibitor restores the baseline density of deep cortical ASPA+ oligodendrocytes at early and late recovery.
“Depleting cortical microglia post‐cuprizone restored the baseline density of deep cortical ASPA+ oligodendrocytes at early and late recovery.”
- Also stated in: § Depleting Cortical Reactive Microglia During Recovery Restores Cortical Oligodendrocyte Numbers · plain
“we found that the number of ASPA+ oligodendrocytes in the deep cortex was equivalent to baseline oligodendrocyte density at early recovery, and this persisted through late recovery (Figure 3E).”
Quote in the paperSubstantial claim- Rests on an assumption: Depletion of microglia with a Csf1r inhibitor during recovery does not directly affect oligodendrocytes or oligodendrocyte precursor cells.
- Also stated in: § Depleting Cortical Reactive Microglia During Recovery Restores Cortical Oligodendrocyte Numbers · plain
- Findingown data
Superficial cortical microglia did not upregulate CD68 at any time-point.
“In contrast, superficial cortical microglia did not upregulate CD68 at any time‐point, while middle cortical region microglia followed a similar temporal CD68 expression pattern as deep cortical microglia (Figure S2D).”
Quote in the paperNot a substantial claim - Findingown data
There are more deep cortical BCAS1+ differentiating oligodendrocytes at early recovery when microglia are depleted.
“There were also more deep cortical BCAS1+ differentiating oligodendrocytes at early recovery when microglia were depleted,”
Quote in the paperSubstantial claim - Findingown data
Superficial cortical microglia did not significantly reduce TMEM119 expression after cuprizone administration.
“Superficial cortical microglia did not significantly reduce TMEM119 expression after cuprizone administration (Figure S2C).”
Quote in the paperNot a substantial claim - Findingown data
Middle region cortical microglia adopted a reactive morphology in a similar temporal pattern as deep cortical microglia.
“Contrary to deep cortex, most superficial cortical microglia did not adopt a reactive morphology at any time‐point, but middle region cortical microglia adopted a reactive morphology in a similar temporal pattern as the deep cortical microglia (Figure S2A).”
Quote in the paperNot a substantial claim - Findingown data
The dynamics of myelin area coverage following cuprizone treatment and through recovery is similar to ASPA+ oligodendrocytes.
“Overall, the dynamics of myelin area coverage following cuprizone treatment and through recovery is similar to ASPA+ oligodendrocytes.”
Quote in the paperNot a substantial claim - Findingown data
Administration of PLX-5622 following cuprizone during recovery resulted in similar levels of microglial depletion compared to PLX-3397.
“Despite this selectivity difference, administration of PLX‐5622 following cuprizone administration during recovery resulted in similar levels of microglial depletion compared to PLX‐3397 (Figure S3B).”
Quote in the paperNot a substantial claim - Findingown data
The effect of Csf1r inhibitor on ASPA+ oligodendrocytes was primarily due to higher numbers of ASPA+ oligodendrocytes in the deep cortical region.
“and this effect was primarily due to higher numbers of ASPA+ oligodendrocytes in the deep cortical region (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
Middle cortical region microglia followed a similar temporal CD68 expression pattern as deep cortical microglia.
“In contrast, superficial cortical microglia did not upregulate CD68 at any time‐point, while middle cortical region microglia followed a similar temporal CD68 expression pattern as deep cortical microglia (Figure S2D).”
Quote in the paperNot a substantial claim - Findingown data
PLX-5622 treatment during recovery did not lead to significantly higher numbers of ASPA+ oligodendrocytes at early recovery compared to non-PLX mice.
“Unlike treatment with PLX‐3977, PLX‐5622 treatment during recovery did not lead to significantly higher numbers of ASPA+ oligodendrocytes at early recovery compared to non‐PLX mice (Figure S3C).”
Quote in the paperSubstantial claim - Findingown data
ASPA+ cortical oligodendrocyte numbers were not significantly changed after 2 or 5 weeks of PLX-3397 treatment in the sham-treated cortex.
“Despite significant microglia depletion, ASPA+ cortical oligodendrocyte numbers were not significantly changed after 2 or 5 weeks of PLX‐3397 treatment in the sham‐treated cortex (Figure 4B–D).”
Quote in the paperSubstantial claim - Findingown data
The number of cortical reactive astrocytes was unchanged by microglia depletion.
“We found that the number of cortical reactive astrocytes was unchanged by microglia depletion (Figure S5).”
Quote in the paperSubstantial claim - Findingown data
Late recovery ASPA+ oligodendrocyte numbers in PLX-5622 treated mice were not significantly different from baseline.
“However, late recovery ASPA+ oligodendrocyte numbers in PLX‐5622 treated mice were not significantly different from baseline, suggesting ASPA+ cell numbers could be following a similar trajectory as PLX‐3397 treated mice over the course of recovery.”
Quote in the paperSubstantial claim - Findingown data
MBP+ myelin area coverage of sham-treated cortical regions was not altered after 2 or 5 weeks of PLX-3397 treatment compared to sham alone.
“MBP+ myelin area coverage of these sham‐treated cortical regions was also not altered after 2 or 5 weeks of PLX‐3397 treatment compared to sham alone (Figure 4E–G).”
Quote in the paperSubstantial claim - Findingown data
NG2+ OPC density was maintained in the deep cortical region during early recovery when treated with either Csf1r inhibitor.
“However, we found that NG2+ OPC density was maintained in the deep cortical region during early recovery when treated with either Csf1r inhibitor (Figure S3D).”
Quote in the paperSubstantial claim - Findingown data
In the no PLX condition, the number of ASPA+ oligodendrocytes at late recovery was significantly reduced compared to baseline.
“In contrast, in the no PLX condition, the number of ASPA+ oligodendrocytes at late recovery was significantly reduced compared to baseline (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
We did not detect significant changes in myelin density in mice treated with PLX-3397.
“We did not detect significant changes in myelin density in mice treated with PLX‐3397, although the MBP+ signal was less patchy in some examples of PLX‐treated mice at early recovery (Figure S3E).”
Quote in the paperNot a substantial claim - Findingown data
There were ~3-fold more ASPA+ oligodendrocytes at early recovery in the full cortical region with Csf1r inhibitor treatment compared to no PLX treatment.
“There were ~3‐fold more ASPA+ oligodendrocytes at early recovery in the full cortical region with Csf1r inhibitor treatment, compared to no PLX treatment (30.9 ± 6.21 ASPA+ cells Early Recovery no PLX (n = 5) vs. 90.5 ± 11.66 ASPA+ cells Early Recovery + PLX‐3397 mice (n = 5), p = 0.0328)”
Quote in the paperSubstantial claim - Findingown data
Treatment with 2 weeks of PLX-3397 post-sham treatment depleted the majority of Iba1+ cells compared to baseline in both the full and deep cortical regions.
“We found that treatment with 2 weeks of PLX‐3397 post‐sham treatment depleted the majority of Iba1+ cells compared to baseline in both the full (89.7 ± 2.21 cells Baseline mice (n = 5) vs. 15.17 ± 5.86 cells 2 weeks post‐sham + PLX‐3397 mice (n = 6), p < 0.0001) and the deep region (31.4 ± 1.81 cells Baseline mice (n = 5) vs. 5.0 ± 1.83 cells 2 weeks post‐sham + PLX‐3397 mice (n = 6), p < 0.0001).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in the number of BCAS1 + GFP+ cells at baseline, after 4 weeks of cuprizone, or after recovery with or without PLX-3397.
“We saw no difference in the number of BCAS1 + GFP+ cells at baseline, after 4 weeks of cuprizone, or after recovery with or without PLX‐3397 (Figure 5C,D), despite the restored baseline levels of deep cortical ASPA+ oligodendrocytes by late recovery with PLX‐treatment (Figure 3).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in the number of early-myelinating BCAS1+ cells at any time point.
“There were more pre‐myelinating BCAS1+ cells at early recovery in the PLX‐treated mice (Figure 5F) but no difference in the number of early‐myelinating BCAS1+ cells at any time point (Figure 5G).”
Quote in the paperSubstantial claim - Findingown data
Deep cortical ASPA+ oligodendrocytes were not fully restored to baseline levels at late recovery.
“Similar to our prior study, we found that deep cortical ASPA+ oligodendrocytes were not fully restored to baseline levels at late recovery (Figure 1).”
Quote in the paperSubstantial claim - Findingown data
There were more pre-myelinating BCAS1+ cells at early recovery in the PLX-treated mice.
“There were more pre‐myelinating BCAS1+ cells at early recovery in the PLX‐treated mice (Figure 5F) but no difference in the number of early‐myelinating BCAS1+ cells at any time point (Figure 5G).”
Quote in the paperSubstantial claim - Findingown data
There was no corresponding change in the number of BCAS1+ oligodendrocytes at early or late recovery to match the loss of baseline oligodendrocytes from cuprizone treatment.
“Instead, we found no corresponding change in the number of BCAS1+ oligodendrocytes at early or late recovery to match the loss of baseline oligodendrocytes from cuprizone treatment.”
Quote in the paperSubstantial claim - Findingown data
Only a small proportion of deep cortical BCAS1+ cells expressed CC3 (3.57% ± 1.79), corresponding to approximately 1 BCAS1+ cell per region quantified.
“Only a small proportion of deep cortical BCAS1+ cells (all with pre‐myelinating morphology, not shown) expressed CC3 (3.57% ± 1.79), corresponding to a ~1 BCAS1+ cell per region quantified.”
Quote in the paperSubstantial claim - Findingown data
OPC density was maintained at all time points and cortical depths.
“Reassuringly, we found that OPC density was maintained at all time points and cortical depths.”
Quote in the paperSubstantial claim - Interpretationown data
Transient deep cortical reactive microglia impair oligodendrocyte differentiation following demyelinating injury.
“suggesting that transient deep cortical reactive microglia impair oligodendrocyte differentiation following demyelinating injury.”
Quote in the paperSubstantial claim- Rests on an assumption: The reactive markers and morphology changes observed in deep cortical microglia indicate a functional state that can impair oligodendrocyte regeneration.
- Study design and conductown data
Nearly all Iba1+ cells in Cx3cr1-eGFP mice are also GFP+.
“Last, nearly all Iba1+ cells in Cx3cr1‐eGFP are also GFP+ (Figure S2F).”
Quote in the paperSubstantial claim - Study design and conductown data
There were no significant differences in the number of Iba1+ cells in WT compared to GFP+ cells in Cx3Cr1-eGFP mice.
“Then, we quantified and compared the number of Iba1+ cells in WT to GFP+ cells in Cx3Cr1‐eGFP mice and found no significant differences (Figure S2E).”
Quote in the paperSubstantial claim - Study design and conductown data
ASPA+ oligodendrocyte dynamics following cuprizone administration in Cx3Cr1-eGFP mice were similar to WT mice.
“To ensure that these transgenic lines could be used interchangeably to study cortical microglia reactivity to cuprizone, we confirmed that ASPA+ oligodendrocyte dynamics following cuprizone administration in Cx3Cr1‐eGFP mice were similar to WT mice (Mobp‐eGFP and WT littermate controls; Figure S1E,F).”
Quote in the paperSubstantial claim - Interpretationown data
Cortical microglia adopt spatially restricted reactive functions after demyelination.
“Together, we found that cortical microglia adopt spatially restricted reactive functions after demyelination and deep cortical reactive microglia transiently reduce differentiating oligodendrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: The reactive markers and morphology changes observed in deep cortical microglia indicate a functional state that can impair oligodendrocyte regeneration.
- Interpretationown data
Deep cortical reactive microglia are a barrier to oligodendrocyte regeneration following demyelination.
“These results suggest that deep cortical reactive microglia are a barrier to oligodendrocyte regeneration following demyelination.”
Quote in the paperSubstantial claim- Rests on an assumption: Depletion of microglia with a Csf1r inhibitor during recovery does not directly affect oligodendrocytes or oligodendrocyte precursor cells.
- Rests on an assumption: The reactive markers and morphology changes observed in deep cortical microglia indicate a functional state that can impair oligodendrocyte regeneration.
- Study design and conductown data
The data supports using both WT and Cx3Cr1-eGFP mice to characterize the reactive states of cortical microglia following cuprizone.
“Together, this data supports using both WT and Cx3Cr1‐eGFP mice to characterize the reactive states of cortical microglia following cuprizone.”
Quote in the paperSubstantial claim - Interpretationown data
Deep cortical reactive microglia transiently reduce differentiating oligodendrocytes.
“Together, we found that cortical microglia adopt spatially restricted reactive functions after demyelination and deep cortical reactive microglia transiently reduce differentiating oligodendrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: The reactive markers and morphology changes observed in deep cortical microglia indicate a functional state that can impair oligodendrocyte regeneration.
- Interpretationown data
Deep cortical reactive microglia adopt novel functions post-cuprizone that influence oligodendrocyte density.
“This finding highlights that deep cortical reactive microglia adopt novel functions post‐cuprizone that influence oligodendrocyte density.”
Quote in the paperSubstantial claim - Interpretationown data
More mature ASPA+ oligodendrocytes were formed by late recovery, approaching baseline levels, in PLX-treated mice.
“This finding in PLX‐treated mice suggests that more mature ASPA+ oligodendrocytes were formed by late recovery, approaching baseline levels.”
Quote in the paperSubstantial claim- Rests on an assumption: Depletion of microglia with a Csf1r inhibitor during recovery does not directly affect oligodendrocytes or oligodendrocyte precursor cells.
- Interpretationown data
The effect of PLX-5622 on oligodendrocyte recovery was less robust than PLX-3397.
“Overall, the effect of PLX‐5622 on oligodendrocyte recovery was less robust than PLX‐3397.”
Quote in the paperSubstantial claim - Interpretationown data
The lack of compensatory increase in BCAS1+ differentiating oligodendrocytes in the setting of maintained OPC density supports the hypothesis that there are external barriers to forming replacement oligodendrocytes in the deep cortex following cuprizone administration.
“This lack of compensatory increase in BCAS1+ differentiating oligodendrocytes in the setting of maintained OPC density supports the hypothesis that there are external barriers to forming replacement oligodendrocytes in the deep cortex following cuprizone administration.”
Quote in the paperSubstantial claim - Interpretationreasoning
It is unlikely that the depletion of microglia alone will be a sufficient therapeutic intervention to promote oligodendrocyte recovery following inflammatory demyelinating attacks in MS, given the distinct roles of microglia in white and gray matter lesions.
“It is unlikely that the depletion of microglia alone will be a sufficient therapeutic intervention to promote oligodendrocyte recovery following inflammatory demyelinating attacks in MS, given the distinct roles of microglia in white and gray matter lesions.”
Quote in the paperSubstantial claim - Interpretationown data
Our results reveal spatial and temporal heterogeneity of cortical microglia responses to demyelination.
“Taken together, our results reveal spatial and temporal heterogeneity of cortical microglia responses to demyelination.”
Quote in the paperSubstantial claim - Interpretationreasoning
The differential spatial responses of cortical microglia are likely driven, at least in part, by environmental differences.
“The differential spatial responses of cortical microglia are likely driven, at least in part, by environmental differences.”
Quote in the paperNot a substantial claim - Interpretationown data
Deep cortical microglia adopt a reactive state in response to demyelination that reduces oligodendrocyte numbers during early recovery.
“Together, our findings indicate that deep cortical microglia adopt a reactive state in response to demyelination that reduces oligodendrocyte numbers during early recovery.”
Quote in the paperSubstantial claim - Interpretationreasoning
Deep cortical reactive microglia impair deep cortical oligodendrocyte regeneration during recovery from demyelination by blocking OPCs from transitioning to a BCAS1+ state.
“This finding suggests that deep cortical reactive microglia impair deep cortical oligodendrocyte regeneration during recovery from demyelination by blocking OPCs from transitioning to a BCAS1+ state.”
Quote in the paperSubstantial claim - Interpretationreasoning
The increased number of pre-myelinating BCAS1+ cells conceivably provides a larger available pool of BCAS1+ cells at early recovery, tipping the scales in favor of differentiation.
“The increased number of pre‐myelinating BCAS1+ cells‐oligodendrocyte lineage cells that are predominantly on the immature end of the differentiation trajectory – conceivably provides a larger available pool of BCAS1+ cells at early recovery, tipping the scales in favor of differentiation.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 36
- May combine two claims. 25
- The quote only partly states this claim. 1
Classified as probably not a substantial claim.
PremisecitationAlthough OPCs represent an available pool to replace lost oligodendrocytes and myelin, replacement is limited, particularly in cortical lesions.
“Although OPCs represent an available pool to replace lost oligodendrocytes and myelin, replacement is limited, particularly in cortical lesions (Chang et al. 2012).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Chang et al. 2012 source
The Results section, “Oligodendrocyte Progenitor Cell Density is Not Decreased in Cortical Lesions,” supports the availability of OPCs in cortical lesions. But the Discussion reports significantly greater oligodendrocyte generation and remyelination in cortex than in adjacent white matter—the opposite of the claim that replacement is particularly limited in cortical lesions. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPLX-5622 has 100-fold higher selectivity for Csf1r compared to other members of the platelet-derived growth factor receptor (PDGFRα) family of type III receptor tyrosine kinases.
“PLX‐5622 has 100‐fold higher selectivity for Csf1r compared to other members of the platelet‐derived growth factor receptor (PDGFRα) family of type III receptor tyrosine kinases (Liu et al. 2019).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Liu et al. 2019 source
The Introduction reports at least 50-fold selectivity over four related kinases and over 100-fold selectivity against a broader panel. The Discussion describes 50- to 100-fold higher affinity for CSF1R than for related kinases and identifies PDGFRα and β as members of the same receptor family. Neither passage establishes 100-fold selectivity over every other member of that family. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationBCAS1 is expressed by newly differentiated, pre-myelinating, and early-myelinating oligodendrocytes that derive from NG2+ OPCs but do not yet express all mature oligodendrocyte markers.
“Recent studies showed that BCAS1 (breast carcinoma amplified sequence 1) is expressed by a subset of the oligodendrocyte lineage: newly differentiated, pre‐myelinating, and early‐myelinating oligodendrocytes that derive from NG2+ OPCs but do not yet express all mature oligodendrocyte markers (Chapman et al. 2024; Fard et al. 2017).”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeep cortical astrocytes persistently upregulate GFAP following cuprizone administration.
“We previously showed that deep cortical astrocytes persistently upregulate GFAP following cuprizone administration (Orthmann‐Murphy et al. 2020);”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationA blinded observer categorized BCAS1+ cells as either early-myelinating or pre-myelinating.
“To quantify BCAS1+ cell morphology, a blinded observer categorized BCAS1+ cells as either ‘early‐myelinating’ (possessing multiple processes) or ‘pre‐myelinating’ (possessing few processes) as previously described (Fard et al. 2017; Bergner et al. 2024).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Fard et al. 2017 source
The Results section distinguishes BCAS1+ premyelinating cells from myelinating cells by morphology, and Materials and Methods (Study design) says quantitative analyses were performed blinded. But the cited paper describes premyelinating cells as having multiple, symmetrically radiating processes—not few processes—and myelinating cells as having segments aligned in parallel. It does not establish the citing sentence’s process-count criteria for the two categories. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Bergner et al. 2024
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBoth microglia and astrocytes contribute to cuprizone-induced pathology and could influence oligodendrocyte regeneration.
“Both microglia and astrocytes contribute to cuprizone‐induced pathology and could influence oligodendrocyte regeneration (Vega‐Riquer et al. 2019).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Vega‐Riquer et al. 2019 source
The ‘Immune System Influence in the CPZ Model’ section (page not provided) says that cytokines from microglia and astrocytes have cytotoxic roles in cuprizone-induced demyelination, supporting their contribution to pathology. It also links astrocytes to reduced myelin synthesis, but does not establish that both cell types influence oligodendrocyte regeneration. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationNew oligodendrocytes formed after cessation of the cuprizone-supplemented diet, with a peak rate of formation at 2 weeks post-cuprizone.
“We found that new oligodendrocytes formed after cessation of the cuprizone‐supplemented diet, with a peak rate of formation at 2 weeks post‐cuprizone (“early” recovery).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
The Results sections on inefficient regeneration and layer-specific remyelination report that new oligodendrocytes appeared rapidly after cuprizone cessation and that replacement peaked during the first two weeks of recovery. They do not establish that the peak rate occurred specifically at the two-week time point. (LLM, conf=0.83)
Experimental — accuracy not yet measured
May combine two claims.
Premiseown dataOligodendrocyte regeneration in the somatosensory cortex is incomplete, driven primarily by inefficient oligodendrocyte replacement in deep cortical regions.
“We found that oligodendrocyte regeneration in the somatosensory cortex is incomplete, and this is driven primarily by inefficient oligodendrocyte replacement in deep cortical regions.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
Classified as probably not a substantial claim.
PremisecitationBoth pre-myelinating and early-myelinating oligodendrocytes express BCAS1.
“Notably, both pre‐myelinating and early‐myelinating oligodendrocytes express BCAS1 (Fard et al. 2017).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Fard et al. 2017 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCD68 is a lysosomal protein expressed by activated and phagocytosing microglia and macrophages.
“reactive microglia are commonly identified by upregulation of CD68, a lysosomal protein expressed by activated and phagocytosing microglia and macrophages (Bennett and Viaene 2021).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Bennett and Viaene 2021 source
Section 1.1, “Microglial activation” (page not available), identifies CD68 as a lysosomal marker that is upregulated in morphologically activated microglia in some pathological contexts, and lists it among macrophage markers. It does not establish that CD68 identifies phagocytosing cells, and its “some pathological contexts” qualifier does not support identifying reactive microglia by CD68 upregulation generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationBCAS1 + GFP+ oligodendrocytes represent a relatively more mature differentiating oligodendrocyte state than BCAS1 + GFP- cells.
“BCAS1 + GFP+ oligodendrocytes should represent a relatively more mature differentiating oligodendrocyte state than BCAS1 + GFP‐ cells (Chapman et al. 2024; Hughes et al. 2018; Orthmann‐Murphy et al. 2020).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Chapman et al. 2024 source
- cites Hughes et al. 2018 source
The Results section, “Oligodendrocyte generation continues in the adult cortex” (page unavailable), says Mobp-EGFP marks oligodendrocytes and that Mobp is expressed late in maturation, supporting the proposed interpretation if GFP denotes Mobp-EGFP. The paper does not compare BCAS1+ GFP+ and BCAS1+ GFP− cells; moreover, its NG2-mEGFP reporter loses fluorescence during differentiation, so the inference depends on which GFP reporter is meant. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Orthmann‐Murphy et al. 2020 source
The Materials and methods section describes Mobp-EGFP imaging as following newly formed mature oligodendrocytes, supporting the use of GFP expression as an indicator of maturity in this mouse model. Our copy does not address BCAS1 or compare BCAS1+ GFP+ cells with BCAS1+ GFP− cells, so it does not establish the claimed relative differentiation state. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn Cx3Cr1-eGFP mice, GFP is expressed by CNS-resident macrophages, which are predominantly represented by microglia.
“In Cx3Cr1‐eGFP mice, GFP is expressed by CNS‐resident macrophages (Jung et al. 2000), which, as noted above, are predominantly represented by microglia (Zhao et al. 2023).”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeep cortical oligodendrogenesis was selectively impaired, with only ~55% of the baseline oligodendrocyte population replaced after 9 weeks of recovery in the deepest cortical zone examined (200-300 μm).
“In our prior in vivo imaging study, however, we showed that deep cortical oligodendrogenesis was selectively impaired, with only ~55% of the baseline oligodendrocyte population replaced after 9 weeks of recovery in the deepest cortical zone examined (200–300 μm; Orthmann‐Murphy et al. 2020).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
Classified as probably not a substantial claim.
Study design and conductcitationA blinded observer quantified the number of NG2+, GFAP+, Iba1+, ASPA+, BCAS1+, and GFP+ cells within each region.
“For cell counts, a blinded observer quantified the number of NG2+, GFAP+, Iba1+, ASPA+, BCAS1+, and GFP+ cells within each 500 μm × 750 μm region using a custom counting macro in FIJI/ImageJ (Orthmann‐Murphy et al. 2020).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
The Immunohistochemistry methods (page unavailable) report that a blinded observer counted NG2+, GFAP+, and EGFP+ cells, supporting the core counting procedure. They specify 425 μm × 500 μm regions, not 500 μm × 750 μm regions, and do not report blinded counts of Iba1+, ASPA+, or BCAS1+ cells. The Image processing and analysis methods mention FIJI/ImageJ, but not a custom counting macro for these counts. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationMicroglia and astrocytes influence each other's state and function.
“Given that microglia and astrocytes influence each other's state and function (Matejuk and Ransohoff 2020), we wanted to ensure that cortical astrocyte numbers were not also altered by microglia depletion following demyelination.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Matejuk and Ransohoff 2020 source
Classified as probably not a substantial claim.
PremisecitationIn 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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Miron et al. 2013 source
Classified as probably not a substantial claim.
PremisecitationTMEM119 is a canonical microglia marker not expressed by other CNS resident macrophages.
“we performed in situ RNA labeling for TMEM119, a canonical microglia marker not expressed by other CNS resident macrophages (Bennett et al. 2016).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Bennett et al. 2016 source
Classified as probably not a substantial claim.
PremisecitationMicroglia within the healthy cortex exhibit spatially heterogeneous gene expression.
“However, microglia are uniquely attuned to their local environment, and within the healthy cortex exhibit spatially heterogeneous gene expression (Hammond et al. 2019; Paolicelli et al. 2022; Tarozzo et al. 2003).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Hammond et al. 2019
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Paolicelli et al. 2022 source
The “Microglial heterogeneity: It all depends on the context” section says microglia differ in transcriptional profiles among CNS areas and respond to local cues, including without perturbation. It does not specifically establish spatial differences in gene expression within the healthy cortex; its geographic comparison is among CNS areas. No page number is available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites Tarozzo et al. 2003 source
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationDeep cortical astrocytes also become persistently reactive.
“In addition, deep cortical astrocytes also become persistently reactive (Figure S4; Orthmann‐Murphy et al. 2020) and likely influence deep cortical reactive microglia function (Liddelow and Barres 2017).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Orthmann‐Murphy et al. 2020 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIn 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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Miron et al. 2013 source
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 measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationMicroglia clear myelin debris and influence oligodendrocytes and myelin formation in MS lesions.
“Accumulating evidence shows that microglia clear myelin debris and influence oligodendrocytes and myelin formation in MS lesions (Irfan et al. 2022; Li and Barres 2018).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Irfan et al. 2022 source
The section “Microglia phagocytose OPCs to regulate myelin formation” says microglia engulf oligodendrocyte progenitor cells and thereby regulate myelin formation during early postnatal development. The “Relevance to disease pathology” section does not establish that they clear myelin debris or have these effects in MS lesions; it says relevance beyond the studied corpus callosum warrants further investigation. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Li and Barres 2018 source
Classified as probably not a substantial claim.
PremisecitationThere are more oligodendrocytes in the deep cortex compared to the superficial cortex.
“For example, there are more oligodendrocytes in the deep cortex compared to the superficial cortex (Hughes et al. 2018).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hughes et al. 2018 source
The Results section (page unavailable) says oligodendrocyte density varies by cortical depth, but it does not state that deeper cortex has more oligodendrocytes than superficial cortex. The Discussion (page unavailable) says the analysis was limited to layers I–IV and did not resolve deeper cortical layers. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn the healthy middle-aged cortex, only 22% of pre-myelinating oligodendrocytes stably integrated into the cortex, and the remaining differentiating cells died.
“We previously showed in the healthy middle‐aged cortex that only 22% of pre‐myelinating oligodendrocytes stably integrated into the cortex (Hughes et al. 2018), and the remaining differentiating cells died.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hughes et al. 2018 source
Classified as probably not a substantial claim.
PremisecitationMicroglial phagocytosis of OPCs and oligodendrocytes during early postnatal development in white matter limits the number of oligodendrocytes and myelin sheaths formed.
“In fact, microglial phagocytosis of OPCs and oligodendrocytes during early postnatal development in white matter limits the number of oligodendrocytes and myelin sheaths formed (Nemes‐Baran et al. 2020).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Nemes‐Baran et al. 2020 source
The Results and Discussion (page not available) show that microglia engulf OPCs in the early postnatal corpus callosum and that reduced engulfment increases the number of mature oligodendrocytes. The claim overextends this to phagocytosis of oligodendrocytes as a separate population and to limiting the number of myelin sheaths formed: the paper reports no change in the number of myelinated axons when engulfment is reduced, but thinner myelin. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMicroglia are a salient feature of white and gray matter lesions, representing a major part of ongoing compartmentalized inflammation induced by an initial inflammatory attack.
“Microglia are a salient feature of white and gray matter lesions, representing a major part of ongoing compartmentalized inflammation induced by an initial inflammatory attack (Absinta et al. 2021).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Absinta et al. 2021 source
The ‘MIMS and AIMS at the chronic active lesion edge’ section identifies inflamed microglia as a substantial immune-cell population in chronic active white-matter lesions, and Extended Data Fig. 4 describes frequent activated microglia at the lesion edge (page numbers unavailable). The paper does not establish the same finding for gray-matter lesions or show that the ongoing inflammation was induced by an initial inflammatory attack. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationPrevious 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).”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSuperficial cortical microglia did not decrease P2RY12 expression following cuprizone treatment.
“Superficial cortical microglia, by comparison, did not decrease P2RY12 expression following cuprizone treatment (Figure S2B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe reactive changes in deep cortical microglia persist through early recovery and resolve by late recovery.
“These reactive changes persisted through early recovery post‐cuprizone but resolved by late recovery.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataP2RY12 expression returned to baseline levels by late recovery.
“This pattern was similarly observed in middle cortical microglia after 4 weeks of cuprizone and through early recovery, and P2RY12 expression returned to baseline levels by late recovery (Figure S2B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDeep cortical microglia downregulate P2RY12 after 4 weeks of cuprizone, and this downregulation persists through early recovery.
“After 4 weeks of cuprizone, deep cortical GFP+ microglia downregulated the expression of P2RY12, and this persisted through early recovery (Figure 2C,D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAfter 2 weeks of PLX-3397, there were substantially fewer Iba1+ cortical microglia, but they were not fully eliminated.
“After 2 weeks, there were substantially fewer Iba1+ cortical microglia, but they were not fully eliminated.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt early recovery with PLX-3397, there were more cortical BCAS1+ oligodendrocytes in the full cortical region compared to no PLX treatment, with approximately 2-fold more BCAS1+ cells in the PLX-treated deep cortical region.
“At early recovery with PLX‐3397, there were more cortical BCAS1+ oligodendrocytes in the full cortical region compared to no PLX treatment (17.6 ± 2.03 BCAS1+ cells Early Recovery no PLX mice (n = 5) vs. 30.5 ± 1.68 BCAS1+ cells Early Recovery + PLX‐3397 mice (n = 7), p = 0.0203), with ~2‐fold more BCAS1+ cells in the PLX‐treated deep cortical region (Figure 5A,B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the deep cortical region, only 17.9% ± 3.91% of cortical microglia were depleted compared to baseline at early recovery, and then further reduced to 68.8% ± 10.84% of baseline by late recovery.
“In the deep cortical region, only 17.9% ± 3.91% of cortical microglia were depleted compared to baseline at early recovery, and then further reduced to 68.8% ± 10.84% of baseline by late recovery (Figure 3C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the superficial region, Iba1+ cells were reduced by 90.64% ± 37.32% at early recovery and by 90.22% ± 41.82% at late recovery compared to baseline.
“In comparison to baseline, Iba1+ cells in the superficial region were reduced by 90.64% ± 37.32% at early recovery, and then by 90.22% ± 41.82% at late recovery (Superficial region, Baseline mice (n = 5) vs. Early Recovery + PLX‐3397 mice (n = 6), p < 0.0001; vs. Late Recovery + PLX‐3397 mice (n = 5), p < 0.0001).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSuperficial microglia maintain homeostatic morphology and expression of homeostatic markers P2RY12 and TMEM119.
“In contrast, superficial microglia maintain homeostatic morphology and expression of homeostatic markers P2RY12 and TMEM119.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDeep cortical microglia adopt a reactive state, characterized by an amoeboid morphology, downregulation of homeostatic markers P2RY12 and TMEM119, and upregulation of CD68; this response persists through early recovery and resolves by late recovery.
“We found that deep cortical microglia adopt a reactive state, characterized by an amoeboid morphology, downregulation of homeostatic markers P2RY12 and TMEM119, and upregulation of CD68; this response persists through early recovery and resolves by late recovery.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAdministration of PLX depleted microglia throughout the cortical region, and we observed more deep cortical ASPA+ oligodendrocytes and BCAS1+ differentiating oligodendrocytes at early recovery, in the same region and time period as the transient deep cortical reactive microglia phenotype.
“Although administration of PLX depleted microglia throughout the cortical region, we observed more deep cortical ASPA+ oligodendrocytes and BCAS1+ differentiating oligodendrocytes at early recovery (Figures 3 and 5), in the same region and same time period we identified the transient deep cortical reactive microglia phenotype (Figures 2 and S2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDepleting cortical microglia led to increased numbers of deep cortical BCAS1+ and ASPA+ cells at early recovery, and a few deep cortical reactive microglia survived in PLX-treated mice.
“Although we found that depleting cortical microglia led to increased numbers of deep cortical BCAS1+ and ASPA+ cells at early recovery, a few deep cortical reactive microglia survived in PLX‐treated mice (Figure 3B,C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe mature oligodendrocyte population is reduced after 4 weeks of cuprizone compared to baseline, reaches a nadir at early recovery, and then approaches baseline density by late recovery in the upper somatosensory cortex.
“By quantifying ASPA+ oligodendrocytes with this updated approach, we confirmed that the mature oligodendrocyte population is reduced after 4 weeks of cuprizone compared to baseline, reaches a nadir at early recovery, and then approaches baseline density by late recovery in the upper somatosensory cortex.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenA blinded observer categorized Iba1+ or GFP+ microglia as either homeostatic or reactive.
“To quantify changes in microglial morphology, a blinded observer categorized Iba1+ (in Mobp‐eGFP or WT littermates) or GFP+ microglia (in Cx3Cr1‐egfp mice) as either homeostatic (small, circular cell body with ramified processes) or reactive (larger and amoeboid cell body with short and thick processes).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAdult mice of both sexes were randomly assigned to experimental groups.
“Adult mice of both sexes were used for experiments and randomly assigned to experimental groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHomeostatic microglia typically have a small circular cell body and ramified processes, whereas reactive microglia typically have larger cell bodies with an amoeboid shape and short, thick processes.
“Homeostatic microglia typically have a small circular cell body and ramified processes, whereas in the setting of injury, reactive microglia typically have larger cell bodies with an amoeboid shape and short, thick processes (Woodburn et al. 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Woodburn et al. 2021
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal experiments were performed in strict accordance with protocols approved by the Institution of Animal Care and Use Committee at the University of Pennsylvania.
“All animal experiments were performed in strict accordance with protocols approved by the Institution of Animal Care and Use Committee at the University of Pennsylvania (Philadelphia, PA).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo animals were excluded from the analysis.
“All mice were healthy and did not display any overt behavioral phenotypes, and no animals were excluded from the analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBCAS1+ cells die by a caspase-3 dependent mechanism.
“Most of these differentiating cells likely died by apoptosis; BCAS1+ cells were recently shown to die by a caspase‐3 dependent mechanism (Chapman et al. 2024).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Chapman et al. 2024 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe long-term consequence of demyelination in the CNS is axonal damage and neurodegeneration in both white and gray matter lesions, leading to progressive disease.
“The long‐term consequence of demyelination in the CNS is axonal damage and neurodegeneration (Chang et al. 2002) in both white and gray matter lesions, leading to progressive disease.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Chang et al. 2002 source
May combine two claims.
Interpretationown dataThe majority of BCAS1+ cells appear to be healthy at early recovery in PLX-treated mice and could mature into ASPA+ oligodendrocytes.
“Although we would not expect all BCAS1+ cells to survive based on prior studies, the majority of BCAS1+ cells appear to be healthy at early recovery in PLX‐treated mice and could mature into ASPA+ oligodendrocytes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningFollowing cuprizone-induced demyelination, deep cortical microglia will be exposed to relatively more myelin debris than superficial microglia, potentially inducing different reactive responses.
“Following cuprizone‐induced demyelination, deep cortical microglia will be exposed to relatively more myelin debris than superficial microglia, potentially inducing different reactive responses.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningTargeting specific reactive microglia functions at key time-points to promote oligodendrocyte regeneration could prevent axonal damage and progressive disease in MS.
“Ultimately, targeting specific reactive microglia functions at key time‐points to promote oligodendrocyte regeneration could prevent axonal damage and progressive disease in MS.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationMicroglia depletion after lysophosphatidylcholine-induced spinal cord demyelination led to reduced OPC recruitment, proliferation, and differentiation.
“Similarly, Baaklini et al. (2023) showed that microglia depletion after lysophosphatidylcholine‐induced spinal cord demyelination led to reduced OPC recruitment, proliferation, and differentiation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Baaklini et al. 2023 source
May combine two claims. The quote only partly states this claim.
Interpretationown dataDepleting microglia after cuprizone treatment leads to higher numbers of deep cortical pre-myelinating BCAS1+ oligodendrocytes, thereby forming a larger available pool of differentiating oligodendrocytes during recovery from demyelination.
“Our findings indicate that the depletion of cortical reactive microglia post‐cuprizone increased the available pool of early differentiating BCAS1+ cells.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationDeep cortical reactive astrocytes likely influence deep cortical reactive microglia function.
“In addition, deep cortical astrocytes also become persistently reactive (Figure S4; Orthmann‐Murphy et al. 2020) and likely influence deep cortical reactive microglia function (Liddelow and Barres 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liddelow and Barres 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenNeither pre-existing nor dying oligodendrocytes would be expected to express BCAS1+.
“However, neither pre‐existing nor dying oligodendrocytes would be expected to express BCAS1+.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
ASPA+ cells in the cortex represent mature oligodendrocytes.
“For cell counts, a blinded observer quantified the number of NG2+, GFAP+, Iba1+, ASPA+, BCAS1+, and GFP+ cells within each 500 μm × 750 μm region using a custom counting macro in FIJI/ImageJ (Orthmann‐Murphy et al. 2020).”
The paper relies on this without support.
Depletion of microglia with a Csf1r inhibitor during recovery does not directly affect oligodendrocytes or oligodendrocyte precursor cells.
“To determine whether deep cortical reactive microglia impair oligodendrocyte regeneration, we fed WT (Mobp‐eGFP or WT littermates) mice chow supplemented with Csf1r inhibitor PLX‐3397 (Elmore et al. 2014) to deplete microglia following cuprizone administration (Figure 3A).”
The paper relies on this without support.
The reactive markers and morphology changes observed in deep cortical microglia indicate a functional state that can impair oligodendrocyte regeneration.
“Overall, we observed a spatially heterogeneous cortical reactive microglia response to demyelination, where deep cortical microglia changed morphology, downregulated homeostatic markers P2RY12 and TMEM119, and upregulated CD68, and this response persisted through early recovery.”
The paper relies on this without support.
There are currently no available reparative treatments to fix demyelinated lesions in multiple sclerosis.
“There are currently no available reparative treatments to fix demyelinated lesions in multiple sclerosis (MS).”
The paper relies on this without support.
Prior to this study, it was not known whether cortical microglia promote or impair oligodendrocyte recovery after cortical demyelination.
“Although there is a growing understanding of the diverse reactive states and functions that microglia adopt in response to CNS damage (Tan et al. 2020), prior to this study, it was not known whether cortical microglia promote or impair oligodendrocyte recovery after cortical demyelination.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 3 gives conflicting inhibitor names
MinorThe Figure 3 caption calls the administered inhibitor PLX‐3977 in its experimental paradigm, but identifies the treated group as receiving PLX‐3397 in the same caption.
“(A) Experimental paradigm with administration of Csf1r antagonist PLX‐3977 post‐cuprizone to deplete reactive microglia during recovery.”
“treatment with PLX‐3397 (blue).”
Second Csf1r inhibitor has two different names
MinorThe Methods identify the second inhibitor as PLX‐5562, while the Results identify it as PLX‐5622. The text does not establish whether these are the same treatment.
“PLX‐5562 (1200 ppm; SelleckChem and Research Diets)”
“administration of PLX‐5622 following cuprizone administration during recovery”
Cites
Neurotoxic reactive astrocytes are induced by activated microglia
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“…to newly forming oligodendrocytes and/or induce the recruitment of other cytotoxic immune cells (Lee et al. 2018; Wang et al. 2018; Wies Mancini et al. 2023) or induce other local cells, such as astrocytes, to become directly toxic to oligodendrocytes (Guttenplan et al. 2020; Liddelow et al. 2017).”
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“To determine whether deep cortical reactive microglia impair oligodendrocyte regeneration, we fed WT (Mobp-eGFP or WT littermates) mice chow supplemented with Csf1r inhibitor PLX-3397 (Elmore et al. 2014) to deplete microglia following cupri-zone administration (Figure 3A).”
New tools for studying microglia in the mouse and human CNS
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“In parallel, to ensure our findings were specific to microglia, we performed in situ RNA labeling for TMEM119, a canonical microglia marker not expressed by other CNS resident macrophages (Bennett et al. 2016).”
M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination
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“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).”
InfluentialThe P2Y12 receptor regulates microglial activation by extracellular nucleotides
Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D. (2006) · Nature Neuroscience · doi:10.1038/nn1805 · Cited by 1,542 · cited 1× · see citing works
“To determine changes in homeostatic marker P2RY12 expression (Haynes et al. 2006), we co-immunostained for both P2RY12 and GFP in Cx3Cr1-eGFP mice from each time point.”
Premyelinating Oligodendrocytes in Chronic Lesions of Multiple Sclerosis
Chang, A., Tourtellotte, W. W., Rudick, R., & Trapp, B. D. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa010994 · Cited by 991 · cited 1× · see citing works
“The long-term consequence of demyelination in the CNS is axonal damage and neurodegeneration (Chang et al. 2002) in both white and gray matter lesions, leading to progressive disease.”
Origin and differentiation of microglia
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“Microglia are the resident innate immune cells of the brain (Ginhoux et al. 2013).”
Differential roles of microglia and monocytes in the inflamed central nervous system
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“In the setting of demyelinating injury, microglia remove myelin debris by phagocytosis (Yamasaki et al. 2014), thereby eliminating at least one barrier to OPC differentiation (Kotter 2006; Plemel et al. 2013).”
The Semantics of Microglia Activation: Neuroinflammation, Homeostasis, and Stress
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A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis
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“In the setting of demyelinating injury, microglia remove myelin debris by phagocytosis (Yamasaki et al. 2014), thereby eliminating at least one barrier to OPC differentiation (Kotter 2006; Plemel et al. 2013).”
Microglial regional heterogeneity and its role in the brain
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Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex
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InfluentialSelf-citationMicroglia regulate central nervous system myelin growth and integrity
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Crosstalk Between Astrocytes and Microglia: An Overview
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“Given that microglia and astrocytes influence each other's state and function (Matejuk and Ransohoff 2020), we wanted to ensure that cortical astrocyte numbers were not also altered by microglia depletion following demyelination.”
Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model
Guttenplan, K. A., Weigel, M. K., Adler, D. I., Couthouis, J., Liddelow, S. A., Gitler, A. D., & Barres, B. A. (2020) · Nature Communications · doi:10.1038/s41467-020-17514-9 · Cited by 278 · see citing works
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“To test the latter possibility, we quantified the number of BCAS1+ newly formed oligodendrocytes (Fard et al. 2017) in the early and late recovery period in mice treated with PLX-3397 (Figure 5).”
InfluentialCortical remyelination: A new target for repair therapies in multiple sclerosis
Chang, A., Staugaitis, S. M., Dutta, R., Batt, C. E., Easley, K. E., Chomyk, A. M., Yong, V. W., Fox, R. J., Kidd, G. J., & Trapp, B. D. (2012) · Annals of Neurology · doi:10.1002/ana.23693 · Cited by 216 · cited 1× · see citing works
“Although OPCs represent an available pool to replace lost oligodendrocytes and myelin, replacement is limited, particularly in cortical lesions (Chang et al. 2012).”
Nemes-Baran, A. D., White, D. R., & DeSilva, T. M. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108047 · Cited by 196 · cited 1× · see citing works
“In fact, microglial phagocytosis of OPCs and oligodendrocytes during early postnatal development in white matter limits the number of oligodendrocytes and myelin sheaths formed (Nemes-Baran et al. 2020).”
Five Decades of Cuprizone, an Updated Model to Replicate Demyelinating Diseases
Vega-Riquer, J. M., Mendez-Victoriano, G., Morales-Luckie, R. A., & Gonzalez-Perez, O. (2019) · Current Neuropharmacology · doi:10.2174/1570159x15666170717120343 · Cited by 188 · see citing works
Activated microglia drive demyelination via <scp>CSF1R</scp> signaling
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“Depletion of microglia, using an inhibitor of colony stimulating factor 1 receptor (Csf1r) either before or during cuprizone administration, led to delayed or reduced demyelination in the corpus callosum (Marzan et al. 2021).”
Lee, S., Shi, X., Fan, A., West, B. L., & Zhang, J. (2018) · Molecular Pain · doi:10.1177/1744806918764979 · Cited by 134 · cited 1× · see citing works
“…cytokines that could be directly toxic to newly forming oligodendrocytes and/or induce the recruitment of other cytotoxic immune cells (Lee et al. 2018; Wang et al. 2018; Wies Mancini et al. 2023) or induce other local cells, such as astrocytes, to become directly toxic to…”
Neely, S. A., Williamson, J. M., Klingseisen, A., Zoupi, L., Early, J. J., Williams, A., & Lyons, D. A. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-01009-x · Cited by 132 · see citing works
Remyelination alters the pattern of myelin in the cerebral cortex
Orthmann-Murphy, J., Call, C. L., Molina-Castro, G. C., Hsieh, Y. C., Rasband, M. N., Calabresi, P. A., & Bergles, D. E. (2020) · eLife · doi:10.7554/elife.56621 · Cited by 111 · cited 19× · see citing works
“BCAS1 + GFP+ oligodendrocytes should represent a relatively more mature differentiating oligodendrocyte state than BCAS1 + GFP-cells (Chapman et al. 2024; Hughes et al. 2018; Orthmann-Murphy et al. 2020).”
InfluentialSelf-citationPlemel, J. R., Manesh, S. B., Sparling, J. S., & Tetzlaff, W. (2013) · Glia · doi:10.1002/glia.22535 · Cited by 107 · cited 1× · see citing works
“In the setting of demyelinating injury, microglia remove myelin debris by phagocytosis (Yamasaki et al. 2014), thereby eliminating at least one barrier to OPC differentiation (Kotter 2006; Plemel et al. 2013).”
Fractalkine protein localization and gene expression in mouse brain
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“Whether baseline heterogeneity in cortical microglia (Hammond et al. 2019; Paolicelli et al. 2022; Tarozzo et al. 2003) also influences spatially distinct reactive responses is not yet known.”
Liu, Y., Given, K. S., Dickson, E. L., Owens, G. P., Macklin, W. B., & Bennett, J. L. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.04.011 · Cited by 105 · cited 1× · see citing works
“PLX-5622 has 100-fold higher selectivity for Csf1r compared to other members of the platelet-derived growth factor receptor (PDGFRα) family of type III receptor tyrosine kinases (Liu et al. 2019).”
A limited capacity for microglial repopulation in the adult brain
Najafi, A. R., Crapser, J., Jiang, S., Ng, W., Mortazavi, A., West, B. L., & Green, K. N. (2018) · Glia · doi:10.1002/glia.23477 · Cited by 99 · cited 1× · see citing works
“While our findings are consistent with previous studies that showed incomplete depletion of microglia with PLX-3397 (Najafi et al. 2018), we also tested whether administration of a different Csf1r inhibitor, PLX-5622, would show improved Iba1+ cell depletion over PLX-3397.”
Baxi, E. G., DeBruin, J., Jin, J., Strasburger, H. J., Smith, M. D., Orthmann‐Murphy, J. L., Schott, J. T., Fairchild, A. N., Bergles, D. E., & Calabresi, P. A. (2017) · Glia · doi:10.1002/glia.23229 · Cited by 97 · cited 1× · see citing works
“…irradiated 18% protein rodent diet (Teklad Global) alone (sham) or supplemented with 0.2% w/v bis(cyclohexanone) oxaldihydrazone (Cuprizone, Santa Cruz Biotechnology) for 4 weeks, and then returned to a standard pellet diet as previously described (Baxi et al. 2017; Orthmann-Murphy et al. 2020).”
InfluentialSelf-citationWhat are activated and reactive glia and what is their role in neurodegeneration?
Bennett, M. L., & Viaene, A. N. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105172 · Cited by 77 · cited 1× · see citing works
“In addition to morphology changes, reactive microglia are commonly identified by upregulation of CD68, a lysosomal protein expressed by activated and phagocytosing microglia and macrophages (Bennett and Viaene 2021).”
Microglia promote remyelination independent of their role in clearing myelin debris
Baaklini, C. S., Ho, M. F. S., Lange, T., Hammond, B. P., Panda, S. P., Zirngibl, M., Zia, S., Himmelsbach, K., Rana, H., Phillips, B., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113574 · Cited by 73 · cited 2× · see citing works
“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).”
Wang, Y., Wang, Y.-R., Mao, X.-F., et al. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.03.177 · Cited by 44 · cited 1× · see citing works
“…that could be directly toxic to newly forming oligodendrocytes and/or induce the recruitment of other cytotoxic immune cells (Lee et al. 2018; Wang et al. 2018; Wies Mancini et al. 2023) or induce other local cells, such as astrocytes, to become directly toxic to oligodendrocytes (Guttenplan…”
Irfan, M., Evonuk, K. S., & DeSilva, T. M. (2022) · The FEBS Journal · doi:10.1111/febs.16190 · Cited by 39 · see citing works
Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination
Chapman, T. W., Kamen, Y., Piedra, E. T., & Hill, R. A. (2024) · The Journal of Neuroscience · doi:10.1523/jneurosci.1794-23.2024 · Cited by 33 · see citing works
The effect of CX3CL1/ CX3CR1 signal axis on microglia in central nervous system diseases
Zhao, J., Li, Q., Ouyang, X., Wang, F., Li, Q., Xu, Z., Ji, D., Wu, Q., Zhang, J., Lu, C., et al. (2023) · Journal of Neurorestoratology · doi:10.1016/j.jnrt.2023.100042 · Cited by 29 · cited 2× · see citing works
“To do so, we quantified the number of cortical Iba1+ cells (which should mainly represent microglia (Zhao et al. 2023)) in Mobp-eGFP mice (or their wild-type littermates) following cuprizone administration and at early and late recovery.”
Microglial phagocytosis of single dying oligodendrocytes is mediated by CX3CR1 but not MERTK
Olveda, G. E., Barasa, M. N., & Hill, R. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114385 · Cited by 23 · cited 1× · see citing works
“The first is that there is delayed clearance of dying baseline oligodendrocytes, as deep cortical reactive microglia are not present to phagocytose these cells (Olveda et al. 2024).”
Microglia depletion as a therapeutic strategy: friend or foe in multiple sclerosis models?
Mancini, V. S. B. W., Pietro, A. A. D., & Pasquini, L. A. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.346538 · Cited by 20 · see citing works
BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis
Bergner, C. G., van der Meer, F., Franz, J., Vakrakou, A., Würfel, T., Nessler, S., Schäfer, L., Nau-Gietz, C., Winkler, A., Lagumersindez-Denis, N., et al. (2025) · Brain · doi:10.1093/brain/awae293 · Cited by 16 · cited 2× · see citing works
“We also quantified BCAS1+ cells by morphology, defining pre-myelinating cells and early-myelinating BCAS1+ cells as previously described (Figure 4E; corresponding to resting and activated BCAS1+ cells, respectively, from Bergner et al. 2024).”
Zivadinov, R., Keenan, A., Le, H. H., Ait-Tihyaty, M., Gandhi, K., Zierhut, M. L., Salvo‐Halloran, E. M., Ramirez, A. O., Vuong, V., Singh, S. R., et al. (2024) · BMC Neurology · doi:10.1186/s12883-024-03888-6 · Cited by 5 · see citing works
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Song, H., Zhu, Z., Xiao, L., Zhao, Q., Li, C., Lv, A., Yu, X., Gao, Z., Lin, J., Wang, Y., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03829-9
CSF1R inhibition following antibody mediated demyelination has limited impact on remyelination
Golden, L. C., Peet, G. C., Rodriguez, R. E., Jahahn, N. J., Owens, G. P., Bennett, J. L., & Macklin, W. B. (2026) · Acta Neuropathologica Communications · doi:10.1186/s40478-026-02370-3
“These findings are similar to recent effects reported in response to microglial depletion in a cuprizone demyelination model [20] suggesting that microglial depletion may enhance OPC differentiation to premyelinating cells.”
- Authors
- Loo, H. K., Gallegos, J., Mialki, C., Perrin, G. E., Malloy, T., & Orthmann‐Murphy, J. L.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Orthmann‐Murphy, Jennifer L.
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2026-01-08
- Volume
- 74
- Issue
- 3
- Pages
- e70120-e70120
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC12784134
- OpenAlex
- W7119538417
- Semantic Scholar
- 6906e1b7b3d721527c5e812441b2bd0ac4cb0636
- Cited by
- 2
- References
- 33
- Citations by year
- 2026: 2
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Glia (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS132793)
- National Multiple Sclerosis Society (RG‐2207‐40022)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- microglia depletion, oligodendrocyte regeneration, cuprizone-induced demyelination, multiple sclerosis, reactive microglia, CSF1R inhibitor, oligodendrocyte differentiation, BCAS1, aspartoacylase, CD68
- MeSH terms
- Remyelination, Animals, Cell Count, Cerebral Cortex, Cuprizone, Demyelinating Diseases, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Oligodendroglia, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Microglia, Mice
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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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