Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Open accessAbstract
Microglia are myeloid cells of the CNS that participate both in normal CNS function and in disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia versus myeloid and other immune cells. Of the 239 genes, 106 were enriched in microglia as compared with astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS, and was also observed in human microglia. We found that TGF-β was required for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia and that microglia were absent in the CNS of TGF-β1-deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling and provide insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
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- Findingown data
Loss of microglial cells in the CNS of adult CNS-TGFβ1−/− mice as measured by anti-P2ry12 antibody at 20 and 90 days of age and in TGF-β1−/− mice just prior to death at 20 days.
“We found a loss of microglial cells in the CNS of adult CNS-TGFβ1−/− mice as measured by immunohistochemistry with anti-P2ry12 antibody at 20 and 90 days of age and in TGF-β1−/− mice just prior to death at 20 days (Fig. 7a).”
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No effect was observed when TGF-β1 was added to GM-CSF.
“Adult microglia do not survive in the presence of TGF-β1 alone and no effect was observed when TGF-β1 was added to GM-CSF.”
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CD39+CD11bLow cells were decreased in an identical fashion to F4/80+CD11bLow cells in CNS-TGFβ1−/− mice.
“we found that CD39+CD11bLow cells were decreased in an identical fashion to F4/80+CD11bLow cells (Fig. 7f,g).”
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Microglia expressed the lowest level of microglial genes between embryonic (E10.5, E12.5) and postnatal P4 stages.
“Heatmap hierarchical cluster analysis showed that microglia expressed the lowest level of microglial genes between embryonic (E10.5, E 12.5) and postnatal P4 stages (Supplementary Fig. 9 and Source data - Supplementary Fig. 9).”
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455 proteins were enriched in microglia compared with Ly6C monocytes.
“455 of these proteins were enriched in microglia and 926 proteins (greater than 2-fold difference) were enriched in Ly6C monocytes (Source data Fig. 1).”
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- Findingown data
miR-342-3p was enriched in microglia compared with other CNS cells.
“We found that miR-342-3p was enriched in microglia, whereas both miR-125b-5p and miR-99a were highly expressed in microglia, astrocytes and neurons but not in oligodendrocytes (Supplementary Fig. 7).”
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CNS-TGFβ1−/− mice had loss of FCRLS+ microglia at 20, 90 and 160 days.
“FACS analysis with anti-FCRLS antibody at 20 and 90 days of age (Fig. 7d) and quantitative analysis of FCRLS+CD11b+ cells at 20, 90 and 160 days showed that CNS-TGFβ1−/− mice had loss of FCRLS+ microglia (Fig. 7e).”
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74 proteins were uniquely expressed in microglia.
“we identified a total of 74 proteins which were uniquely expressed in microglia (Supplementary Fig. 1c and Source data Fig. 1).”
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19 genes, mostly related to pro-inflammatory responses including Ccl2 and Ccl3, were suppressed when cultured with MCSF or MCSF+TGF-β1.
“19 genes, mostly related to pro-inflammatory responses including Ccl2 and Ccl3, were suppressed when cultured with MCSF or MCSF+TGF-β1 (Fig. 6b).”
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Of 103 microglial enriched proteins above 5-fold compared with Ly6CLow and Ly6CHi monocytes, 64 were also identified in gene profiling of microglia.
“out of 103 microglial enriched proteins above 5 fold as compared with Ly6CLow and Ly6CHi monocytes (Supplementary Fig. 1d), 64 of the proteins were also identified in gene profiling of microglia (Source data Fig. 1).”
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1381 proteins were differentially expressed between microglia and Ly6C monocyte subsets.
“we found that 1381 of these proteins were differentially expressed between microglia and Ly6C subsets.”
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M1 microglia express a high level of inflammatory-related transcripts including Ccl2, Ccl3, Ccl5.
“We found that M1 microglia express a high level of inflammatory-related transcripts including Ccl2, Ccl3, Ccl5, whereas M2 microglia express genes including IGF-1 (Supplementary Fig. 10a,b), which play a role in tissue development and neural cell renewal28.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Butovsky, O. et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J. Clin. Invest. 116, 905–915 (2006). source
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- Findingown data
Microglia are different from astrocytes, oligodendrocytes and neurons based on hierarchical clustering of MG400 gene expression.
“A dendogram based on unsupervised hierarchical clustering of CNS cell types demonstrates that microglia are different from CNS cells (Fig. 2a).”
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Analysis of a published database found 152 genes specifically expressed in microglia with expression >3-fold across microglia, oligodendrocytes, astrocytes and neurons.
“We compared the identified molecular signature of genes with expression >3-fold across all four populations and found 152 genes which were specifically expressed in microglia (Supplementary Table 2 and Source data – Supplementary Table 2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Cahoy, J.D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008). source
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- Findingown data
miR-99a, miR-125-5p and miR-342-3p were highly expressed in human microglia.
“we found that miR-99a, miR-125-5p and miR-342-3p were highly expressed in human microglia.”
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The highest expression of microglial genes occurred between P21 and 2 months of age.
“The highest expression of microglial genes occurred in the second period, between P21 and 2 months of age (Supplementary Fig. 9a).”
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926 proteins were enriched in Ly6C monocytes compared with microglia, with greater than 2-fold difference.
“455 of these proteins were enriched in microglia and 926 proteins (greater than 2-fold difference) were enriched in Ly6C monocytes (Source data Fig. 1).”
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Top upstream regulators in M0 microglia were related to TGF-β1 signaling.
“we found that the top upstream regulators in M0 microglia were related to TGF-β1 signaling (Supplementary Fig. 10d).”
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81 genes were expressed by both microglia and organ-specific F4/80+CD11b+ macrophages.
“We found 239 genes which were specifically expressed by microglia and 81 genes which were expressed by both microglia and organ specific F4/80+CD11b+ macrophages (Source data Fig. 1).”
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Recruited GFP+Ly6CHi, GFP+Ly6CLow and GFP+Ly6CNeg monocyte subsets did not acquire the microglia signature during EAE.
“We found that recruited GFP+Ly6CHi, GFP+Ly6CLow and GFP+Ly6CNeg monocyte subsets did not acquire the microglia signature during EAE and FCRLS+CD11b+GFP− resident microglia express the microglial signature as defined by the MG400 chip (Fig. 4j and Source data - Figure 4).”
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106 genes were specifically expressed in microglia across microglia, astrocytes, oligodendrocytes and neurons.
“We compared the identified molecular signature of detected genes across all four populations and found 106 genes which were specifically expressed in microglia (Fig. 2d).”
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Anti-FCRLS stained >97% of total CD11b-gated cells in the brain, spinal cord and eye.
“anti-FCRLS stained >97% of total CD11b-gated cells in the brain, spinal cord and eye.”
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miR-125b-5p and miR-99a were highly expressed in microglia, astrocytes and neurons but not in oligodendrocytes.
“We found that miR-342-3p was enriched in microglia, whereas both miR-125b-5p and miR-99a were highly expressed in microglia, astrocytes and neurons but not in oligodendrocytes (Supplementary Fig. 7).”
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Iba-1+ cells in CNS-TGFβ1−/− mice had a round morphology without ramified processes compared with wild type mice.
“these cells had a round morphology without ramified processes as compared to wild type mice (Fig. 7b).”
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Genes related to the TAM system (Mertk, Pros1 and Gas6) were highly expressed in microglia.
“we found that genes related to the TAM system (e.g. Mertk, Pros1 and Gas6) were highly expressed in microglia (Fig. 1g).”
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qPCR analysis of 10 selected microglial genes found minimal if any expression in microglial cell lines.
“We found minimal if any expression of these 10 microglial genes in microglial cell lines.”
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qPCR demonstrated that microglia unique genes Fcrls, Olfml3, Tmem119, P2ry12, Hexb and Tgfbr1 were absent in oligodendrocytes, astrocytes and neurons.
“qPCR analysis demonstrated that the microglia unique genes Fcrls, Olfml3, Tmeme119, P2ry12, Hexb and Tgfbr1 were absent in oligodendrocytes, astrocytes and neurons (Fig. 2g).”
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The microglial signature was also observed in human microglia.
“This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia.”
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No neuronal loss was observed in CNS-TGFβ1−/− or TGF-β1−/− mice.
“We did not observe neuronal loss in either CNS-TGFβ1−/− or TGF-β1−/− mice (Fig. 7b,c).”
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Gene array identified 1572 genes enriched in microglia compared with splenic Ly6C+ monocytes from naïve adult mice.
“Gene array identified 1572 genes that were enriched in microglia (Source data Fig. 1).”
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CD11b+CD45Low microglia were lost in CNS-TGFβ1−/− mice.
“CD11b+CD45Low microglia were lost in CNS-TGFβ1−/− mice (Supplementary Fig. 11a).”
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Iba-1+ myeloid cells were reduced in number in CNS-TGFβ1−/− mice.
“quantitative analysis of Iba-1+ myeloid cells demonstrated a reduced number of Iba-1+ cells in CNS-TGFβ1−/− mice (Fig. 7c)”
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Freshly sorted newborn and cultured primary microglia were closest to adult microglia by hierarchical clustering.
“Hierarchical clustering demonstrated that freshly sorted newborn and cultured primary microglia were closest to adult microglia (Fig. 5a and Source data Fig. 5).”
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Immunohistochemical staining of murine and human brain with anti-P2ry12 antibody identified cells with a microglia morphology.
“Immunohistochemical staining of both murine and human brain with anti-P2ry12 antibody identified cells with a microglia morphology (Fig. 4d).”
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Three microRNAs (miR-125b-5p, miR-342-3p, miR-99a) were specifically expressed in microglia compared with other immune cell types.
“Three of these (miR-125b-5p, miR-342-3p, miR-99a) were specifically expressed in microglia as compared to other immune cell types.”
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24 microRNAs were highly expressed in Ly6C+ inflammatory monocytes and immune cells.
“we identified 24 microRNAs that were highly expressed in Ly6C+ inflammatory monocytes and immune cells.”
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TGF-β1 plus MCSF induced expression of 60 microglial genes above two fold compared with microglia cultured in MCSF only.
“TGF-β1 plus MCSF induced the expression of 60 microglial genes above two fold as compared to microglia cultured in the presence of MCSF only and 108 microglial genes as compared to microglia cultured in the presence of GM-CSF (Source data Fig. 6).”
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FCRLS+CD11b+GFP− resident microglia express the microglial signature as defined by the MG400 chip during EAE.
“We found that recruited GFP+Ly6CHi, GFP+Ly6CLow and GFP+Ly6CNeg monocyte subsets did not acquire the microglia signature during EAE and FCRLS+CD11b+GFP− resident microglia express the microglial signature as defined by the MG400 chip (Fig. 4j and Source data - Figure 4).”
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Adult microglia do not survive in the presence of TGF-β1 alone.
“Adult microglia do not survive in the presence of TGF-β1 alone and no effect was observed when TGF-β1 was added to GM-CSF.”
Quote in the paperSubstantial claim - Findingown data
P2ry12, Gpr34, Mertk, C1qa, Pros1 and Gas6 are highly or uniquely expressed in human microglia compared with human blood-derived CD14+CD16− and CD14+CD16+ monocytes.
“we found that P2ry12, Gpr34, Mertk, C1qa, Pros1 and Gas6 are highly or uniquely expressed in human microglia.”
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Canonical pathway and upstream regulator analysis revealed that TGF-β was among the most affected molecules in microglia.
“canonical pathway (Supplementary Fig. 5) and upstream regulator analysis (Supplementary Table 4) revealed that TGF-β was among the most affected molecules in microglia (Supplementary Fig. 6).”
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qPCR analysis of 6 selected microglial genes found minimal if any expression in other immune cells or organ-specific macrophages.
“We found minimal if any expression of these 6 microglial genes in other immune cells or organ-specific macrophages.”
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TGF-β1 plus MCSF induced expression of 108 microglial genes compared with microglia cultured in GM-CSF.
“TGF-β1 plus MCSF induced the expression of 60 microglial genes above two fold as compared to microglia cultured in the presence of MCSF only and 108 microglial genes as compared to microglia cultured in the presence of GM-CSF (Source data Fig. 6).”
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Red pulp macrophages are the tissue resident macrophages closest to microglia.
“we found that red pulp macrophages are the tissue resident macrophages closest to microglia (Fig. 1f and Source data Fig. 1).”
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There was an increase in CD39−CD11bHi cells which express Ly6C in CNS-TGFβ1−/− mice.
“we found an increase in CD39−CD11bHi cells which express Ly6C (Fig. 7g) and which represent peripherally infiltrating monocytes9,12.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [9] Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS ONE 5, e13693 (2010). source
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- cites [12] Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012). source
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- Findingown data
Three microRNAs (miR-223, miR-148a, miR-15b) were specifically expressed in Ly6C monocyte subsets.
“Three of these (miR-223, miR-148a, miR-15b) were specifically expressed in Ly6C monocyte subsets.”
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239 genes were specifically expressed by microglia compared with organ-specific macrophages and immune cells.
“We found 239 genes which were specifically expressed by microglia and 81 genes which were expressed by both microglia and organ specific F4/80+CD11b+ macrophages (Source data Fig. 1).”
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M2 microglia express genes including IGF-1.
“We found that M1 microglia express a high level of inflammatory-related transcripts including Ccl2, Ccl3, Ccl5, whereas M2 microglia express genes including IGF-1 (Supplementary Fig. 10a,b), which play a role in tissue development and neural cell renewal28.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Butovsky, O. et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J. Clin. Invest. 116, 905–915 (2006). source
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- Findingown data
PCA showed that adult cultured microglia in the presence of MCSF+TGF-β1 most closely resemble freshly sorted adult microglia.
“Principal component analysis of cells analyzed with the MG400 chip showed that adult cultured microglia in the presence of MCSF+TGF-β1 most closely resemble freshly sorted adult microglia (Fig. 6d).”
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None of newborn microglia (P1), primary cultured newborn microglia (P1-P2), microglial cell lines (N9, BV2), embryonic stem cell microglia (ESdMs) or RAW264.7 macrophages expressed the adult microglia signature.
“We found that none of these cells expressed the adult microglia signature we identified.”
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Microglial functions in M0-polarized microglia were related to nervous system development and were not observed in M1 or M2 polarized microglia.
“We found that microglial functions in M0-polarized microglia were related to nervous system development and were not observed in M1 or M2 polarized microglia (Supplementary Fig. 10c).”
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No staining of human cells was observed with anti-FCRLS.
“No staining of human cells was observed with anti-FCRLS.”
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Rat anti-P2ry12 antibody stained Iba-1+GFP− resident microglia in naïve CX3CR1GFP/+ chimeric mice but not recruited Iba-1+GFP+ monocytes.
“rat anti-P2ry12 antibody stained Iba-1+GFP− resident microglia in naïve CX3CR1GFP/+ chimeric mice but not recruited Iba-1+GFP+ monocytes.”
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P2ry12 signal co-localized on CX3CR1GFP microglia.
“the P2ry12 signal co-localized on CX3CR1GFP microglia in which GFP is expressed in resident microglia17,23 (Fig. 4e).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013). source
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- cites [23] Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell Biol. 20, 4106–4114 (2000). source
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- Findingown data
MCSF+TGF-β1 did not induce expression of microglial genes or microglial miRNAs in the N9 microglia cell line or RAW264.7 macrophage cell line.
“MCSF+TGF-β1 did not induce the expression of microglial genes (Fig. 6e) or microglial miRNAs (Fig. 6f) in either the N9 microglia cell line or the RAW264.7 macrophage cell line.”
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No differences in peripheral organ macrophages, dendritic cells or Langerhans cells were found in CNS-TGFβ1−/− mice.
“we did not find differences in peripheral organ macrophages, dendritic cells (DCs) or Langerhans cells (LCs) in CNS-TGFβ1−/− mice (Supplementary Fig. 12)”
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Increased apoptosis of CD39+CD11b+ cells at 20, 90 and 160 days of age in CNS-TGFβ1−/− mice.
“We also found increased apoptosis of CD39+CD11b+ cells at 20, 90 and 160 days of age (Supplementary Fig. 11b,c).”
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The study identified a unique genetic and microRNA signature for both mouse and human microglia cells that distinguishes microglia in the CNS from peripheral monocytes and other immune cells and from other cells of the nervous system.
“Using a multifaceted approach we identified a unique genetic and microRNA signature for both mouse and human microglia cells that distinguishes microglia in the CNS from peripheral monocytes and other immune cells and from other cells of the nervous system.”
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P2ry12 and Sall1 were undetectable in microglia from CNS-TGFβ1−/− mice at P1.
“We found that P2ry12, Sall1 and Fcrls were markedly decreased in microglia from CNS-TGFβ1−/− mice at E14.5 and that P2ry12 and Sall1 were undetectable at P1.”
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Expression of Apoe was markedly increased in CD39+Ly6C−CD11b+ cells from CNS-TGFβ1−/− mice.
“Of note, the expression of Apoe was markedly increased in CD39+Ly6C−CD11b+ cells from CNS-TGFβ1−/− mice (Fig. 8c).”
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There is no difference in CD39+CD11b+ cells between wild type and CNS-TGFβ1−/− mice at E10.5.
“We found no difference in CD39+CD11b+ cells between wild type and CNS-TGFβ1−/− mice at E10.5 (Supplementary Fig. 13).”
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At 60 days of age, CD39+Ly6C−CD11b+ cells from CNS-TGFβ1−/− mice only expressed low levels of microglial genes.
“We found that at 60 days of age, CD39+Ly6C−CD11b+ cells from CNS-TGFβ1−/− mice only expressed low levels of microglial genes and recruited CD39−CD11bHi cells did not express microglial genes (Fig. 8a,b and Source data Fig. 8).”
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Using microglial specific markers and molecular signature, there is loss of microglia as opposed to microgliosis in CNS-TGFβ1−/− mice.
“Using our microglial specific markers and molecular signature, we demonstrate that there is loss of microglia as opposed to microgliosis, and this loss is associated with infiltration of Ly6C positive monocytes into the brain.”
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Genearray analyses and mass spectrometry quantitative TMT-analysis identified 254 genes and 100 proteins that were specifically or highly expressed in adult mouse microglia.
“Genearray analyses and mass spectrometry quantitative TMT-analysis, described above, were used to identify 254 genes and 100 proteins which were specifically or highly expressed in adult mouse microglia.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The data distribution was normal for all statistical analyses.
- Findingown data
CNS-TGF-β1−/− mice developed late onset motor dysfunction.
“Although there was no overt neuronal loss in CNS-TGF-β1−/− mice, these mice developed late onset motor dysfunction.”
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There was no overt neuronal loss in CNS-TGF-β1−/− mice.
“Although there was no overt neuronal loss in CNS-TGF-β1−/− mice, these mice developed late onset motor dysfunction.”
Quote in the paperNot a substantial claim - Findingown data
This loss of microglia is associated with infiltration of Ly6C positive monocytes into the brain.
“Using our microglial specific markers and molecular signature, we demonstrate that there is loss of microglia as opposed to microgliosis, and this loss is associated with infiltration of Ly6C positive monocytes into the brain.”
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High expression of Tgfb1 and Tgfbr1 is observed in microglia.
“We observed high expression of Tgfb1 and the Tgfbr1 in microglia (Fig. 1f).”
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Microglia have different phenotypes that are linked to development.
“We found that microglia have different phenotypes that are linked to development.”
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Microglia loss occurs in the spinal cord of CNS-TGFβ1−/− mice.
“We also observed microglia loss in the spinal cord of CNS-TGFβ1−/− mice; the number of neurons were not affected (Supplementary Fig. 14).”
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At E14.5, there is an increase in CD39−CD11b+ cells (from 6.8% to 44.5%) in CNS-TGFβ1−/− mice.
“In addition, at E14.5 we found an increase in CD39−CD11b+ cells (from 6.8% to 44.5%).”
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The genetic and microRNA signature observed in mice was also found in human microglia.
“The genetic and microRNA signature we observed in mice was also found in human microglia.”
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The same pattern of changes in CD39+CD11b+ and CD39−CD11b+ cells is observed in newborn brain (P1) of CNS-TGFβ1−/− mice.
“This same pattern was observed in newborn brain (P1).”
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CNS-TGFβ−/− mice appear to show a healthy behavior phenotype throughout much of their adult life.
“CNS-TGFβ−/− mice appear to show a healthy behavior phenotype throughout much of their adult life.”
Quote in the paperNot a substantial claim - Findingown data
At 160 days of age, there is a concomitant increase in CD39−CD11b+Ly6C+ cells in CNS-TGFβ1−/− mice.
“At 160 days of age we found that CD39+CD11bLow cells were lost in CNS-TGFβ1−/− mice and this was associated with a concomitant increase in CD39−CD11b+Ly6C+ cells (Fig. 7h and Supplementary Fig. 13a).”
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P2ry12, Sall1 and Fcrls were markedly decreased in microglia from CNS-TGFβ1−/− mice at E14.5.
“We found that P2ry12, Sall1 and Fcrls were markedly decreased in microglia from CNS-TGFβ1−/− mice at E14.5 and that P2ry12 and Sall1 were undetectable at P1.”
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qPCR analysis demonstrated that microglial genes were absent in CD39+Ly6C−CD11b+ cells from CNS-TGFβ1−/− mice.
“qPCR analysis demonstrated that microglial genes were absent (Fig. 8c).”
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There is no change in the number of F4/80+CD11b+ primitive macrophages in the yolk sac at E10.5 in CNS-TGFβ1−/− mice.
“We did not find a change in the number of F4/80+CD11b+ primitive macrophages in the yolk sac at E10.5 (Supplementary Fig. 13b,c).”
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There was increased expression of Apoe at both E14.5 and P1 in CNS-TGFβ1−/− mice.
“Of note, there was increased expression of Apoe at both E14.5 and P1 (Fig. 8e).”
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IPA identified neuronal and development function as the most significantly expressed pathways in microglia.
“In addition to the known innate immune function of microglia, IPA identified neuronal and development function as the most significantly expressed pathways in microglia.”
Quote in the paperSubstantial claim - Findingown data
Organ-resident macrophages in the gut and liver are "microglia-like" as they express Gas6 and Mertk.
“We also found that organ-resident macrophages in the gut and liver are “microglia-like” as they express Gas6 and Mertk and these genes may have a role in maintaining tissue homeostasis which is consistent with a recent transcriptional profiling of murine tissue macrophages14.”
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IPA analysis revealed that TGF-β pathway and downstream microglial molecules, identified as the most affected molecules in microglia, were suppressed in CNS-TGFβ1−/− mice.
“revealed that TGF-β pathway and downstream microglial molecules, which we identified as the most affected molecules in microglia, were suppressed in CNS-TGFβ1−/− mice (Supplementary Figure 15).”
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Recruited CD39−CD11bHi cells did not express microglial genes in CNS-TGFβ1−/− mice.
“We found that at 60 days of age, CD39+Ly6C−CD11b+ cells from CNS-TGFβ1−/− mice only expressed low levels of microglial genes and recruited CD39−CD11bHi cells did not express microglial genes (Fig. 8a,b and Source data Fig. 8).”
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Microglia specific miRNAs miR-99a, miR-125-5p, and miR-342-3p were markedly decreased in CD39+Ly6C−CD11b+ cells from CNS-TGFβ1−/− mice.
“The microglia specific miRNAs miR-99a, miR-125-5p, and miR-342-3p were markedly decreased in CD39+Ly6C−CD11b+ cells (Fig. 8d).”
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Loss of microglia occurs in mice deficient for TGF-β1 in the CNS.
“Consistent with this, we found loss of microglia in mice deficient for TGF-β1 in the CNS.”
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The number of neurons is not affected in the spinal cord of CNS-TGFβ1−/− mice.
“We also observed microglia loss in the spinal cord of CNS-TGFβ1−/− mice; the number of neurons were not affected (Supplementary Fig. 14).”
Quote in the paperSubstantial claim - Findingown data
At 160 days of age, CD39+CD11bLow cells are lost in CNS-TGFβ1−/− mice.
“At 160 days of age we found that CD39+CD11bLow cells were lost in CNS-TGFβ1−/− mice and this was associated with a concomitant increase in CD39−CD11b+Ly6C+ cells (Fig. 7h and Supplementary Fig. 13a).”
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CNS-TGFβ1−/− mice steadily progressed to paralysis and death by 23-25 weeks of age.
“These mice steadily progressed to paralysis and death by 23–25 weeks of age.”
Quote in the paperSubstantial claim - Premisecitation
In the EAE model, infiltrating monocytes do not contribute to the residual microglial pool.
“in the experimental autoimmune encephalomyelitis (EAE) model, infiltrating monocytes do not contribute to the residual microglial pool8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Ajami, B., Bennett, J.L., Krieger, C., McNagny, K.M. & Rossi, F.M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011). source
- Premisecitation
Microglia can be distinguished from monocytes using red-green mice in which microglia and monocyte-derived macrophages are labeled with CX3CR1 (GFP) and CCR2 (RFP) respectively.
“microglia can be distinguished from monocytes using red-green mice in which microglia and monocyte-derived macrophages are labeled with CX3CR1 (GFP) and CCR2 (RFP) respectively9.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS ONE 5, e13693 (2010). source
Not checked in the free run.
- Interpretationown data
TGF-β is required for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia.
“the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia”
Quote in the paperSubstantial claim - Interpretationown data
Microglia are absent in CNS TGF-β1 deficient mice.
“the absence of microglia in CNS TGF-β1 deficient mice”
Quote in the paperSubstantial claim - Interpretationown data
Microglia and recruited monocytes maintain their own molecular signature during neuroinflammation.
“Thus, microglia and recruited monocytes maintain their own molecular signature during neuroinflammation.”
Quote in the paperSubstantial claim - Premisecitation
There is a resident pool of microglia that is separate from peripheral myeloid cells that infiltrate the nervous system.
“Thus, there is a resident pool of microglia that is separate from peripheral myeloid cells that infiltrate the nervous system.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [4] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). source
Not checked in the free run.
- cites [5] Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012). source
- cites [6] Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013). source
- Interpretationown data
The microglial signature is dependent on TGF-β signaling.
“Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.”
Quote in the paperSubstantial claim - Interpretationcitation
Apart from previously described physiologic changes, the only morphological changes in the brains of CNS-TGFβ1−/− mice were loss of microglia.
“Thus, apart from the physiologic changes described previously33, the only morphological changes in the brains of CNS-TGFβ1−/− mice were loss of microglia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Koeglsperger, T. et al. Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-beta1 in the CNS. Glia 61, 985–1002 (2013). source
- Premisenone given
In prior studies, microglia were identified as F4/80+ cells, which does not distinguish resident microglia from infiltrating macrophages.
“In these studies, microglia were identified as F4/80+ cells which does not distinguish resident microglia from infiltrating macrophages.”
Quote in the paperSubstantial claim - Premisecitation
TGF-β1−/− mice develop a lethal autoinflammatory syndrome shortly after birth linked to a T-cell specific deficiency of TGF-β.
“TGF-β1−/− mice develop a lethal autoinflammatory syndrome shortly after birth29,30 which is linked to a T-cell specific deficiency of TGF-β31.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [29] Kulkarni, A.B. et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774 (1993). source
- cites [30] Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992). source
- cites [31] Gorelik, L. & Flavell, R.A. Transforming growth factor-beta in T-cell biology. Nat. Rev. Immunol. 2, 46–53 (2002). source
- Study design and conductown data
The expression of 6 selected microglial genes in MCSF+TGF-β1 cultured microglia was confirmed by qPCR.
“The expression of 6 selected microglial genes in MCSF+TGF-β1 cultured microglia was confirmed by qPCR (Fig. 6c).”
Quote in the paperNot a substantial claim - Study design and conductown data
qPCR analysis validated the expression of 6 selected microglial genes in different cell populations.
“We then performed quantitative RT-PCR (qPCR) analysis of 6 selected microglial genes to validate their expression in different cell populations (Fig. 1g).”
Quote in the paperSubstantial claim - Interpretationreasoning
Microglia are clearly more diverse than an M1/M2 classification.
“A similar plasticity exists in microglia that are clearly more diverse than an M1/M2 classification.”
Quote in the paperSubstantial claim - Study design and conductown data
In chimeric naïve or EAE mice, mononuclear cells stained for CD11b can be subdivided into CD11b+GFP−FCRLS+ microglia and CD11b+GFP+FCRLS− peripheral macrophages.
“In chimeric naïve or EAE mice, mononuclear cells stained for the monocyte marker CD11b could be easily subdivided into three distinct subsets: 1) CD11b+GFP−FCRLS+ microglia and 2) CD11b+GFP+FCRLS− peripheral macrophages (Fig. 4i).”
Quote in the paperSubstantial claim - Study design and conductown data
The purity of CNS cell types was established by qPCR analysis using their known unique markers.
“The purity of CNS cells types was established by qPCR analysis using their known unique markers (Fig. 2f).”
Quote in the paperSubstantial claim - Premisecitation
TGF-β1−/− mice are not viable on a 100% C57BL6 background.
“Because TGF-β1−/− mice are not viable on a 100% C57BL6 background29, we refrained from backcrossing them.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Kulkarni, A.B. et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774 (1993). source
- Interpretationown data
TGF-β1 is a major differentiation factor for microglia both in vitro and in vivo.
“We identified TGF-β1 as a major differentiation factor for microglia both in vitro and in vivo.”
Quote in the paperSubstantial claim - Study design and conductown data
In chimeric mice, 95-97% of F4/80+CD11b+ cells in the spleen were GFP+ 8 weeks after transplant.
“We found that 95–97% of F4/80+CD11b+ cells in the spleen were GFP+.”
Quote in the paperSubstantial claim
- May combine two claims. 34
- The quote only partly states this claim. 2
- Classified as probably not a substantial claim. 40
May combine two claims.
Findingown dataQuantitative analysis showed significant reduction of CD39+CD11b+ cells and a reciprocal increase in Ly6C+CD11b+ cells at 20, 90 and 160 days in CNS-TGFβ1−/− mice.
“Quantitative analysis showed significant reduction of CD39+CD11b+ cells and a reciprocal increase in Ly6C+CD11b+ cells at 20, 90 and 160 days in CNS-TGFβ1−/− mice (Fig. 7h).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data8 microRNAs were highly expressed in microglia compared with immune cells.
“We found 8 microRNAs that were highly expressed in microglia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe microglial signature was not observed in microglial lines or in monocytes recruited to the CNS.
“This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAnti-P2ry12 stained a subpopulation of CD14+ myeloid cells isolated from fresh post-mortem brain but did not stain peripheral blood CD14+ monocytes.
“FACS analysis of human cells showed that anti-P2ry12 stained a subpopulation of CD14+ myeloid cells isolated from fresh post-mortem brain but did not stain peripheral blood CD14+ monocytes (Fig. 4c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoe was highly expressed in newborn and primary microglia and had minimal expression in adult microglia.
“Apoe was highly expressed in newborn and primary microglia and had minimal expression in adult microglia (Fig. 5c).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataApoe expression was downregulated in microglia during development and reciprocally correlated with induction of microglial genes.
“Apoe expression was downregulated in microglia during development and expression of Apoe reciprocally correlated with the induction of microglial genes (Supplementary Fig. 9c).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIL2TGF-β1-Tg-TGF-β1−/− mice were protected from lethal inflammation, survived into adulthood and were indistinguishable from IL2TGF-β1-Tg-TGF-β1+/− littermates at 4-10 weeks with no signs of inflammation or organ dysfunction.
“We found that IL2TGF-β1-Tg-TGF-β1−/− mice were protected from lethal inflammation, survived into adulthood and were indistinguishable from IL2TGF-β1-Tg-TGF-β1+/− littermates at the age of 4–10 weeks with no signs of inflammation or organ dysfunction.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThere was significant reduction of F4/80+CD11b+ cells and reduced CD11b expression in CNS-TGFβ1−/− mice compared with wild type mice.
“We found that there was significant reduction of F4/80+CD11b+ cells as compared to wild type mice and that the level of CD11b expression was reduced in CNS-TGFβ1−/− mice (Fig. 7f).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAnti-FCRLS and anti-P2ry12 antibodies stain adult microglia isolated from naïve murine brain but did not stain CD11b-gated myeloid cells from murine spleen, bone marrow and peripheral blood.
“FACS analysis shows that anti-FCRLS and anti-P2ry12 antibodies stain adult microglia isolated by conventional methods22 from naïve murine brain but did not stain CD11b-gated myeloid cells from murine spleen, bone marrow and peripheral blood (Fig. 4a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Cardona, A.E., Huang, D., Sasse, M.E. & Ransohoff, R.M. Isolation of murine microglial cells for RNA analysis or flow cytometry. Nat. Protoc. 1, 1947–1951 (2006). source
May combine two claims.
Findingown dataIPA found that top microglial functions in naïve adult microglia were related to nervous system development and were not observed in monocytes.
“We found that the top microglial functions in naïve adult microglia were related to nervous system development and were not observed in monocytes (Supplementary Fig. 2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataP2ry12 signal was not observed on GFAP+ astrocytes or NeuN+ neurons or peripheral tissue resident macrophages in splenic red and white pulp, lung, kidney, liver and skin.
“The P2ry12 signal was not observed on GFAP+ astrocytes or NeuN+ neurons (Fig. 4f) or peripheral tissue resident macrophages in splenic red and white pulp, lung, kidney, liver and skin (Supplementary Fig. 8a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGenes Fcrls, P2ry12, Tmem119, Olfml3, Hexb, Tgfbr1, Gpr34 and Sall1 appear to be expressed in microglia as they were not detected in immune cells, Ly6C monocytes or organ-specific macrophages.
“we identified genes (e.g., Fcrls, P2ry12, Tmem119, Olfml3, Hexb, Tgfbr1, Gpr34 and Sall1), which appear to be expressed in microglia as we did not detect them in immune cells, Ly6C monocytes or organ specific macrophages.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataMass spectrometry identified 1991 proteins in microglia and splenic Ly6CHi and Ly6CLow subsets.
“Mass spectrometry identified a total of 1991 proteins (Supplementary Fig. 1a,b and Source data Fig. 1).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationIL2TGF-β1-Tg-TGF-β1−/− mice did not express TGF-β1 in the brain or spinal cord and had no TGF-β1-producing T-cells in the CNS.
“we found that these animals did not express TGF-β1 in the brain or spinal cord and we found no TGF-β1-producing T-cells in the CNS of those animals33.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Koeglsperger, T. et al. Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-beta1 in the CNS. Glia 61, 985–1002 (2013). source
May combine two claims.
Findingown dataIn EAE, recruited GFP+ monocytes do not express P2ry12 and resident GFP− microglia are positive for P2ry12 in both naïve and EAE mice.
“recruited GFP+ monocytes do not express P2ry12 and resident GFP− microglia are positive for P2ry12 in both naïve and EAE mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-15b, miR-148a and miR-223 were highly expressed in human monocytes, with miR-223 the most selectively expressed miRNA.
“we also found that miR-15b, miR-148a and miR-223 were highly expressed in human monocytes with miR-223 the most selectively expressed miRNA.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingnone givenIL2TGF-β1-Tg-TGF-β1+/− mice do not show any clinical or pathological abnormalities and breed well.
“IL2TGF-β1-Tg-TGF-β1+/− mice do not show any clinical or pathological abnormalities and breed well.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Findingown dataA set of 399 microglial genes and 611 monocyte genes was identified.
“A set of identified 399 microglial genes and 611 monocyte genes (see Fig. 1a and Supplementary Table 1) were imported into MetaCore to build an analysis of functional ontologies including GeneGo process, GeneGo disease process, canonical pathway maps, and networks.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The data distribution was normal for all statistical analyses.
May combine two claims.
Findingown dataCNS-TGFβ1−/− mice were normal until 100-120 days of age, when they developed motor abnormalities as measured by decreased body weight and reduced rotorod performance.
“CNS-TGFβ1−/− mice were normal until they reached 100–120 days of age when they developed motor abnormalities (Supplementary Movie 1) as measured by decreased body weight and reduced rotorod performance (Fig. 7j).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt E14.5, there is a significant reduction in CD39+CD11b+ cells (from 82.7% to 14.7%) in CNS-TGFβ1−/− mice compared with wild type, associated with reduced surface expression of CD11b.
“However, at E14.5 we found a significant reduction in CD39+CD11b+ cells (from 82.7% to 14.7%) associated with reduced surface expression of CD11b.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe study identified a TGFβ-1 dependent microglial signature and structures on the surface of microglia that provide the ability to distinguish microglia from infiltrating myeloid cells in the CNS.
“In summary, we have identified a TGFβ-1 dependent microglial signature and structures on the surface of microglia that provide the ability to distinguish microglia from infiltrating myeloid cells in the CNS.”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenCommonly studied microglia cell lines and primary microglia do not express the adult microglial molecular signature and do not express the signature after culture with TGF-β1.
“Commonly studied microglia cell lines and primary microglia do not express the adult microglial molecular signature and do not express the signature after culture with TGF-β1.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe MG400 chip contains 40 inflammation-related genes that were significantly affected in EAE, APP/PS1 and SOD1 mice.
“In addition, the MG400 chip contains 40 inflammation-related genes which were significantly affected in EAE, APP/PS1 and SOD1 mice (see Supplementary Table 6).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: The data distribution was normal for all statistical analyses.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe microglial lineage is mainly regulated by CSFR1 and its ligand IL-34.
“This lineage is mainly regulated by CSFR14 and its ligand, IL-347.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). source
Not checked in the free run.
- cites [7] Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAdult microglia derive from primitive macrophages in a Myb-independent manner via PU.1 and IRF8 dependent pathways.
“adult microglia derive from primitive macrophages4 in a Myb-independent manner5 via PU.1 and IRF8 dependent pathways6.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). source
Not checked in the free run.
- cites [5] Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012). source
- cites [6] Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe mouse anti-GFAP antibody used was validated in ref. 33.
“mouse anti-GFAP (1:300; BD Pharmingen, clone 2E1, validated in ref. 33)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites ref. 33
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 conductcitationThe rabbit anti-P2ry12 pAb used for staining in Fig. 4d was validated in ref. 21.
“The tissue shown in Fig. 4d was stained with a rabbit anti-P2ry12 pAb (1:200, validated in ref. 21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites ref. 21
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.
PremisecitationMacrophage progenitors develop from the primitive ectoderm of the yolk sac and give rise to tissue macrophages that do not have a monocytic progenitor.
“Our findings are consistent with reports that macrophage progenitors develop from the primitive ectoderm of the yolk sac4 and give rise to tissue macrophages that do not have a monocytic progenitor16,17.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). source
Not checked in the free run.
- cites [16] Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013). source
Not checked in the free run.
- cites [17] Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTgfb1−/− animals die at 3 weeks of age of a severe multifocal autoinflammatory disorder.
“Tgfb1−/− animals die at 3 weeks of age of a severe multifocal autoinflammatory disorder30 and it has been reported that the loss of TGF-β1 in these mice leads to increased neuronal cell death and microgliosis in the brain47.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992). source
Classified as probably not a substantial claim.
Study design and conductcitationThe dataset was filtered to an MS2 spectra assignment false discovery rate of smaller than 1% at the protein level, using probabilities from linear discrimination scores.
“Linear discrimination scores were used to assign probabilities to each MS2 spectrum for being assigned correctly and these probabilities were further used to filter the dataset with an MS2 spectra assignment FDR of smaller than a 1% at the protein level58.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [58] Huttlin, E.L. et al. A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143, 1174–1189 (2010). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAll tissue resident macrophages are different to an extent yet cluster together when compared to monocytes and DCs, and spleen red pulp macrophages are closely associated with microglia.
“Recent work demonstrated that all tissue resident macrophages are different to an extent yet cluster together when compared to monocytes and DCs and that spleen red pulp macrophages were closely associated with microglia14.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Gautier, E.L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData collection and analysis were performed blind to the conditions of the experiments.
“Data collection and analysis were performed blind to the conditions of the experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe MS2 spectra assignment false discovery rate was less than 1%, achieved by applying the target-decoy database search strategy.
“A MS2 spectra assignment false discovery rate (FDR) of less than 1% was achieved by applying the target-decoy database search strategy60.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] Elias, J.E. & Gygi, S.P. Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat. Methods 4, 207–214 (2007). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOthers have reported that in vitro, TGF-β1 signaling induces a quiescent microglial phenotype and promotes resting microglial properties.
“others have reported that in vitro, TGF-β1 signaling induces a quiescent microglial phenotype25 and promotes resting microglial properties26”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [25] Abutbul, S. et al. TGF-beta signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia 60, 1160–1171 (2012). source
- cites [26] Schilling, T., Nitsch, R., Heinemann, U., Haas, D. & Eder, C. Astrocyte-released cytokines induce ramification and outward K+ channel expression in microglia via distinct signaling pathways. Eur. J. Neurosci. 14, 463–473 (2001). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeficits in microglia function contribute to synaptic abnormalities which may be present in neuro-developmental disorders.
“Consistent with this, deficits in microglia function have been reported to contribute to synaptic abnormalities which may be present in neuro-developmental disorders41.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Paolicelli, R.C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCD39 is expressed on adult microglia and can distinguish recruited Ly6C+ monocytes from resident microglia.
“We previously reported that CD39 is expressed on adult microglia and can distinguish recruited Ly6C+ monocytes from resident microglia12.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationPrimitive macrophages exit the yolk sac blood islands at the onset of circulation and colonize the neuroepithelium from E9.5 to give rise to microglia.
“Thus, primitive macrophages exit the yolk sac blood islands at the onset of circulation and colonize the neuroepithelium from E9.5 to give rise to microglia.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationLoss of TGF-β1 in Tgfb1−/− mice leads to increased neuronal cell death and microgliosis in the brain.
“Tgfb1−/− animals die at 3 weeks of age of a severe multifocal autoinflammatory disorder30 and it has been reported that the loss of TGF-β1 in these mice leads to increased neuronal cell death and microgliosis in the brain47.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [47] Brionne, T.C., Tesseur, I., Masliah, E. & Wyss-Coray, T. Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 40, 1133–1145 (2003). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll qRT-PCRs were performed in duplicate or triplicate, and the data are presented as mean ± standard error of mean.
“All qRT-PCRs were performed in duplicate or triplicate, and the data are presented as mean ± standard error of mean (s.e.m).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTGF-β1 exerts a protective effect against various neuronal insults.
“Numerous studies have demonstrated that TGF-β1 exerts a protective effect against various neuronal insults46.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Flanders, K.C., Ren, R.F. & Lippa, C.F. Transforming growth factor-betas in neurodegenerative disease. Prog. Neurobiol. 54, 71–85 (1998). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationOur sample sizes are similar to those reported in previous publication12.
“No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publication12.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites previous publication12
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Study design and conductown dataAll RNA samples used for microarray analysis had high-quality RNA, with RNA integrity numbers (RIN) between 8.7 and 10, as assessed by Bioanalyzer 2100.
“RNA quality and integrity were assessed using Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA) with all samples having high-quality RNA [RNA integrity number (RIN) = 8.7–10].”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTAM family receptors/ligands are expressed in macrophages.
“It is well known that TAM family receptors/ligands are expressed in macrophages15.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Rothlin, C.V., Ghosh, S., Zuniga, E.I., Oldstone, M.B. & Lemke, G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131, 1124–1136 (2007). source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe results are consistent with previous studies on the role of microglia in the development and function of the nervous system.
“Our results are consistent with previous studies on the role of microglial in the development and function of the nervous system41,48–50.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [41] Paolicelli, R.C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). source
Not checked in the free run.
- cites [48] Wake, H., Moorhouse, A.J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009). source
- cites [49] Saijo, K. et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47–59 (2009). source
- cites [50] Peri, F. & Nusslein-Volhard, C. Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133, 916–927 (2008). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPU.1 deficient mice do not develop myeloid cells.
“which confirms previous observations that PU.1 deficient mice do not develop myeloid cells19,20.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [19] Scott, E.W. et al. PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors. Immunity 6, 437–447 (1997). source
- cites [20] Beers, D.R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103, 16021–16026 (2006). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAnimals were assigned to various experimental groups randomly.
“Also, data for each experiment were collected and processed randomly and animals were assigned to various experimental groups randomly as well.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningEmbryonic and early post-natal microglia acquire the features of adult microglia after post-natal day four, possibly as newly-proliferated microglial cells begin to express differentiated functions.
“Thus, embryonic and early post-natal microglia acquire the features of adult microglia after post-natal day four, possibly as newly-proliferated microglial cells begin to express differentiated functions.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo statistical methods were used to predetermine sample sizes.
“No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publication12.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe blood brain barrier begins to form at E13.5 and may isolate the developing brain from the contribution of fetal liver hematopoiesis.
“The blood bran barrier begins to form at E13.5 and may isolate the developing brain from the contribution of fetal liver hematopoiesis40.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Ginhoux, F., Lim, S., Hoeffel, G., Low, D. & Huber, T. Origin and differentiation of microglia. Front. Cell. Neurosci. 7, 45 (2013). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe rabbit anti-Iba1 antibody used was validated in ref. 12.
“rabbit anti-Iba1 (1:500; Wako, cat. no. 019-19741, validated in ref. 12)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites ref. 12
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 conductcitationThe mouse anti-NeuN antibody used was validated in ref. 12.
“mouse anti-NeuN (1:500; Millipore, validated in ref. 12)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites ref. 12
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 givenThe quality of cDNA and fragmented cDNA was assessed in the Agilent bioanalyzer.
“The quality of cDNA and fragmented cDNA was assessed in the Agilent bioanalyzer.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataLack of TGF-β1 affected microglial development beginning at E14.5 but did not affect microglial progenitors at the E10.5 stage.
“In summary, lack of TGF-β1 affected microglial development beginning at E14.5 but did not affect microglial progenitors at the E10.5 stage.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn mice, microglia arise early during development from progenitors in the embryonic yolk sac.
“Subsequent reports showed that microglia arise early during development from progenitors in the embryonic yolk sac4,38,39.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). source
Not checked in the free run.
- cites [38] Herbomel, P., Thisse, B. & Thisse, C. Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor–dependent invasive process. Dev. Biol. 238, 274–288 (2001). source
Not checked in the free run.
- cites [39] Chan, W.Y., Kohsaka, S. & Rezaie, P. The origin and cell lineage of microglia: new concepts. Brain Res. Rev. 53, 344–354 (2007). source
May combine two claims.
PremisecitationCNS-TGFβ1−/− mice have defects in extracellular glutamate homeostasis and synaptic plasticity.
“These animals have defects in extracellular glutamate homeostasis and synaptic plasticity33”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Koeglsperger, T. et al. Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-beta1 in the CNS. Glia 61, 985–1002 (2013). source
May combine two claims.
Interpretationown dataThe presence of genes related to neuronal function in cultured and ex vivo adult microglia does not simply represent extracellular absorption, as the microglial genes identified were upregulated by exogenous TGF-β1 in vitro.
“Because we identified genes related to neuronal function both in cultured as well as ex vivo adult microglia, the presence of these genes does not simply represent extracellular absorption as the microglial genes we identified were upregulated by exogenous TGF-β1 in vitro.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductreasoningDensitometry values between arrays were normalized using the Robust Multichip Average function and log2-transformed to minimize technical (nonbiological) variability among arrays.
“To minimize technical (nonbiological) variability among arrays, densitometry values between arrays were normalized using the Robust Multichip Average function and further transformed to the logarithmic scale (log2).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationEndogenous TGF-β1 is essential for normal murine Langerhans cell development and TGF-β1 acts directly on Langerhans cells through an autocrine/paracrine loop.
“it has been reported that endogenous TGF-β1 is essential for normal murine Langerhans cell development35 and TGF-β1 acts directly on Langerhans cells through an autocrine/paracrine loop36.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35] Borkowski, T.A., Letterio, J.J., Farr, A.G. & Udey, M.C. A role for endogenous transforming growth factor beta 1 in Langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal Langerhans cells. J. Exp. Med. 184, 2417–2422 (1996). source
- cites [36] Kaplan, D.H. et al. Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells. J. Exp. Med. 204, 2545–2552 (2007). source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationGas6 and Mertk may have a role in maintaining tissue homeostasis.
“We also found that organ-resident macrophages in the gut and liver are “microglia-like” as they express Gas6 and Mertk and these genes may have a role in maintaining tissue homeostasis which is consistent with a recent transcriptional profiling of murine tissue macrophages14.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Gautier, E.L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012). source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationOn the C57BL6/Sv129 background, 60-80% of homozygous TGF-β1−/− conceptuses reached parturition.
“On the C57BL6/Sv129 background, 60–80% of (statistically expected) homozygous TGF-β1−/− conceptuses reached parturition as described29.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Kulkarni, A.B. et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774 (1993). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData for each experiment were collected and processed randomly.
“Also, data for each experiment were collected and processed randomly and animals were assigned to various experimental groups randomly as well.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTGF-β and their receptors are expressed at low levels by both neurons and glial cells, and their expression is upregulated in response to a wide range of neuronal insults and during aging.
“TGF-β and their receptors are expressed at low levels by both neurons and glial cells42,43, and their expression is upregulated in response to a wide range of neuronal insults and during aging44,45.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [42] Flanders, K.C. et al. Localization and actions of transforming growth factor-beta s in the embryonic nervous system. Development 113, 183–191 (1991). source
- cites [43] Hamby, M.E., Hewett, J.A. & Hewett, S.J. Smad3-dependent signaling underlies the TGF-beta1–mediated enhancement in astrocytic iNOS expression. Glia 58, 1282–1291 (2010). source
- cites [44] Henrich-Noack, P., Prehn, J.H. & Krieglstein, J. TGF-beta 1 protects hippocampal neurons against degeneration caused by transient global ischemia. Dose-response relationship and potential neuroprotective mechanisms. Stroke 27, 1609–1614, discussion 1615 (1996). source
- cites [45] Wiessner, C. et al. Expression of transforming growth factor-beta 1 and interleukin-1 beta mRNA in rat brain following transient forebrain ischemia. Acta Neuropathol. 86, 439–446 (1993). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationC1q, Csfr1 and Cd34 genes are known to be expressed on tissue resident macrophages.
“we found increased microglial expression of C1q, Csfr1 and Cd34 genes, which are known to be expressed on tissue resident macrophages14.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Gautier, E.L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012). source
Not checked in the free run.
May combine two claims.
PremisecitationThese mice have defects related to glutamate recycling and synaptic plasticity.
“We have previously reported that these mice have defects related to glutamate recycling and synaptic plasticity33.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Koeglsperger, T. et al. Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-beta1 in the CNS. Glia 61, 985–1002 (2013). source
May combine two claims.
Study design and conductown dataqPCR analysis validated microglial miRNAs and inflammatory Ly6C+ miRNAs and found a similar expression pattern to Nanostring.
“To validate these findings, we performed qPCR analysis of microglial miRNAs (miR-125b-5p, miR-99a, miR-342-3p) and inflammatory Ly6C+ miRNAs (miR-15b, miR-148a, miR-223) and found a similar expression pattern that we observed by Nanostring (Fig. 3c,d).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenControl sections not treated with primary antibody were used to distinguish specific from nonspecific staining or autofluorescent components.
“Control sections (not treated with primary antibody) were used to distinguish specific from nonspecific staining or autofluorescent components.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The CD11b+CD45Low cells isolated from the CNS are pure microglia and not contaminated by other myeloid cells.
“CD11b+CD45Low microglia isolated from the CNS and CD11b+Ly6C+ monocyte subsets isolated from the spleen of naïve adult mice.”
The paper relies on this without support.
There is no human orthologous gene of Fcrls.
“Of note, there is no human orthologous gene of Fcrls in humans, the most highly expressed gene in murine microglia.”
The paper relies on this without support.
TGF-β1 is the relevant TGF-β family member for microglial development and maintenance in the CNS.
“We found a loss of microglial cells in the CNS of adult CNS-TGFβ1−/− mice as measured by immunohistochemistry with anti-P2ry12 antibody at 20 and 90 days of age and in TGF-β1−/− mice just prior to death at 20 days (Fig. 7a).”
The authors state this as an assumption.
The data distribution was normal for all statistical analyses.
“For all statistical analyses, data distribution was assumed to be normal, but this was not formally tested.”
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 unique molecular signature of microglia is dependent upon CSF-1 signaling.
“Moreover, this unique molecular signature is dependent upon CSF-1 [7].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [7]
The Abstract and Discussion identify the unique microglial signature as dependent on TGF-β signaling, not CSF-1 signaling. The Results section, “TGF-β is required for development of microglia in vitro,” reports that adding TGF-β1 to MCSF increased expression of signature genes compared with MCSF alone. MCSF was used in the culture conditions, but the paper does not attribute the signature’s dependence to it. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPU.1 expression levels regulate multiple functions of myeloid and microglial cells, including proliferation, survival, and differentiation.
“PU.1 expression levels regulate multiple myeloid/microglial cell functions47, including proliferation, survival and differentiation”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [47]
The Results section (“Identification of a unique microglial signature”; page unavailable) identifies PU.1 as differentially expressed in microglia and says PU.1-deficient mice do not develop myeloid cells, supporting a role in development. It does not show that PU.1 expression levels regulate proliferation or cell survival, or establish the claimed range of functions. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMost microglial signature genes are downregulated in culture.
“Most signature genes were downregulated by cells in culture (Fig. 6F), consistent with prior reports (Butovsky et al., 2014; Gosselin et al., 2014).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Butovsky et al., 2014
The Results section, “Microglia cell lines do not express a microglia signature” (page unavailable), reports that cultured newborn microglia and microglial cell lines did not express the adult microglial signature. This supports reduced signature expression in those preparations, but does not establish that most signature genes are downregulated by culture itself; the comparison includes differences in developmental stage and cell type. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMicroglia rapidly de-differentiate in culture.
“Our findings that microglia rapidly de-differentiate in culture reecho and expand upon previous reports (Butovsky et al., 2014; Gosselin et al., 2014).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Butovsky et al., 2014
The Results sections on microglial cell lines and TGF-β in vitro report that cultured microglia can lack the adult microglial molecular signature, while TGF-β1 plus MCSF makes cultured adult microglia more closely resemble freshly isolated cells. The paper does not establish that this change happens rapidly, and it shows that the outcome depends on culture conditions. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCR3-positive microglia are resident cells.
“indicating they are resident cells (22).”
From Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016) · cites this paper as [22]
The Introduction states that microglia are resident CNS cells, and the Results distinguish resident microglia from recruited monocytes. But the cited paper does not establish that CR3 positivity identifies cells as resident; its resident-cell identification uses other markers. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
These genes included a large spectrum of intracellular signaling components from the MAP-kinase pathways, as well as TGFβ and receptor, both of which are implicated in the naïve microglial phenotype.
“These genes included a large spectrum of intracellular signaling components from the MAP-kinase pathways, as well as TGFβ and receptor, both of which are implicated in the naïve microglial phenotype (Butovsky et al., 2014).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Butovsky et al., 2014
The Results section identifies Tgfbr1 as a microglia-specific gene and reports that TGF-β is important for microglial development and maintenance. The passages do not establish that a broad spectrum of MAP-kinase signaling components is implicated in the naïve microglial phenotype; searches for MAP-kinase and MAPK did not find that point. Page numbers were unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe detailed profiling after separating cells via CD45dim status showed distinct mRNA, miRNA, and protein expression by microglia as compared with infiltrating monocytes or neuroepithelial brain cells.
“The detailed profiling after separating cells via CD45dim status showed distinct mRNA, miRNA, and protein expression by microglia as compared with infiltrating monocytes or neuroepithelial brain cells (Butovsky et al., 2014).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Butovsky et al., 2014
The Results (‘Identification of a unique microglial signature’; page not provided) report distinct gene and protein expression in CD11b+CD45Low microglia versus splenic Ly6C+ monocytes. The paper also compares microglial genes and miRNAs with astrocytes, oligodendrocytes and neurons, but does not report a protein-expression comparison with those CNS cells. The monocytes in the principal profiling comparison were isolated from spleen, not identified as infiltrating cells in the brain. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThese findings partially explain a divergent response of these two cell types to the same stimuli.
“These findings partially explain a divergent response of these two cell types to the same stimuli (Butovsky et al., 2014).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Butovsky et al., 2014
The Results (Identification of a unique microglial signature; page unavailable) show substantial molecular differences between microglia and monocytes, which could help explain different responses. The cited paper does not establish that the two cell types respond divergently to the same stimuli; its reported stimulation experiments concern microglia rather than a direct comparison between the cell types. (LLM, conf=0.78)
Experimental — accuracy not yet measuredA unique signature of microglia leads to a more quiescent, anti-inflammatory phenotype when microglia are cultured with CSF-1.
“There is evidence to suggest that a unique signature of microglia leads to a more quiescent, anti-inflammatory phenotype when microglia are cultured with CSF-1.”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [7]
In Results (‘TGF-β is required for development of microglia in vitro’; page not available), the paper reports that MCSF (CSF-1) culture suppressed several pro-inflammatory genes. But the adult-like microglial signature required MCSF plus TGF-β1; the paper does not show that the signature itself causes a quiescent, anti-inflammatory phenotype with CSF-1 alone. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCSF-1, IL-34, and TGF-β1 have been shown to play important roles in microglial proliferation and/or survival.
“because these cytokines have been shown to play important roles in microglial proliferation and/or survival [43, 44].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [43]
The Results sections on microglial development in vivo and in vitro (pages unavailable) support roles for TGF-β1 and MCSF (CSF-1): CNS TGF-β1 deficiency was associated with microglial loss and increased apoptosis, while adult microglia did not survive in culture with TGF-β1 alone rather than with MCSF. No passage found for IL-34 supports its role in microglial proliferation or survival (searched: IL-34 and the three cytokines together). (LLM, conf=0.87)
Experimental — accuracy not yet measuredN9 and BV2 cell lines and primary cultured microglia derived from P1 and P2 mice lack the molecular signatures of adult microglia in vivo, including key homeostatic genes Tmem119, P2ry12, Cx3cr1, and Hexb.
“However, N9 and BV2, two common microglial cell lines, as well as primary cultured microglia derived from P1 and P2 mice, lack the molecular signatures of adult microglia in vivo, including key homeostatic genes Tmem119, P2ry12, Cx3cr1, and Hexb [8].”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [8]
The Results section, “Microglia cell lines do not express a microglia signature” (page unavailable), reports that N9, BV2, and primary cultured P1–P2 microglia did not express the identified adult microglial signature. The Results section, “Identification of a unique microglial signature” (page unavailable), identifies Tmem119, P2ry12, and Hexb as microglial genes, but the copy does not establish that all four named genes—including Cx3cr1—are lacking in each of those preparations. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn general, microglia across in vitro systems suffer from disseminated molecular changes attributed to loss of signaling with other cells in the brain microenvironment that is required to maintain them in a homeostatic state.
“In general, microglia across in vitro systems suffer from disseminated molecular changes attributed to loss of signaling with other cells in the brain microenvironment that is required to maintain them in a homeostatic state.”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [8]
The Results (‘Microglia cell lines do not express a microglia signature’; page not provided) show that the tested cell lines and primary newborn cultures lacked the adult microglial signature. The Results on TGF-β in vitro also show that adding TGF-β1 and MCSF made cultured adult microglia more closely resemble freshly isolated cells. The paper does not establish that microglia across in vitro systems undergo widespread changes because they lose signaling from other brain cells; that causal explanation and scope go beyond its findings. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTGF-β supplementation was used to promote a more homeostatic phenotype in vitro.
“TGF-β supplementation was used to promote a more homeostatic phenotype in vitro56,57.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [56]
Mice lacking TGF-β1 in the CNS fail to develop cells expressing microglia-specific markers.
“Mice lacking TGF-β1 in the CNS fail to develop cells expressing microglia-specific markers (Butovsky et al., 2014), and Cre-ER dependent deletion of TGFBR2 (a necessary receptor for TGF-β1 and TGF-β2 signaling) from adult microglia leads to loss of mature microglial character in the CNS (Buttgereit et al., 2016).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Butovsky et al., 2014
TMEM119 and P2RY12 have been shown to be expressed solely by microglial cells and not by infiltrating macrophages.
“TMEM119 and P2RY12 are especially useful, since they have been shown to be expressed solely by microglial cells and not by infiltrating macrophages [41,42,43].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [42]
The study described transcription factors and miRNAs characteristic of microglia in healthy brain but not in peripheral monocytes.
“The study described transcription factors and miRNAs characteristic of microglia in healthy brain but not in peripheral monocytes.”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Butovsky et al., 2014
The authors characterized resident microglia by profiling mRNA, miRNA, and protein in comparison with infiltrated brain macrophages, nonmicroglial resident brain cells, and peripheral macrophages.
“we characterized resident microglia by profiling mRNA, miRNA, and protein in comparison with infiltrated brain macrophages, nonmicroglial resident brain cells, and peripheral macrophages (Butovsky et al., 2014).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Butovsky et al., 2014
P2RY12 is a specific microglia marker.
“P2RY12, a purinergic receptor increasingly considered to be a specific microglia marker [7].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [7]
Under these conditions, there is suppression of 19 genes, many associated with a pro-inflammatory response.
“Under these conditions, there is suppression of 19 genes, many associated with a pro-inflammatory response [7].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [7]
APOE4 predisposes to AD pathology in part via the induction of TGFβ-dependent microglia homeostatic regulators that impair microglia-astrocyte cross-talk in response to neurodegeneration.
“These findings in mice and in humans suggest that APOE4 predisposes to AD pathology in part via the induction of TGFβ-dependent microglia homeostatic regulators 13 that impair microglia-astrocyte cross-talk in response to neurodegeneration.”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [13]
Validation data for non-commercial antibodies (anti-Fcrls, anti-Apoe, anti-Abeta, anti-Itgb8) were published in cited works.
“Validation data for non-commercial antibodies: anti-Fcrls mab was published by Butovsky et al. 2014 (PMID: 24316888). Validation data for anti-Apoe mab was published by Kim et al. 2012 (PMID: 23129750), anti-Abeta mab was published by Bero et al. 2012 (PMID: 22457485), and anti-Itgb8 mAb was published by Dodagatta-Marri et al., 2021 (PMID: 34233193).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as Butovsky et al. 2014
The addition of TGF-β to culture aids microglia in developing a transcriptional signature that is somewhat more similar to what is observed in vivo.
“supporting an earlier finding that the addition of TGF-β to culture aids microglia in developing a transcriptional signature that is somewhat more similar to what is observed in vivo [8]”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [8]
Microglia distinctiveness from other immune cells is marked by expression of miR-125b-5p, miR-342-3p, and miR-99a.
“Nevertheless, the distinctiveness of microglia from other immune cells is marked by expression of miR-125b-5p, miR-342-3p, and miR-99a [226].”
From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [226]
Microglia is lost in the CNS-specific TGFβ1 deficient mice that exhibit progressive motor paralysis and death by 23-25 weeks of age, indicating that TGFβ1 acts as a major differentiation and survival factor for microglia.
“Microglia is lost in the CNSspecific TGFβ1 deficient mice that exhibit progressive motor paralysis and death by 23-25 weeks of age, indicating that TGFβ1 acts as a major differentiation and survival factor for microglia (28).”
From Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease (2017) · cites this paper as [28]
TGFβ1 plays a pivotal role in development and maintenance of microglia both in vitro and in vivo.
“TGFβ1 plays a pivotal role in development and maintenance of microglia both in vitro and in vivo (28).”
From Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease (2017) · cites this paper as [28]
Previous data showed decreased uptake of Aβ42 in primary microglial cells isolated from adult human brain tissue and transfected with siRNA targeting SPI1.
“This is in line with previous data showing decreased uptake of Aβ42 (also a TLR2 agonist) in primary microglial cells isolated from adult human brain tissue and transfected with siRNA targeting SPI147.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [47]
The Methods section on human microglia isolation and cell culture describes isolating cells from adult human brain tissue. Searches for SPI1, siRNA, Aβ42 uptake, and related terms found no passage reporting the claimed transfection or decreased uptake; the available copy therefore does not verify the result. (LLM, conf=0.73)
Experimental — accuracy not yet measuredTREM2 is expressed by microglia in the CNS, especially after activation.
“The general consensus is that TREM2 is expressed by microglia in the CNS, especially after activation [6, 21, 47].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [6]
The Results sections on microglial gene signatures and surface molecules discuss other markers, including P2ry12, but do not address TREM2. Searches for TREM2 expression and activation found no passage in our copy establishing that TREM2 is expressed by CNS microglia, especially after activation. (LLM, conf=0.74)
Experimental — accuracy not yet measuredThe loss of homeostatic microglial proteins is visible in immunofluorescence double-staining of IBA1 and TMEM119 in terminally sick mice and mock-infected healthy control brains, and shows reciprocal regulation of both proteins in prion disease.
“The loss of homeostatic microglial proteins is visible in immunofluorescence double-staining of IBA1 and TMEM119 in terminally sick mice and mock-infected healthy control brains, and shows the reciprocal regulation of both proteins in prion disease (Figure 5A) [55,73,88,89,90,91].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [88]
Analysis of the microglia transcriptome compared with other tissue macrophages revealed a strong influence of TGF-β signaling, culminating in SMAD activation that induces transcription of specific target genes including P2Y12.
“Analysis of the microglia transcriptome in comparison with that of other tissue macrophages has revealed a strong influence of TGF-β signaling, which culminates in the activation of SMAD proteins that induce transcription of specific target genes, including the purinergic receptor P2Y12 (37, 38, 43).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [37]
During normal CNS function, microglia have a resting or homeostatic transcriptome profile that reflects a surveilling activity.
“During normal CNS function, microglia have a “resting,” or homeostatic, transcriptome profile that reflects a surveilling activity (36–41) (Figure 1).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [37]
Microglia isolated from the brain may not maintain the same functions as microglia in vivo.
“Considering that microglia isolated from the brain may not maintain the same functions as microglia in vivo (32)”
From IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis (2021) · cites this paper as [32]
Previous studies using transgenic mouse models of AD have identified various mechanisms that lead to synaptic impairment in AD, including the accumulation of soluble amyloid-beta, Tau hyperphosphorylation, loss of VGF signaling, and glial state dysregulation.
“For example, previous studies using transgenic mouse models of AD have identified various mechanisms that lead to synaptic impairment in AD, including the accumulation of soluble amyloid-beta, Tau hyperphosphorylation, loss of VGF signaling, and glial state dysregulation (e.g., the induction of disease-associated microglia and disease-associated astrocytes) (9, 23–30).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [27]
Blocking TGF-beta signaling has no major effect on microglial cell number but causes a drastic gene-expression shift, including widespread upregulation of genes found in Cluster 6 and brain border macrophages, including Mrc1.
“blocking TGF-beta signaling (which helps to confer microglia identity, (Butovsky et al., 2014)) has no major effect on microglia cell number, but causes a drastic shift in their gene expression including widespread upregulation of (or failure to downregulate) genes found in Cluster 6 microglia and in brain border macrophages, including Mrc1 (Wong et al., 2017).”
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 Butovsky et al., 2014
In the healthy brain, microglia have a unique homeostatic molecular signature, comprising a distinct transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages.
“In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [25]
Microglia, but not peripheral myeloid cells, express P2ry12, Tmem119, Siglech, Gpr34, Socs3, Hexb, Olfml3, and Fcrls.
“microglia — but not peripheral myeloid cells — were shown to express P2Y purinoceptor 12 (P2ry12), transmembrane protein 119 (Tmem119), sialic acid binding Ig-like lectin H (Siglech), probable G protein coupled receptor 34 (Gpr34), suppressor of cytokine signalling 3 (Socs3), β-hexosaminidase subunit β (Hexb), olfactomedin-like protein 3 (Olfml3) and Fc receptor-like S, scavenger receptor (Fcrls).”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [25]
P2RY12 and TMEM119 are also expressed in human microglia.
“Several of these microglial genes were also observed in human microglia, including P2RY12 and TMEM119 (REFs25,33–36).”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [25]
CNS-conditional Tgfb1−/− mice exhibit motor deficits, loss of homeostatic microglia, and appearance of peripherally derived monocytes in the CNS.
“CNS-conditional Tgfb1−/− mice exhibit motor deficits, a loss of homeostatic microglia and the appearance of peripherally derived monocytes in the CNS25.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [25]
Absence of TGFβ1 in the CNS causes a paralytic neurologic disease in mice, and TGFβ1 signalling is inhibited in microglia associated with neurodegeneration where the homeostatic signature is suppressed.
“the absence of TGFβ1, a factor known to be required for the in vitro development of the molecular signature characteristic of adult microglia, in the CNS results in a paralytic neurologic disease in mice25.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [25]
SALL1 is expressed in human and mouse microglia, and SALL1 mutations cause neural or behavioural abnormalities in humans and abnormal microglial morphology and homeostatic signature downregulation in mice.
“Sal-like protein 1 (SALL1), regulates cortical neurogenesis and is expressed in human and mouse microglia25.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [25]
TREM2 is an important microglial molecule involved in regulating microglial signatures in disease.
“Indeed, TREM2 is an important microglial molecule25,27,28 thought to be involved in the regulation of microglial signatures in disease1,58.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [25]
FACS purification of murine microglia using an anti-P2ry12 antibody revealed over 100 genes enriched compared to neurons and other oligodendrocytes.
“Purification of murine microglia by FACS with an antibody against P2ry12, a glia-specific surface protein, has revealed over 100 genes that are enriched compared to neurons and other oligodendrocytes53.”
From Decoding neuroproteomics: integrating the genome, translatome and functional anatomy (2014) · cites this paper as [53]
PU.1 binds to purine-rich PU-box sequences and activates gene expression during immune cell development.
“PU.1 binds to purine-rich sequence (PU-box) and activates gene expression during immune cell development [24, 25].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [24]
Through miRNA and mRNA microarray assays, gene regulators miR-124 and miR-155 have been identified in microglial activation pathways.
“Through miRNA and mRNA microarray assays, gene regulators such as miR-124 and miR-155 have been identified in microglial activation pathways [24, 43].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [24]
Tissue microenvironmental factors trigger cascades that lead certain transcription factors to bind cooperatively with PU.1, creating a unique enhancer profile that lets microglia respond dynamically to their surroundings.
“Tissue micro-environmental factors activate cascades resulting in co-operative binding of certain transcription factors with PU.1, leading to a unique enhancer profile enabling microglial dynamic response to its surrounding micro-environment [24, 72].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [24]
TGFβ is a crucial upstream regulator of microglia survival, differentiation, and maintenance of the microglia signature in vitro.
“Butovsky et al. showed TGFβ act as a crucial upstream regulator in microglia survival, differentiation and maintenance of microglia signature In vitro [24].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [24]
Well-known and recently identified microglial-enriched genes are expressed at high levels in microglia from all analyzed regions.
“well-known and recently identified microglial-enriched genes (Chiu et al., 2013; Hickman et al., 2013; Butovsky et al., 2014; Zhang et al., 2014) were expressed at high levels in microglia from all analyzed regions”
From Local cues establish and maintain region-specific phenotypes of basal ganglia microglia (2017) · cites this paper as Butovsky et al., 2014
Microglia in the striatum display a homeostatic surveillance phenotype.
“In contrast, microglia in the striatum, which like the cerebellum, is characterized by a rather homogenous neuron population, display a homeostatic surveillance phenotype14,15.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [14]
Striatal microglia are enriched in mRNAs encoding mature microglia-specific homeostatic surveillance proteins, including those mediating G-protein-coupled chemosensing, chemotaxis, GTP signaling, and actin polymerization.
“In contrast, stMg are enriched in mRNAs encoding mature microglia-specific homeostatic surveillance proteins14,15, including those that mediate G-protein-coupled chemosensing, chemotaxis, GTP signaling, and actin polymerization20 (Fig. 1d,e, Supplementary Fig. 5a,b, Supplementary Table 3).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [14]
Loss of H3K27me3 and up-regulation of cerebellar microglia-enriched clearance genes in Eed-deficient striatal microglia is accompanied by significant down-regulation of a large number of striatal microglia signature genes (313/643) implicated in homeostatic surveillance functions.
“The loss of H3K27me3 and the up-regulation of cbMg-enriched clearance genes in Eed-deficient stMg is accompanied by a significant down-regulation of a large number of stMg signature genes (313/643) implicated in the regulation of homeostatic surveillance functions14,15 (Fig. 6a,b, Supplementary Fig. 11g, Supplementary Table 8).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [14]
Mature pMGLs stained positive for markers of murine and human microglia, with TMEM119 and P2RY12 displaying broad membrane and punctate vesicular expression.
“Mature pMGLs stained positive for markers of murine and human microglia 10,11,29,30, with both TMEM119 and P2RY12 displaying a broad membrane and punctate vesicular expression pattern”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [29]
In addition to induction of cell clearance genes, cerebellar microglia are characterized by a significant reduction in homeostatic microglia genes.
“In addition to the induction of cell clearance genes, the cbMg are further characterized by a significant reduction in homeostatic microglia genes14,15.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [14]
Murine studies identified key cytokines, cell receptors, and transcription factors required for microglia development and survival in vivo.
“Recently, murine studies identified key cytokines, cell receptors, and transcription factors required for microglia development and survival in vivo.”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Butovsky et al., 2014
IL-34 and TGFβ-1 are among the factors required for microglia development and survival in vivo.
“These factors include IL-34 and TGFβ-1 (Butovsky et al., 2014; Greter et al., 2012; Wang et al., 2012; Yamasaki et al., 2014).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Butovsky et al., 2014
The enriched terms reflect expected processes in which iMGLs respond to the environment and possess a capacity for renewal and maturation previously reported in cultured microglia.
“These terms reflect expected processes in which iMGLs are cued to respond to the environment and possess a capacity for renewal and maturation that have previously been reported in cultured microglia (Butovsky et al., 2014).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Butovsky et al., 2014
TGFβ is needed for murine microglia development in vivo and for maintaining the microglial-specific transcriptome signature.
“TGFβ, a glia-derived cytokine, is needed for murine microglia development in vivo and in maintaining the microglial-specific transcriptome signature (Abutbul et al., 2012; Butovsky et al., 2014; Schilling et al., 2001).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Butovsky et al., 2014
P2Y12 is selectively expressed in non-activated microglia.
“we focused on the P2Y12 purinergic receptor, which is selectively expressed in non-activated microglia and mediates process motility during early injury responses.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [23]
P2Y12 is exclusively and extensively expressed by homeostatic microglia within the brain, distinguishing resident microglia from phenotypically similar infiltrating macrophages.
“P2Y12 is exclusively and extensively expressed by homeostatic microglia within the brain, even distinguishing resident microglia from phenotypically similar infiltrating macrophages23, suggesting that P2Y12 may serve microglia-specific roles within the normal brain parenchyma.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [23]
P2Y12 expression correlates strongly with ramified microglial morphology characteristic of healthy neurophysiology.
“In addition, its expression correlates strongly with a ramified microglial morphology characteristic of healthy neurophysiology, indicating that it primarily functions during rapid responses to perturbations of brain homeostasis2123.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [23]
TMEM119 is a highly specific and well-validated marker of brain-derived microglia in both mice and humans.
“We analyzed TMEM119 in bulk human brain tissue data from the Allen Brain Institute (13) because it is a highly specific and well-validated marker of brain-derived microglia in both mice and humans.”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [11]
Microglia gene expression may be influenced by factors present in the central nervous system microenvironment.
“Microglia also express hundreds of genes at higher levels than other macrophage subsets (24–26) that may be influenced by factors present in the CNS microenvironment (25, 27), suggesting mechanisms by which the brain environment influences the activity and functions of one of its primary support cells.”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [27]
This definition captures a mouse microglia gene signature set that is larger but mostly inclusive of previously described microglia signature sets.
“This definition captures a mouse microglia gene signature set that is larger but mostly inclusive of previously described microglia signature sets (27, 57, 58).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [27]
TGF-β1 is necessary for maintenance of the in vivo mouse microglia phenotype.
“which is necessary for maintenance of the in vivo mouse microglia phenotype (27, 64).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [27]
Microglia rapidly lose their unique identity when removed from the brain environment and cultured in monoculture in vitro.
“Moreover, microglia rapidly lose their unique identity when removed from the brain environment and cultured in monoculture in vitro (Butovsky et al., 2014).”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Butovsky et al., 2014
The six key microglia-specific genes identified by Butovsky et al. (2014), MERTK, GPR34, PROS1, C1QA, GAS6, and P2RY12, were all strongly expressed in co-pMG, whereas bloodMono poorly expressed most of these markers.
“Most notably, the six key microglia-specific genes identified by Butovsky et al. (2014), MERTK, GPR34, PROS1, C1QA, GAS6, and P2RY12, were all strongly expressed in co-pMG, whereas bloodMono poorly expressed most of these markers (highlighted in magenta, Figure 2C)”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Butovsky et al., 2014
Genes previously identified to be associated specifically with microglia but not with blood monocytes showed similar expression in co-pMG and fetalMG.
“As a set, genes previously identified to be associated specifically with microglia but not with blood monocytes (Bennett et al., 2016, Butovsky et al., 2014, Melief et al., 2012) (Figure 2C) showed similar expression in co-pMG and fetalMG.”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Butovsky et al., 2014
These cells do not express a convincing microglia signature.
“Moreover, these cells do not express a convincing microglia signature (Butovsky et al., 2014, Melief et al., 2012).”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Butovsky et al., 2014
P2RY12 is an established microglial marker.
“P2RY12, an established microglial marker 3,4 ,”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [3]
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.
Primary-antibody incubation conditions conflict
MinorThe immunohistochemistry method gives primary-antibody incubation as one hour at room temperature, then describes sections incubated with primary antibody for 12 hours at 4°C without distinguishing these as separate protocols.
“Primary antibodies were applied for 1 hour in a humidified chamber at room temperature.”
“Sections were incubated with the primary antibody for 12 hours at 4°C, washed with PBS, and incubated with the secondary antibodies in PBS for 1 hour at room temperature while protected from light.”
Fourth vaccination has conflicting adjuvant descriptions
MinorThe first description assigns incomplete Freund's adjuvant to the three injections after the first, which includes the fourth injection. The detailed schedule instead assigns Titermax to the fourth injection.
“The first vaccination was given with Complete Freund’s Adjuvant (CFA) and then next 3 injections with Incomplete Freund’s Adjuvant (IFA) combined with the synthetic P2ry12 peptide ip to generate rat antibodies.”
“A 4th injection was given two weeks later with 50μg of the synthetic peptide conjugated to KLH plus Titermax (200μl).”
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- Authors
- Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., Fanek, Z., Liu, L., Chen, Z., Rothstein, J. D., Ransohoff, R. M., Gygi, S. P., Antel, J. P., & Weiner, H. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Montreal Neurological Institute and Hospital (CA)
- Cleveland Clinic (US)
- Johns Hopkins University (US)
- Corresponding author
- Butovsky, Oleg
- Weiner, Howard L
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2013-12-08
- Volume
- 17
- Issue
- 1
- Pages
- 131-143
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4066672
- OpenAlex
- W2124836944
- Semantic Scholar
- 52486c83a41de8949de6905ae15a994d75388a8b
- Cited by
- 2,543
- References
- 60
- Citations by year
- 2026: 187 · 2025: 147 · 2024: 223 · 2023: 178 · 2022: 247 · 2021: 291 · 2020: 270 · 2019: 207 · 2018: 233 · 2017: 201 · 2016: 173 · 2015: 134 · 2014: 48 · 2012: 1
- FWCI
- 59.00
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-08-26)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (R01AG043975, R21AG046399, R01AG027437, R01AG054672)
- National Institute of Neurological Disorders and Stroke (R01NS085207, R01NS088137)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- microglia, TGF-beta signaling, TGF-β1, gene expression signatures, microRNA signature, microglial development, astrocytes, oligodendrocytes, neuroinflammation
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Cells, Cultured, Central Nervous System, Chromatography, Ion Exchange, Embryo, Mammalian, Female, Flow Cytometry, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Mass Spectrometry, Signal Transduction, Antigens, CD, Microglia, Gene Expression Regulation, Developmental, MicroRNAs, Tissue Array Analysis, Mice, Transforming Growth Factor beta1, Receptors, Purinergic P2Y12
About these checks
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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