Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice
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Abstract
Abstract Microglia are established in embryogenesis forming a self-containing cellular compartment resisting seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦ) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex. Parenchymal MoMΦ adopt bona fide microglia expression profiles. Unlike microglia, these monocyte-derived microglia (MoMg) are due to their hematopoietic origin targets of clonal hematopoiesis (CH). Using a chimeric transfer model, we show that hematopoietic expression of DNMT3A R822H , a prominent mutation in human CH, renders MoMg pathogenic promoting motor deficits resembling atypical Parkinsonian disorders. Collectively, these data establish in a mouse model that MoMg progressively seed the brains of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.
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TL;DR
Monocyte-derived macrophages progressively seed selected non-cortical brain regions in aging healthy mice and can adopt bona fide microglia transcriptomes, including Sall1 expression. When derived from hematopoietic stem cells expressing the clonal hematopoiesis-associated hDNMT3A R882H/R822H variant, these monocyte-derived microglia accumulate in nigrostriatal regions, impair dopaminergic circuits, and cause motor deficits resembling atypical parkinsonism.
Key findings
- In Ms4a3Cre:R26-TdTomato fate-mapping mice, monocyte-derived macrophages accumulated with age at brain borders and in selected parenchymal regions, including nigrostriatum and medulla, but not frontal cortex; parenchymal MoMg increased from 0.29% to 0.57% with age (Fig. 2e), and regional ratios increased in midbrain (0.47% to 0.695%), diencephalon (0.41% to 1.003%), and substantia nigra (1.44% to 2.625%) in Supplementary Table 1.
- Single-cell RNA sequencing of 1-year-old double-reporter mice showed that parenchymal monocyte-derived microglia (MoMg) contributed to all 33 MetaCells covered by YS-derived microglia and formed 4 MoMg-specific MetaCells expressing MHCII-related genes and Ccr2; unlike experimentally engrafted macrophages, MoMg expressed Sall1. Leptomeningeal MoMF remained transcriptionally distinct from YS-derived border macrophages.
- In BM chimeras, HSC-MF never exceeded ~5% of the parenchymal brain MF population, whereas GFP+TdTom+ MoMF constituted almost half of the Tmem119+ brain MF compartment by 8 months; Sall1 lineage tracing showed progressive labeling of parenchymal, but not CD206+ BAM, cells.
- Chimeras receiving VavCre:hDNMT3A R882H/R822H BM developed motor impairment: CatWalk PCA segregated mutant recipients, with reduced speed and cadence and extended standing; pole test performance was worse; and TH+ neurons in the substantia nigra pars compacta were lost. Mutant MoMg showed 3,153 DEG versus microglia, with 1,966 genes higher than control MoMg, including Cd74, H2-Ab1, Slc15a2, and Ccl5.
Methods
- Mouse fate-mapping and transplantation models: Ms4a3Cre:R26-TdTomato, Cx3cr1gfp, Cxcr4CreER, Sall1ncre:Cx3cr1ccre, and VavCre:hDNMT3A R882H/R822H mice; lethal irradiation (950 cGy) followed by BM transfer (5×10^6 donor cells i.v.).
- Cell isolation from brain parenchyma and leptomeninges for flow cytometry and sorting; bulk RNAseq and scRNAseq (MARS-seq/MetaCell); MERFISH spatial transcriptomics using a 140-gene panel; immunofluorescence and Imaris-based spatial analysis.
- Behavioral testing with CatWalk gait analysis and pole test; statistical analysis included Student’s t tests, multiple t tests, PCA, DESeq2 with Benjamini-Hochberg correction, and k-means clustering.
Limitations
- The paper states that mutant monocytes also seed peripheral macrophage compartments, so a contribution of peripheral cells to the observed phenotype cannot be ruled out; the effect is assumed to result from the altered HSC methylome rather than direct mutant DNMT3A expression in mature MoMF, and MoMg-specific conditional mutagenesis is proposed for future work.
- The paper notes that SPF housing may underestimate MoMg seeding compared with wild animals, that human MoMg frequencies and medical histories differ from the mouse model, and that a link between CH and Parkinsonism or other CNS disorders will require dedicated human cohort studies.
- Evident from the text: the mechanism linking mutant MoMg to dopaminergic neuron loss is not defined, and the functional relevance of specific candidates such as Ccl5 or Il1b was not directly tested; MoMg numbers in aging mice are low and regionally restricted, and the study does not establish functional equivalence between YS-derived microglia and MoMg.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
54 of 81 cited sources checked · 10 supported · 1 flagged · accuracy not yet measured
- Findingown data§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 8
Monocyte-derived microglia and to a lesser extent HSC-macrophages displayed expression of Sall1 compared to leptomeningeal macrophages.
“Interestingly, MoMg and to a lesser extend HSC-M F displayed expression of Sall1 , as compared to leptomeningeal M F ( Fig. 4f ), suggesting that also engrafted cells in BM chimeras can acquire this proposed 'microglia signature' marker 14,18,19 .”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [14] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. source
- cites [18] Cronk, 2018, Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia, J. Exp. Med. source
- cites [19] Lund, 2018, Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells, Nat. Commun. source
The Discussion explicitly states that Sall1 was not expressed in monocyte-derived macrophages, contrary to the claim that monocyte-derived microglia displayed Sall1 expression. The Results section ‘Engrafting macrophages adopt TGF-β driven transcription’ likewise lists Sall1 as an exception among microglia-associated transcription factors detected in engrafting macrophages. Page numbers are not available in the supplied copy. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation§ Introduction · p. 3
In contrast to microglia, monocyte-derived macrophages are exposed to effects of somatic mutations associated with age-related clonal hematopoiesis due to their derivation from HSC.
“In contrast to microglia, MoM F are due to their derivation from HSC exposed to effects of somatic mutations that are associated with age-related clonal hematopoiesis (CH) 29,30 .”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [29] Spiteri, 2022, Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function, Acta Neuropathol. source
The Introduction (page unavailable) says that adult monocytes are renewed from bone-marrow HSCs, whereas microglia are renewed independently of them; it also identifies monocyte-derived macrophages as infiltrating monocyte-derived cells. Our copy does not state that these macrophages are exposed to effects of somatic mutations associated with age-related clonal hematopoiesis (searched: clonal hematopoiesis, somatic mutations). (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [30] Shlush, 2018, Age-related clonal hematopoiesis, Blood source
The Etiology and pathogenesis section says ARCH-related mutations may affect monocytes differently from hematopoietic stem and progenitor cells (HSPCs), and Figure 1 describes mutated HSPCs giving rise to mature cells. Our copy does not address monocyte-derived macrophages specifically or contrast them with microglia, so it supports the proposed basis only in part. Page numbers were not available in the indexed passages. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Interpretationcitation§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10
The progressive gait impairment and poor pole test performance of VavCre:hDNMT3A R822H BM recipients was reminiscent of a hypokinetic motor phenotype associated with parkinsonism that results from dopaminergic deficiencies.
“The progressive gait impairment and poor performance in the pole test of the Vav Cre : hDNMT3A R822H BM recipients was reminiscent of a hypokinetic motor phenotype-associated with parkinsonism 58 that results from dopaminergic deficiencies.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [58] Festa, 2023, Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration, Neuron source
The Results describe motor deficits in Huntington’s disease mice and improvements after CCR5 depletion, but do not characterize those deficits as parkinsonian or link them to dopamine deficiency. A search of our copy for parkinsonism, the pole test, dopaminergic deficiency, and VavCre:hDNMT3A R822H recipients found no passage addressing the cited comparison. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Premisecitation§ Discussion · p. 11
Available reports of monocyte-derived microglia in humans, as defined by CH mutations, refer to brain regions that overlap with areas in which monocyte-derived microglia accumulation is observed in aging mice, including occipital cortex, medulla and putamen.
“Of note, the available reports of monocyte-derived microglia in humans, as defined by CH mutations, so far refer to brain regions that overlap with the areas in which we observe MoMg accumulation in the aging mice, including the occipital cortex, medulla and putamen 28,66 .”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [28] Yan, 2022, Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease, J. Clin. Investig. source
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [66] Mildner, 2007, Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions, Nat. Neurosci. source
- Findingown data§ Discussion · p. 12
MoMg that derive from HSC expressing the DNMT3A R822H variant cause a motor impairment reminiscent of the hypokinetic motor phenotype seen in parkinsonism.
“Specifically, using a BM transfer model, we show that MoMg that derive from HSC that express the DNMT3A R822H variant cause a motor impairment reminiscent of the hypokinetic motor phenotype seen in parkinsonism 72 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [72] Skelly, 2013, A Systematic Analysis of the Peripheral and CNS Effects of Systemic LPS, IL-1Β, TNF-α and IL-6 Challenges in C57BL/6 Mice, PLoS One source
The Sickness behaviour section (page unavailable) reports reduced locomotor activity after systemic inflammatory challenges in mice, not a parkinsonian motor phenotype. The passages found for DNMT3A R822H, bone-marrow transfer, and hypokinetic parkinsonism do not address the comparison for which this citation appears to be offered; the variant-specific result is framed as the citing authors’ own finding. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 8
hDNMT3A R882H monocyte-derived microglia expressed significant levels of Ccl5.
“Notably, hDNMT3A R882H MoMg also expressed significant levels of Ccl5 , a chemokine that has been associated with brain pathologies and was shown to act on immune cells and neurons 53-55 .”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [53] Scheller, 2021, Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response, Nat. Cancer source
The Abstract describes DNMT3A-R882H effects in hematopoietic and leukemia cells, while the other retrieved passages concern methylation and sequencing methods. Searches for Ccl5, monocyte-derived microglia, and brain-related effects found no passage reporting Ccl5 expression in hDNMT3A R882H MoMg. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [54] Zioni, 2023, Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis, Nat. Commun. source
The Results passages on human DNMT3A R882H cells concern bone-marrow HSPCs and engraftment, not monocyte-derived microglia. Searches for Ccl5, microglia, and the hDNMT3A R882H combination found no passage reporting the claimed expression; page numbers were unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [55] Shumliakivska, 2024, DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts, Nat. Commun. source
The Results section on DNMT3A R882H mice reports Ccr2 expression in cardiac macrophage subclusters, not Ccl5 expression in monocyte-derived microglia. The Methods section on monocyte culture describes THP-1-derived macrophages. Searches for Ccl5 and microglia found no passage in our copy addressing the attributed finding; page numbers were unavailable. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Findingown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 5
TdTom+ monocyte-derived macrophages progressively accumulate with age in both parenchyma and leptomeninges.
“Analysis of the parenchyma and the leptomeninges of young and old DR animals revealed that in both locations TdTom + MoM F progressively accumulated with age ( Fig. 2b-d ).”
Quote in the paperSubstantial claim - Findingown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 5
TdTom+ monocyte-derived macrophages were more frequently found in ventral leptomeninges compared to dorsal side.
“Of note, TdTom + MoM F were more frequently found in the ventral leptomeninges, as compared to the dorsal side.”
Quote in the paperNot a substantial claim - Findingown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 4
Percentages of MHCII+ cells were significantly higher in TdTom+ monocyte-derived macrophages compared to YS-derived macrophages among both CD206+ and Tmem119+ brain macrophage populations.
“Percentages of MHCII + cells were significantly higher in TdTom + MoM F as compared to YS-derived M F (TdTom -) among both CD206 + and Tmem119 + brain M F .”
Quote in the paperNot a substantial claim - Findingown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 5
Monocyte-derived macrophage abundance in aged brain increased from 0.29% to 0.57% with age.
“the increase of MoM F abundance with age (0.29% vs. 0.57 %) ( Fig. 2e ).”
Quote in the paperSubstantial claim - Findingown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 4
Flow cytometric analysis of brains of Ms4a3Cre:R26-TdTomato animals revealed TdTom+ cells in leptomeninges and parenchyma.
“Flow cytometric analysis of brains of Ms4a3 Cre : R26-TdTomato animals revealed the presence of TdTom + cells, both in the leptomeninges and in the parenchyma ( Fig. 1a) .”
Quote in the paperSubstantial claim - Findingown data§ Abstract · p. 2
Parenchymal monocyte-derived microglia adopt bona fide microglia expression profiles.
“Parenchymal MoM F adopt bona fide microglia expression profiles.”
- Also stated in: § Transcriptome comparison of YS-derived brain M F and MoM F accumulating in the aging mouse brain · p. 7 · boosted
“Taken together, these data establish that, as opposed to what was reported for experimentally engrafted cells 14-16 , MoMg that accumulate in the aging brain of mice acquire transcriptomic identities of YS-derived microglia.”
Quote in the paperSubstantial claim - Also stated in: § Transcriptome comparison of YS-derived brain M F and MoM F accumulating in the aging mouse brain · p. 7 · boosted
- Findingown data§ Transcriptome comparison of YS-derived brain M F and MoM F accumulating in the aging mouse brain · p. 6
Monocyte-derived microglia contributed to all 33 MetaCells covered by YS-derived microglia, although to varying degree.
“Highlighting their ability to adopt microglia identity, MoMg contributed to all 33 MetaCells covered by YS-derived microglia, although to varying degree ( Fig. 3e,f, Suppl. Fig. 3c ).”
Quote in the paperNot a substantial claim - Findingnone given§ Discussion · p. 11
In aging unmanipulated mice, MoMg progressively seed largely non-cortical brain areas.
“In aging unmanipulated mice, MoMg progressively seed largely non-cortical brain areas.”
Quote in the paperNot a substantial claim - Findingown data§ Transcriptome comparison of YS-derived brain M F and MoM F accumulating in the aging mouse brain · p. 6
Leptomeningeal monocyte-derived macrophages showed only very minor overlap with their YS-derived leptomeningeal macrophage counterpart.
“As opposed to MoMg, LeptoMoM F did show only very minor overlap with their YS-derived LeptoM F counterpart ( Fig. 3e,f ).”
Quote in the paperSubstantial claim - Findingown data§ Discussion · p. 12
The BAM replacement rates observed considerably exceeded earlier reports.
“The BAM replacement rates we observed considerably exceeded earlier reports 7,69 , which could be related to animal housing conditions but requires further studies.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingown data§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10
Immuno-histochemical quantification revealed a loss of TH+ neurons in mice harboring hDNMT3A R882H monocyte-derived microglia compared to controls.
“Immuno-histochemical quantification / TH + volume revealed a loss of TH + neurons in mice harboring hDNMT3A R882H MoMg, as compared to controls ( Fig. 6e , f , Suppl. Fig. 6c,d ), suggesting local impairment of neuronal transmission.”
Quote in the paperSubstantial claim - Findingown data§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 7
Monocyte-derived microglia and HSC-macrophages mostly differed in quantitative rather than qualitative expression of selected genes, including MHCII-related transcripts (Cd74, H2-Ab1).
“Notably, MoMg and HSC-M F mostly differed in quantitative rather than qualitative expression of selected genes, including MHCII-related transcript ( Cd74, H2-Ab1 ) ( Fig. 4e ).”
Quote in the paperNot a substantial claim - Findingown data§ Discussion · p. 12
The presence of mutant MoMg in the substantia nigra pars compacta resulted in a loss of dopaminergic TH+ neurons.
“In line with a Parkinson-related pathology, the presence of mutant MoMg in the substantia nigra pars compacta , resulted in a loss of dopaminergic TH + neurons.”
Quote in the paperSubstantial claim - Findingown data§ Figure 3. Single cell RNA sequencing of YS-derived M F and MoM F isolated from Ms4a3 cre/+ : R26 TdTomato : Cx3cr1 gfp/+ parenchyma and leptomeninges · p. 26
There are differentially expressed genes between microglia and MoMg in the brain parenchyma.
“Volcano plots showing differentially expressed genes between microglia and MoMg in parenchyma.”
Quote in the paperNot a substantial claim - Findingown data§ Discussion · p. 11
MoMg express MHC II.
“Specifically, MHC II expressing 'microglial cells' identified in the nigrostriatal compartment 67 could, for instance, represent MoMg, that as we show express MHC II.”
Quote in the paperNot a substantial claim - Findingown data§ Discussion · p. 13
MoMg derived from hDNMT3A R882H HSC prominently expressed Ccl5.
“Interestingly though, in particular the MoMg derived from hDNMT3A R882H HSC also prominently expressed Ccl5 , encoding a chemokine that acts on immune cells and neurons, and has been associated with brain pathologies, including PD 53-55 .”
Quote in the paperNot a substantial claim - Findingown data§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10
Chimeras harboring mutant monocyte-derived microglia performed less well in a pole test compared to controls.
“As compared to controls, chimeras harboring mutant MoMg also performed less well in a pole test, a widely used assay for basal ganglia-related movement disorders in mice 57 ( Fig. 6c ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [57] Kim, 2013, A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells, Blood source
- Findingown data§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10
PCA of gait parameters revealed segregation of recipients of mutant BM that developed in particular at the late time point.
“Principle component analysis (PCA) of the collected gait parameters, two, three, and four months after engraftment, revealed segregation of the recipients of the mutant BM that developed in particular at the late time point ( Fig. 6a, Suppl. Fig. 6a ).”
Quote in the paperSubstantial claim - Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 9
hDNMT3A R882H-related epigenome alteration impacts the transcriptome of monocyte-derived macrophages in the brain of recipient animals, including expression of Ccl5.
“Collectively, these data establish that the hDNMT3A R882H -related epigenome alteration impacts the transcriptome of MoM F in the brain of the recipient animals, including the expression of Ccl5.”
Quote in the paperSubstantial claim - Findingcitation§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 8
Up to three months after engraftment, no TdTom+ cells were detected in the brain of Sall1ncre:Cx3cr1ccre:R26TdTom chimeras by flow cytometry.
“In line with our earlier report 14 , up to three months after engraftment we did not detect any TdTom + cells in the brain of these chimeras by flow cytometry ( Fig. 4h, Suppl. Fig. 4h ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. source
- Findingown data§ Discussion · p. 12
Analysis of the leptomeninges showed robust seeding of the BAM compartment with MoMF, in particular for the ventral sides of the aging brain.
“Our study largely focused on parenchymal M F , but analysis of the leptomeninges also showed robust seeding of the BAM compartment with MoM F , in particular for the ventral sides of the aging brain.”
Quote in the paperNot a substantial claim - Findingown data§ Figure 6. Motoric impairment caused by hDNMT3A R822H/+ MoMg · p. 28
Mice that received Vavcre/+:hDNMT3AR822H/+ bone marrow (mutated BM recipients) show motor impairment compared with control BM recipients, as indicated by CatWalk gait parameters.
“CatWalk gait results of parameters that indicated motor impairment of mutated BM recipients compared with the control BM recipients.”
- Also stated in: § Supplementary Figure 6. Analysis of Gait and quantification of dopaminergic neurons in substantia nigra of Vav cre/+ : hDNMT3A R822H/+ BM chimeras and controls · p. 32 · hedged
“CatWalk gait results of parameters that indicated motor impairment of mutated BM recipients compared with the control BM recipients.”
Quote in the paperSubstantial claim - Also stated in: § Supplementary Figure 6. Analysis of Gait and quantification of dopaminergic neurons in substantia nigra of Vav cre/+ : hDNMT3A R822H/+ BM chimeras and controls · p. 32 · hedged
- Findingown data§ Supplementary Figure 1. Flow cytometry and microscope images of brains of Ms4a3 cre/+ : R26 TdTomato mice · p. 30
MoMg are present in the circumventricular organs of 20-week-old Ms4a3cre/+:R26TdTomato:Cx3cr1gfp/+ mice.
“Representative images of circumventricular organs (CVO) of 20-week-old Ms4a3 cre/+ : R26 TdTomato : Cx3cr1 gfp/+ mouse. GFP + cells indicate YS-derived microglia, and GFP + , TdTomato + cells indicate MoMg.”
Quote in the paperNot a substantial claim - Findingown data§ Figure 6. Motoric impairment caused by hDNMT3A R822H/+ MoMg · p. 28
GFP+ TdTomato+ MoMg are present in the TH+ substantia nigra pars compacta of Ms4a3cre/+:R26TdTomato:Cx3cr1gfp/+ mice.
“Representative immunohistochemical analysis of sagittal brain section of Ms4a3 cre/+ : R26 TdTomato : Cx3cr1 gfp/+ mouse indicating presence of GFP + TdTomato + MoMg in TH + substantia nigra pars compacta.”
Quote in the paperSubstantial claim - Findingown data§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 7
By 8 months after transfer, GFP+TdTom+ monocyte-derived macrophages constituted almost half of the Tmem119+ brain macrophage compartment.
“In contrast, GFP + TdTom + MoM F developed only with time, but constituted by 8 months almost half of the Tmem119 + brain M F compartment.”
Quote in the paperSubstantial claim - Findingown data§ Supplementary Figure 4. Flow cytometry, histology and bulk RNA sequencing results of brains of BM chimeras · p. 31
Ramified TdTomato+ cells accumulate in specific brain regions 16 weeks after bone marrow transplantation.
“Regions where ramified TdTomato + cells accumulated 16 weeks post BMT are indicated with a yellow line.”
Quote in the paperNot a substantial claim - Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 8
hDNMT3A R882H monocyte-derived microglia showed an activation signature spanning 3153 DEG compared to microglia.
“Specifically, like control MoMg, MoMg that were derived from hDNMT3A R882H HSC ('hDNMT3A R882H MoMg') showed an 'activation signature' identified in the heatmap as cluster I-IV, spanning a total of 3153 DEG as compared to microglia.”
Quote in the paperNot a substantial claim - Findingown data§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 7
HSC-macrophages never reached more than approximately 5% of the parenchymal brain macrophage population.
“Time course analysis revealed however, that HSC-M F never reached more than ~ 5% of the parenchymal brain M F population ( Fig. 4d ).”
Quote in the paperSubstantial claim - Findingown data§ Transcriptome comparison of YS-derived brain M F and MoM F accumulating in the aging mouse brain · p. 6
Leptomeningeal monocyte-derived macrophages did not acquire Lyve1 expression in the tested time frame.
“Notably, and in contrast to YS-leptoM F , leptoMoM F did not acquire Lyve1 expression in the tested time frame ( Fig. 3d ).”
Quote in the paperSubstantial claim - Findingown data§ Discussion · p. 12
Leptomeningeal MoMF that accumulate at the CNS borders retain transcriptomes distinct from their YS-derived counterpart.
“Notably, the scRNAseq analysis revealed that leptomeningeal MoM F that accumulate at the CNS borders retain transcriptomes distinct from their YSderived counterpart.”
Quote in the paperNot a substantial claim - Findingown data§ Discussion · p. 11
Monocyte-derived microglia (MoMg) that accumulate in aging brains acquire bona fide microglia transcriptomes.
“We show by scRNAseq analysis that MoMg that accumulate in aging brains acquire bona fide microglia transcriptomes.”
Quote in the paperSubstantial claim - Findingown data§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10
Monocyte-derived macrophages were present in the substantia nigra pars compacta (SNc), delineated by TH staining.
“Analysis of brains of DR animals, showed the presence of MoM F in the substantia nigra pars compacta (SNc), delineated by tyrosine hydroxylase (TH) staining, and established as a control center for motor performance ( Fig. 6d ).”
Quote in the paperSubstantial claim - Findingown data§ Discussion · p. 11
MoMg that accumulate or engraft in aging brains acquire Sall1 expression.
“This included acquisition of Sall1 expression, a marker we and others had previously assumed to be restricted to YS-derived cells 14-16,18 .”
- Also stated in: § Discussion · p. 11 · plain
“Indeed, over time engrafted MoMg also acquire Sall1 expression.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · p. 11 · plain
- Interpretationown data§ Abstract · p. 2
When carrying a somatic mutation associated with CH, monocyte-derived microglia can contribute to brain pathology.
“and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.”
- Also stated in: § Discussion · p. 10 · plain
“Unlike microglia, MoMg are however subject to somatic mutations associated with CH, and as established here in a mouse model for the DNMT3A R822H variant, MoMg can hence constitute an age-related risk factor for brain pathologies.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · p. 10 · plain
- Interpretationown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 5
Monocyte-derived macrophages in aged brain were found clustered, suggesting clonal in situ expansion.
“Moreover, MoM F in aged brain were found clustered, suggesting clonal in situ expansion.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract · p. 2
Unlike microglia, monocyte-derived microglia are targets of clonal hematopoiesis due to their hematopoietic origin.
“Unlike microglia, these monocytederived microglia (MoMg) are due to their hematopoietic origin targets of clonal hematopoiesis (CH).”
Quote in the paperSubstantial claim - Premisecitation§ Discussion · p. 12
An unbiased screen for somatic mutation in human brain sections revealed cells harboring DNMT3A and TET2 variants restricted to the medulla.
“Interestingly and in line with our findings of the spatially restricted CNS seeding by MoM F , an unbiased screen for somatic mutation in human brain sections revealed cells harboring DNMT3A and TET2 variants restricted to the medulla, suggesting that these regions harbor islands of MoMg bearing CH mutations 66 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] Mildner, 2007, Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions, Nat. Neurosci. source
- Interpretationown data§ Discussion · p. 11
Despite their distinct origin, MoMg become with time identical to microglia on the transcriptome level.
“These data suggest that, despite of their distinct origin, MoMg become with time identical to microglia on the transcriptome level.”
Quote in the paperSubstantial claim - Study design and conductown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 8
WT and mutant BM showed similar engraftment efficiency as indicated by blood and brain analysis for GFPnegative monocytes or macrophages.
“WT and mutant BM showed similar engraftment efficiency as indicated by blood and brain analysis for the presence of GFPnegative monocytes or M F ( Fig. 5b, Suppl. Fig 5a,b ).”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion · p. 13
Our data in the mouse model suggest that MoMF that seed the nigrostriatal regions of aging brains impair dopaminergic circuits causing motor symptoms of parkinsonism.
“Our data in the mouse model suggest that MoM F that seed the nigrostriatal regions of aging brains impair dopaminergic circuits causing motor symptoms of parkinsonism.”
Quote in the paperSubstantial claim - Interpretationown data§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 8
In old chimeras, labeled ramified microglia-like cells were detected by microscopy in distinct clusters, suggesting clonal expansion.
“In the old chimeras, labeled ramified microglia-like cells could also readily be detected by microscopy in distinct clusters, suggesting clonal expansion of the cells ( Fig. 4i ).”
Quote in the paperSubstantial claim - Premisenone given§ Discussion · p. 12
Single-nucleus chromatin profiling of brain cells of octogenarian CH carriers revealed frequencies of MoMg considerably higher than what would be anticipated from fate mapping studies in mice, including this study.
“The single-nucleus chromatin profiling of brain cells of octogenarian CH carriers revealed frequencies of MoMg considerably higher than what would be anticipated from fate mapping studies in mice, including this study.”
Quote in the paperNot a substantial claim - Interpretationown data§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10
The loss of TH+ neurons suggests local impairment of neuronal transmission.
“Immuno-histochemical quantification / TH + volume revealed a loss of TH + neurons in mice harboring hDNMT3A R882H MoMg, as compared to controls ( Fig. 6e , f , Suppl. Fig. 6c,d ), suggesting local impairment of neuronal transmission.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion · p. 13
Monocyte-derived brain macrophages/MoMg can constitute a risk factor for age-related brain pathology in a mouse model.
“With the example of MoMg derived from hDNMT3A R882H expressing HSC, we demonstrate in a mouse model that MoMg can present a risk factor for age-related brain pathology, since they are, unlike microglia, CH targets.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion · p. 12
In a mouse model, as a result of age-related seeding of selected brain regions with MoMg, the most common human CH mutation, DNMT3A R822H, presents a risk factor for motor pathology.
“Here we show in a mouse model that as a result of age-related seeding of selected brain regions with MoMg, the most common human CH mutation, DNMT3A R822H , presents a risk factor for motor pathology,”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 31
- May combine two claims. 26
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Introduction · p. 3Monocyte-derived macrophages progressively replace embryonic macrophages in barrier tissues such as gut and skin, and selected other organs.
“Monocyte-derived M F (MoM F ) progressively replace embryonic M F in barrier tissues, such as the gut and skin, as well as selected other organs, 6 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] Askew, 2017, Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain, Cell Rep. source
The Introduction and Discussion address the origin and maintenance of brain microglia, not macrophage replacement in the gut, skin, or other barrier tissues. Searches for gut, skin, and progressive replacement by monocyte-derived macrophages found no passage addressing that claim; the brain findings do not establish what happens in those tissues. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
Findingown data§ Transcriptome comparison of YS-derived brain M F and MoM F accumulating in the aging mouse brain · p. 6Monocyte-derived microglia, but not leptomeningeal monocyte-derived macrophages, expressed Sall1.
“Surprisingly, and unlike what was reported for experimentally engrafted M F 14-16 , MoMg, but not leptoMoM F , also expressed Sall1 ( Fig. 3d,g ).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [14] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. source
- cites [15] Ajami, 2007, Local self-renewal can sustain CNS microglia maintenance and function throughout adult life, Nat. Neurosci. source
- cites [16] Shemer, 2018, Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge, Nat. Commun. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introduction · p. 3YS-derived microglia persist throughout adulthood and display proliferation and self-renewal potential.
“YS-derived microglia persist throughout adulthood displaying considerable proliferation and self-renewal potential 4,5 .”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [4] Mass, 2016, Specification of tissue-resident macrophages during organogenesis, Science source
The Abstract (page unavailable) identifies brain microglia as tissue-resident macrophages and says these cells derive at least in part from yolk-sac progenitors and self-maintain in adult tissues under steady-state conditions. It does not establish that adult microglia have considerable proliferation potential; a proliferative burst appears only in a cited reference about tissue macrophages after acute inflammation. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [5] Ratz, 2022, Clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics, Nat. Neurosci. source
The Main section reports that microglia arise from a limited number of progenitors that undergo massive clonal expansion, and the Results describe their early embryonic origins. The Discussion links large clone sizes to proliferation during CNS colonization, but it does not establish that yolk-sac-derived microglia self-renew or retain considerable proliferative potential throughout adulthood. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introduction · p. 3Microglia originate from primitive macrophage progenitors in the yolk sac, infiltrate the developing brain, and clonally expand.
“Microglia originate from primitive macrophage (M F ) progenitors that arise in the yolk sac (YS), infiltrate the developing brain and clonally expand 2,3 .”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [2] Ginhoux, 2010, Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages, Science source
The indexed passages (section labeled Abstract; no page supplied) trace adult microglia to primitive yolk-sac progenitors and describe their infiltration of the developing brain. They also report that embryonic microglia are highly proliferative, but do not establish that they expand clonally. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [3] Kierdorf, 2013, Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways, Nat. Neurosci. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Introduction · p. 3Experimentally seeded parenchymal brain monocyte-derived macrophages lack expression of Sall1, a proposed hallmark of microglia identity.
“This includes, for instance, lack of expression of the transcriptional repressor Spalt Like Transcription Factor 1 (Sall1), a proposed hallmark of microglia identity 14,18,19 .”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [14] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. source
- cites [18] Cronk, 2018, Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia, J. Exp. Med. source
In Results (“beMφs have a predictable genetic signature”; page unavailable), Sall1 is listed among microglia-specific genes in the Mg-52 signature. Materials and methods (“Signature creation”; page unavailable) defines that signature by higher expression in microglia than in engrafted brain macrophages. This supports Sall1 as a microglial identity marker, but lower expression does not establish that the engrafted macrophages lack Sall1 expression altogether. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [19] Lund, 2018, Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells, Nat. Commun. source
Classified as probably not a substantial claim.
Premisecitation§ Introduction · p. 3The parenchymal brain macrophage compartment of unchallenged healthy mice is thought to comprise exclusively YS-derived microglia and no monocyte-derived macrophages.
“Likewise, also parenchymal brain M F are thought to comprise during the life time of healthy mice exclusively YS-derived microglia and no MoM F 8-10 .”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [8] Varol, 2015, Macrophages: Development and Tissue Specialization, Annu. Rev. Immunol. source
- cites [9] Goldmann, 2016, Origin, fate and dynamics of macrophages at central nervous system interfaces, Nat. Immunol. source
- cites [10] Perdiguero E.G., Klapproth K., Schulz C., Busch K., Azzoni E., Crozet L., Garner H., Trouillet C., Bruijn M.F. de, Geissmann F., et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 2015;518:547-55. doi:10.1038/nature13989. source
The introductory paragraph reports that brain microglia are predominantly yolk-sac-derived and that HSC-derived progenitors replace them only marginally under steady-state conditions. It also reports that progenitors and monocytes account for a minor fraction of microglia in young adults, with 2% Flt3Cre labelling of microglia up to one year of age. Thus the source supports the general picture, but not the claim of exclusively yolk-sac-derived microglia and no monocyte-derived contribution throughout life. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Introduction · p. 3Monocyte and monocyte-derived macrophage contributions to brain pathologies are well documented in various animal models and human disorders.
“Involvement of these cells has been shown in the development, progression and resolution of experimental autoimmune encephalitis (EAE) 20-22 , stroke 23,24 , Alzheimer's disease 25,26 and viral encephalitis 27 .”
Quote in the paperNot a substantial claim3 of 8 sources checked- cites [20] Fixsen, 2023, SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity, Nat. Immunol. source
The Main section discusses disease roles for resident microglia, not monocytes or monocyte-derived macrophages. The Results section mentions macrophages engrafting after microglial depletion, but does not link them to the development, progression, or resolution of EAE, stroke, Alzheimer’s disease, or viral encephalitis. Searches for those conditions and for monocyte-derived macrophages found no passage establishing the attributed claim. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [21] Buttgereit, 2016, Sall1 is a transcriptional regulator defining microglia identity and function, Nat. Immunol. source
- cites [22] Wolf, 2018, Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone-induced demyelination, Eur. J. Immunol. source
- cites [23] Giladi, 2020, Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation, Nat. Immunol. source
- cites [24] Amorim, 2022, IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation, Nat. Immunol. source
- cites [25] Wicks, 2022, The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke, Front. Immunol. source
- cites [26] Werner, 2020, Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke, Nat. Neurosci. source
- cites [27] ElAli, 2016, Microglia in Alzheimer’s disease: A multifaceted relationship, Brain Behav. Immun. source
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ Introduction · p. 3Experimentally seeded parenchymal brain monocyte-derived macrophages retain epigenomes and expression signatures distinct from YS-derived cells and respond differentially to challenges, even after prolonged brain residence.
“Experimentally seeded parenchymal brain MoM F were shown to retain epigenomes and expression signatures distinct from YSderived cells and respond differentially to challenges, even following prolonged brain residence 14-17 .”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [14] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. source
- cites [15] Ajami, 2007, Local self-renewal can sustain CNS microglia maintenance and function throughout adult life, Nat. Neurosci. source
- cites [16] Shemer, 2018, Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge, Nat. Commun. source
- cites [17] Bennett, 2018, A Combination of Ontogeny and CNS Environment Establishes Microglial Identity, Neuron source
The Results sections on HSC ontogeny and distinct markers (page unavailable) show that engrafted HSC-derived macrophages retain gene-expression differences from YS-derived cells after months in the brain. Our copy does not establish distinct epigenomes or demonstrate that the engrafted populations respond differently when challenged; it only compares their expression profiles with gene sets associated with prior disease and LPS studies. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ Introduction · p. 3CH-associated variants of Dnmt3a and Tet2 affect the HSPC methylome and have been shown to alter functions of monocyte-derived tissue macrophages and promote cardiovascular pathologies.
“CH-associated variants of the epigenetic writers and erasers Dnmt3a and Tet2, respectively, that affect the HSPC methylome have been shown to alter functions of monocyte-derived tissue M F and promote cardiovascular pathologies 31-34 .”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [31] Zhang, 2016, DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells, Nat. Genet. source
The Introduction and the Results section on DNA methylation in HSCs support that DNMT3A and TET2 mutations occur in clonal hematopoiesis and that loss of these genes changes HSC methylation. The paper does not show altered functions of monocyte-derived tissue macrophages or promotion of cardiovascular pathology; its disease findings concern hematologic disease (Results, “Tet2 and Dnmt3a loss induces myeloid and lymphoid disease”; page numbers unavailable). (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [32] Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat. Med. source
The Results (page unavailable) identify age-associated DNMT3A and TET2 mutations and suggest that they may initiate HSPC clonal expansion. Our copy does not show that these variants alter the HSPC methylome, change monocyte-derived tissue macrophage function, or promote cardiovascular pathology. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [33] Fabre, 2022, The longitudinal dynamics and natural history of clonal haematopoiesis, Nature source
The Main section identifies DNMT3A and TET2 as clonal-haematopoiesis genes involved in epigenetic regulation. It does not establish that their variants change the HSPC methylome, alter monocyte-derived tissue macrophage function, or promote cardiovascular disease. The Discussion addresses clonal growth rather than those outcomes; a cardiovascular-disease title appears only in the References. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [34] Abelson, 2018, Prediction of acute myeloid leukaemia risk in healthy individuals, Nature source
The paper’s main text (labelled Abstract in our copy; page unavailable) identifies DNMT3A and TET2 as commonly mutated in clonal haematopoiesis and says clonal haematopoiesis may play a causal role in cardiovascular disease. It does not report effects of those variants on the HSPC methylome or monocyte-derived tissue macrophage function, and its cardiovascular statement is hedged rather than a finding that both variants promote pathology. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
Premisecitation§ Introduction · p. 3Once microglia are impaired by irradiation or genetic deficiencies, HSC-derived macrophages can efficiently and persistently colonize the brain parenchyma.
“Supporting this notion, once microglia are impaired by irradiation or genetic deficiencies, HSC-derived M F can efficiently and persistently colonize the brain parenchyma 14-17 .”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [14] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. source
- cites [15] Ajami, 2007, Local self-renewal can sustain CNS microglia maintenance and function throughout adult life, Nat. Neurosci. source
- cites [16] Shemer, 2018, Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge, Nat. Commun. source
The Results section, “Engrafted brain macrophages acquire longevity and radioresistance” (page unavailable), shows that bone-marrow-derived cells progressively replaced host microglia after irradiation and persisted in the brain parenchyma for more than two months. The Discussion (page unavailable) also reports macrophage engraftment in mice whose microglia were depleted by a Csf1r deficiency, but does not establish that colonization under that genetic condition was efficient and persistent. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [17] Bennett, 2018, A Combination of Ontogeny and CNS Environment Establishes Microglial Identity, Neuron source
In Results (“Transplanted cells of diverse ontogeny engraft and ramify in the Csf1r−/− CNS”; page unavailable), the paper reports complete donor-cell coverage of the brain parenchyma by one month and stable occupancy for up to a year in genetically deficient mice. This supports efficient, persistent colonization in that setting. The reported experiment was irradiation-free, so this paper does not directly establish the irradiation part of the claim. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 13Emerging data suggest that MoMF could counter AD pathogenesis.
“Likewise, emerging data suggest that MoM F could counter AD pathogenesis 26 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] Werner, 2020, Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke, Nat. Neurosci. source
The Results and Discussion passages concern monocyte-derived macrophages after experimental stroke, not Alzheimer’s disease (AD). Searches for Alzheimer’s disease, AD pathogenesis, and a protective role for these cells found no passage in our copy addressing whether they counter AD pathogenesis. (LLM, conf=0.73)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 12The presence of CH mutations served as a proxy to identify HSC-derived cells among the brain MF compartment in the recent study by Jaiswal and colleagues.
“The presence of CH mutations served also as a proxy to identify HSC-derived cells among the brain M F compartment in the recent study by Jaiswal and colleagues 28 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [28] Yan, 2022, Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease, J. Clin. Investig. source
The Results describe using Flt3-Cre–driven GFP labeling to identify hematopoietic-lineage cells in mouse brain macrophage isolates. Our copy does not address the claimed use of clonal hematopoiesis (CH) mutations as a proxy in a study by Jaiswal and colleagues; searches for CH mutations, Jaiswal, and the proposed proxy found no supporting passage. The supplied passages have no page numbers. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitation§ Materials and Methods · p. 16Flow cytometry methods adhered to published guidelines.
“Methods adhered to published guidelines 77 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [77] Jaiswal, 2014, Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes, New Engl J Med source
The Methods section describes whole-exome and targeted amplicon sequencing, not flow cytometry. Searches for flow cytometry and published guidelines found no passage in our copy addressing whether flow-cytometry methods adhered to guidelines; the claim therefore cannot be verified from this source. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 11A recent study reported a high frequency of monocyte-derived microglia in brains of octogenarians.
“In line with this notion, a recent study reported a high frequency of MoMg in brains of octogenarians 28 , although the medical history of these individuals remains unknown.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [28] Yan, 2022, Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease, J. Clin. Investig. source
The Abstract (page unavailable) reports monocyte-derived cells among plaque-associated macrophages, but the finding is 6% in aged Alzheimer’s-model mice, not a high frequency in brains of human octogenarians. The Results (page unavailable) likewise describe mice aged at least 10 months; the cited paper does not report the claimed human observation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 10Monocyte-derived brain macrophages have been reported earlier, but these studies were largely focused on conditions of experimental challenge.
“Monocyte-derived brain M F have been reported earlier, but these studies were largely focused on conditions of experimental challenge 20-25,59 .”
Quote in the paperNot a substantial claim3 of 7 sources checked- cites [20] Fixsen, 2023, SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity, Nat. Immunol. source
- cites [21] Buttgereit, 2016, Sall1 is a transcriptional regulator defining microglia identity and function, Nat. Immunol. source
- cites [22] Wolf, 2018, Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone-induced demyelination, Eur. J. Immunol. source
- cites [23] Giladi, 2020, Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation, Nat. Immunol. source
- cites [24] Amorim, 2022, IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation, Nat. Immunol. source
- cites [25] Wicks, 2022, The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke, Front. Immunol. source
The Introduction’s ‘Immune Response to Stroke’ section describes monocyte-derived macrophages entering the brain after ischemic injury, and ‘Background: Monocyte-Derived Macrophages’ cites their identification in an infarcted brain (page numbers unavailable). These support earlier reports under experimental challenge, but the paper does not establish that earlier studies were largely confined to such conditions. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [59] Ajoy, 2021, CCL5 promotion of bioenergy metabolism is crucial for hippocampal synapse complex and memory formation, Mol. Psychiatr. source
The Introduction discusses microglia in an Alzheimer’s disease mouse model, and the Methods mention reduced macrophage infiltration after peripheral sensitization. Neither passage addresses whether monocyte-derived brain macrophages had been reported previously or whether those studies were largely conducted under experimental challenge. Searches for monocyte-derived brain macrophages and for macrophage infiltration under challenge found no decisive passage; page numbers were unavailable in our copy. (LLM, conf=0.70)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Discussion · p. 13A common genetic cause of PD are mutations of the LRRK2 gene, which is predominantly expressed in the CNS by MF.
“Specifically, a common genetic cause of PD are mutations of the leucine rich repeat kinase 2 (LRRK2) gene 73 which is predominantly expressed in the CNS by M F .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [73] Uriarte Huarte, 2021, Single-Cell Transcriptomics and In Situ Morphological Analyses Reveal Microglia Heterogeneity Across the Nigrostriatal Pathway, Front. Immunol. source
The Introduction and Discussion discuss Parkinson’s disease and microglia, but do not address LRRK2 mutations or which CNS cells predominantly express LRRK2. Searches of our full-text copy for “LRRK2” and its expanded name found no relevant passage; the copy therefore cannot verify the attributed claim. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitation§ Materials and Methods · p. 15Cells for bulk-RNAseq and scRNAseq were processed with actinomycin D to prevent transcriptomic changes.
“Cells were kept on ice during all steps, except for the enzymatic digestion and cells for bulk-RNAseq and scRNAseq were processed always with actinomycin D (ActD) to prevent transcriptomic changes, as reported before 39 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] Lin, 2024, Clonal Expansion in Cardiovascular Pathology. JACC: Basic Transl, Sci. source
The paper’s discussion of single-cell RNA sequencing in the Aneurysm section concerns cell fates, not sample processing. Neither that section nor the passages retrieved by searching for actinomycin D, ActD, and bulk- and single-cell RNA sequencing describe treating cells with actinomycin D to prevent transcriptomic changes. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 12Clonal hematopoiesis (CH) prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2.
“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
Quote in the paperNot a substantial claim4 of 4 sources checked- cites [34] Abelson, 2018, Prediction of acute myeloid leukaemia risk in healthy individuals, Nature source
- cites [45] Liu, 2019, Fate Mapping via Ms4a3-Expression History Traces Monocyte-Derived Cells, Cell source
The Introduction (p. 4) describes Ms4a3-based tracing of monocyte progenitors, not clonal hematopoiesis. Searches for DNMT3A, TET2, epigenetic regulators, and clonal hematopoiesis found no passage in our copy addressing the attributed claim. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [70] Davalos, 2012, Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation, Nat. Commun. source
The Results section discusses fibrinogen signaling, microglial clustering, and axonal damage in neuroinflammation (page unavailable). Searches for clonal hematopoiesis, DNMT3A, TET2, and epigenetic regulatory genes found no passage in our copy addressing the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [71] Shemer, 2020, Interleukin-10 Prevents Pathological Microglia Hyperactivation following Peripheral Endotoxin Challenge, Immunity source
The supplied passages discuss chromatin analysis and microglial responses, not clonal hematopoiesis. Searches for clonal hematopoiesis, DNMT3A, TET2, and epigenetic regulatory genes found no passage addressing the attributed claim; no page numbers were available in the returned passages. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 13Emerging evidence suggests that cardiovascular pathologies and atherosclerosis exacerbated by CH mutation-afflicted MoMF involve distinct effector molecules, such as Il1b and IL6.
“Emerging evidence suggests that cardiovascular pathologies and atherosclerosis exacerbated by CH mutation-afflicted MoM F involve distinct effector molecules, such as Il1 b and IL6 31,74 .”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [31] Zhang, 2016, DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells, Nat. Genet. source
The Results and Discussion passages address DNMT3A/TET2 loss in hematopoietic stem cells and its relationship to lineage-gene expression and malignancy, not cardiovascular disease or atherosclerosis. Searches for cardiovascular pathology, macrophages, IL1b, and IL6 found no passage linking these molecules to CH-driven vascular disease; IL6 appears only as a component of cell-culture medium. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [74] Moca, 2022, Microglia Drive Pockets of Neuroinflammation in Middle Age, J. Neurosci. source
The Results (pp. 13–15) discuss IL-1β and IL-6 in aging mouse brain tissue and serum, not cardiovascular disease. Searches for clonal hematopoiesis, mutation-afflicted monocyte-derived macrophages, and atherosclerosis found no passage linking those conditions to the cytokines. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 12CH variants such as DNMT3A and TET2 constitute an increased risk for hematologic malignancies, cardiovascular events and stroke.
“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
Quote in the paperNot a substantial claim4 of 4 sources checked- cites [34] Abelson, 2018, Prediction of acute myeloid leukaemia risk in healthy individuals, Nature source
The paper reports that DNMT3A and TET2 are the most commonly mutated genes in its clonal-haematopoiesis groups and examines their association with progression to AML, noting that they confer a lower risk than many other driver mutations (Abstract; page unavailable). It also says clonal haematopoiesis may play a causal role in cardiovascular disease (Abstract; page unavailable). Our copy does not establish increased risk of stroke or of haematological malignancies beyond AML. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [45] Liu, 2019, Fate Mapping via Ms4a3-Expression History Traces Monocyte-Derived Cells, Cell source
The Introduction (p. 4) describes an Ms4a3 fate-mapping model, and the Discussion (pp. 15–16) addresses MS4A3 expression and cell-cycle regulation. Searches for DNMT3A, TET2, clonal hematopoiesis, cardiovascular risk, and stroke found no passage in our copy addressing the claimed disease risks. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [70] Davalos, 2012, Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation, Nat. Commun. source
The Results section on fibrin signaling via CD11b/CD18 addresses microglial clustering and axonal damage in neuroinflammation, not clonal hematopoiesis. Searches for DNMT3A, TET2, clonal hematopoiesis, hematologic malignancies, cardiovascular events, and stroke found no passage in our copy addressing the claimed risks; page numbers were not provided. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [71] Shemer, 2020, Interleukin-10 Prevents Pathological Microglia Hyperactivation following Peripheral Endotoxin Challenge, Immunity source
The Discussion passages concern microglial responses to endotoxin and IL-10 signaling, not clonal hematopoiesis. Searches for DNMT3A, TET2, clonal hematopoiesis, malignancy, cardiovascular risk, and stroke found no passage in our copy addressing the attributed claim; page numbers were not available. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 11Human monocyte-derived microglia were shown to harbor ATACseq signals in the Sall1 loci.
“This is in line with recent data reported for human monocyte-derived microglia which were shown to harbor ATACseq signals in the Sall1 loci 28 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [28] Yan, 2022, Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease, J. Clin. Investig. source
The Results describe marker expression in plaque-associated monocyte-derived cells in mice, and the Methods describe mouse fate-mapping experiments. Searches for Sall1, ATAC-seq, and chromatin accessibility found no passage reporting ATAC-seq signals at the Sall1 locus in human monocyte-derived microglia. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Discussion · p. 13Ccl5 encodes a chemokine that acts on immune cells and neurons and has been associated with brain pathologies, including PD.
“Interestingly though, in particular the MoMg derived from hDNMT3A R882H HSC also prominently expressed Ccl5 , encoding a chemokine that acts on immune cells and neurons, and has been associated with brain pathologies, including PD 53-55 .”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [53] Scheller, 2021, Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response, Nat. Cancer source
The available passages discuss DNMT3A-mutant hematopoietic cells, azacytidine and viral mimicry (Abstract; no page given), not Ccl5’s effects on immune cells or neurons or its association with Parkinson’s disease. Searches for Ccl5 and for the chemokine–Parkinson’s disease connection found no passage addressing the attributed claim. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [54] Zioni, 2023, Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis, Nat. Commun. source
The Introduction and Discussion discuss inflammatory signals from fatty bone marrow, particularly IL-6, but do not address Ccl5’s effects on immune cells or neurons or its association with Parkinson’s disease. Searches of our copy for Ccl5, neurons, and Parkinson’s disease found no passage supporting the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [55] Shumliakivska, 2024, DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts, Nat. Commun. source
The Introduction and Results passages discuss DNMT3A-mutant monocytes, cardiac fibroblasts, and EGF signaling, not Ccl5’s effects on neurons or its association with brain pathologies. Searches for Ccl5, neurons, and Parkinson’s disease found no passage in our copy addressing the attributed claim. (LLM, conf=0.74)
Experimental — accuracy not yet measured
May combine two claims.
Findingown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 5Ventral surface of brain harbored more MHCII+ and less Lyve1+ cells than dorsal leptomeninges, confirming regional difference of BAM replacement rates at brain borders.
“Also in these animals, the ventral surface of the brain harbored more MHCII + and less Lyve1 + cells than the dorsal leptomeninges confirming regional difference of BAM replacement rates at the brain borders ( Suppl. Fig. 2h ).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 4The TdTom+ parenchymal cells included CD206+ BAM and TdTom+ cells expressing Tmem119 at lower frequency.
“The latter included, as expected 7 CD206 + BAM, but also TdTom + cells expressing the microglia marker Tmem119, albeit at lower frequency.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Tay, 2017, A new fate mapping system reveals context-dependent random or clonal expansion of microglia, Nat. Neurosci. source
May combine two claims.
Findingown data§ Abstract · p. 2Monocyte-derived macrophages accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex.
“We report that monocyte-derived macrophages (MoM F ) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex.”
- Also stated in: § Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 5 · plain
“Morphological discrimination revealed an accumulation of Iba1 + MoM F with microglia-like morphology in selected brain regions of the mice, including the occipital cortex, the nigrostriatal parenchyma and the medulla, but not the frontal and parietal-temporal cortex ( Fig. 1d ).”
Quote in the paperSubstantial claim- Also stated in: § Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 5 · plain
May combine two claims.
Findingown data§ Transcriptome comparison of YS-derived brain M F and MoM F accumulating in the aging mouse brain · p. 6Monocyte-derived microglia formed 4 MetaCells with no microglia counterparts (cluster II), characterized by high expression of MHCII-related genes (Cd74, H2ab-1) and Apoe.
“MoMg in addition formed 4 MetaCells that had no microglia counterparts (cluster II), characterized by high expression of MHCII-related genes ( Cd74 , H2ab-1 ), as well as Apoe ( Fig. 3g,h, Suppl. Fig. 3d, e ).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Abstract · p. 2Monocyte-derived microglia progressively seed the brains of aging healthy mice and accumulate in selected areas.
“Collectively, these data establish in a mouse model that MoMg progressively seed the brains of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.”
- Also stated in: § Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 6 · boosted
“Collectively, these data establish that the borders and the parenchyma of selected regions of brains of healthy aged mice are progressively seeded by monocyte-derived cells.”
Quote in the paperSubstantial claim- Also stated in: § Monocyte-derived macrophages accumulate with age at the brain borders and in largely non-cortical parenchyma · p. 6 · boosted
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Supplementary Figure 1. Flow cytometry and microscope images of brains of Ms4a3 cre/+ : R26 TdTomato mice · p. 30MoM_F with microglia morphology reside in the diencephalon/midbrain region of 6-month-old Cxcr4creer/+:R26TdTomato/TdTomato mice.
“Representative image of MoM F with microglia morphology residing in diencephalon/midbrain region of 6-month-old Cxcr4 creer/+ : R26 TdTomato/TdTomato mouse that was TAM pulsed at 6 weeks of age and sacrificed 4 months later for analysis, stained with Iba1 antibodies.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10Compared to controls, VavCre:hDNMT3A R822H BM recipients displayed reduced average speed and cadence, as well as extended standing on three and four legs.
“Specifically, as compared to controls, Vav Cre : hDNMT3A R822H BM recipients displayed reduced average speed and cadence, as well as extended standing on three and four legs ( Fig. 6b, Suppl. Fig. 6b, Suppl. Data 2 ).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 9Monocyte-derived microglia comprised two populations, one of which displayed Ccl5 expression.
“MoMg comprised two populations, one of which displayed Ccl5 expression ( Fig. 5f-h ).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 8Thereafter, the Tmem119+ parenchymal macrophage compartment, but not CD206+ BAM, displayed progressive accumulation of TdTom+ cells.
“Thereafter, however, the Tmem119 + parenchymal M F compartment, but not CD206 + BAM, displayed progressive accumulation of TdTom + cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Discussion · p. 13MoMg in the brain parenchyma, and even more so mutant MoMg, did express Il1b, but no IL6.
“MoMg in the brain parenchyma, and even more so mutant MoMg, did express Il1 b , but no IL6.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingnone given§ Discussion · p. 12Mutant monocytes in the chimeras also seed peripheral MF compartments.
“However, and as in individuals harboring CH variants, mutant monocytes in the chimeras also seed peripheral M F compartments, and we cannot rule out that this contributes to the observed phenotype.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Supplementary Figure 1. Flow cytometry and microscope images of brains of Ms4a3 cre/+ : R26 TdTomato mice · p. 29Ramified MoMg are present in the brain of Cxcr4creer/+:R26TdTomato/TdTomato mice that were TAM pulsed at 6 weeks of age and sacrificed 4 months later.
“Note presence of ramified MoMg.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 3. Single cell RNA sequencing of YS-derived M F and MoM F isolated from Ms4a3 cre/+ : R26 TdTomato : Cx3cr1 gfp/+ parenchyma and leptomeninges · p. 26MetaCell analysis of Ms4a3cre/+:R26TdTomato:Cx3cr1gfp/+ parenchyma and leptomeninges identified 15 cell types grouped into 5 clusters (I-V), with 11 cell types in the microglia and MoMg clusters (I, II) and 4 cell types in the leptoM_F and leptoMoM_F clusters (III-V).
“MetaCell analysis identifying 15 cell types, following into 5 clusters (I-V). 11 cell types were located in the microglia and MoMg clusters (I, II), and 4 cell types were located in the leptoM F and leptoMoM F clusters (III-V).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 8Cluster III, IV comprised 1966 genes with higher expression in mutant monocyte-derived microglia vs control monocyte-derived microglia, including MHCII-related genes (Cd74, H2-Ab1) and Slc15a2.
“Cluster III, IV comprised 1966 genes which displayed higher expression in the mutant MoMg vs control MoMg, including MHCII-related genes ( Cd74, H2-Ab1) and Slc15a2 , encoding the proton-coupled oligopeptide transporter PepT2 ( Fig. 5d,e ).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Figure 3. Single cell RNA sequencing of YS-derived M F and MoM F isolated from Ms4a3 cre/+ : R26 TdTomato : Cx3cr1 gfp/+ parenchyma and leptomeninges · p. 26MoMg overlap with Meta cells referring to microglia.
“Note that MoMg overlap with Meta cells referring to microglia.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Discussion · p. 12Mutant MoMg, including cells that express Ccl5, are located in basal ganglia regions.
“Using spatial transcriptomics we show that mutant MoMg, including cells that express Ccl5 are located in basal ganglia regions, in line with the possibility that they might directly affect the dopaminergic circuits.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 8Microglia of the two types of BM chimeras displayed essentially identical transcriptomes, while control and mutant monocyte-derived microglia were distinct from host microglia.
“K-means clustering showed that microglia of the two types of BM chimeras displayed essentially identical transcriptomes, while control and mutant MoMg were distinct from host microglia ( Fig. 5c, Suppl. Fig. 5c ).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 9Monocyte-derived microglia were excluded from frontal cortical areas but found diffusely spread in nigrostriatal and medullary area.
“Interestingly, and in line with the imaging data ( Fig. 1d, Suppl. Fig. 4a ), MoMg were excluded from frontal cortical areas but found diffusely spread in nigrostriatal and medullary area ( Fig. 5i ).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 2. Flow cytometry and microscope images of brain from Ms4a3 cre/+ : R26 TdTomato : Cx3cr1 gfp/+ mice · p. 25In Ms4a3cre/+:R26TdTomato:Cx3cr1gfp/+ mice, GFP+ cells are yolk-sac-derived microglia and GFP+ TdTomato+ cells are monocyte-derived macrophages (MoM_F).
“GFP + cells, YS-derived microglia; GFP + TdTomato + cells, MoM F .”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 8Mutant leptomeningeal monocyte-derived macrophages displayed subtle changes compared to control leptomeningeal monocyte-derived macrophages, including elevated expression of Slc15a2 and Spint1.
“Also, mutant leptoMoM F displayed subtle changes as compared to control leptoMoM F , including elevated expression of Slc15a2 and Spint1 ( Suppl. Fig. 5d-f ).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Impact of hematopoietic hDNMT3A R882H expression on the MoMg compartment · p. 8Cluster I and II comprised 1187 genes expressed higher by control monocyte-derived microglia than mutant monocyte-derived microglia, including Plac8.
“Cluster I and II comprised 1187 genes expressed higher by control MoMg, than mutant MoMg, including Plac8 .”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ BM transplantation yields HSC-derived brain M F without monocytic intermediate and MoM F that accumulate with age · p. 7In BM chimeras, monocyte-derived macrophages accumulate first in nigrostriatal regions, like age-related monocyte-derived macrophages.
“Analysis of chimeras generated with Ms4a3 Cre : R26-TdTomato BM ( Fig. 4a ) revealed that also MoM F generated in these mice accumulate first in the nigrostriatal regions, like MoM F that arise with age ( Fig. 4b, Suppl. Fig. 4 a,b ).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Introduction · p. 3Other border-associated macrophages in perivascular spaces and leptomeninges are believed to remain largely of embryonic origin under steady-state conditions.
“Other borderassociated M F (BAM) in the perivascular 'Virchow-Robin' spaces and the leptomeninges are believed to remain under steady-state conditions largely of embryonic origin 7 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Tay, 2017, A new fate mapping system reveals context-dependent random or clonal expansion of microglia, Nat. Neurosci. source
May combine two claims.
Interpretationown data§ Abstract · p. 2Hematopoietic expression of DNMT3A R822H renders monocyte-derived microglia pathogenic, promoting motor deficits resembling atypical Parkinsonian disorders.
“Using a chimeric transfer model, we show that hematopoietic expression of DNMT3A R822H , a prominent mutation in human CH, renders MoMg pathogenic promoting motor deficits resembling atypical Parkinsonian disorders.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Introduction · p. 3In the murine CNS, choroid plexus-associated macrophages are replaced by monocyte-derived macrophages.
“In the murine CNS, choroid plexus-associated M F have been reported to be replaced by MoM F 7 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Tay, 2017, A new fate mapping system reveals context-dependent random or clonal expansion of microglia, Nat. Neurosci. source
May combine two claims.
Interpretationown data§ Mice harboring hDNMT3A R882H MoMg develop a motor disability · p. 10Monocyte-derived microglia accumulate in the aging brain in nigrostriatal regions and when derived from hDNMT3A R882H HSC affect dopaminergic circuits and cause with time a motoric deficiency.
“Collectively, these data establish that MoMg accumulate in the aging brain in nigrostriatal regions and when derived from hDNMT3A R882H HSC affect dopaminergic circuits and cause with time a motoric deficiency.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone given§ Materials and Methods · p. 19Animals of the same age, sex, and genetic background were randomly assigned to treatment groups.
“Animals of the same age, sex, and genetic background were randomly assigned to treatment groups.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone given§ Materials and Methods · p. 19Sample sizes were chosen according to standard guidelines.
“Sample sizes were chosen according to standard guidelines.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone given§ Materials and Methods · p. 19Statistical tests were selected based on appropriate assumptions with respect to data distribution and variance characteristics.
“Statistical tests were selected based on appropriate assumptions with respect to data distribution and variance characteristics.”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
The effect of the DNMT3A R822H variant results from the altered HSC methylome of VavCre:hDNMT3A R822H mice rather than the expression of the mutant epigenome writer in MoMF.
“We assume that the effect of the DNMT3A R822H variant results from the altered HSC methylome of Vav Cre : hDNMT3A R822H mice 49 rather than the expression of the mutant epigenome writer in MoM F .”
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.
DNMT3A variant is identified as both R822H and R882H
MinorThe abstract identifies the CH-associated variant as DNMT3A R822H, while the animal methods identify the mice used in the study as carrying DNMT3A R882H. These specify different amino-acid substitutions for the mutation central to the paper's conclusion.
“hematopoietic expression of DNMT3A R822H , a prominent mutation in human CH”
“LSLDNMT3A R882H mice 49 . All Ms4a3 cre , Cx3cr1 gfp and DNMT3A R882H animals in this study were heterozygotes.”
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Self-citationMicroglia drive pockets of neuroinflammation in middle age
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Classical monocyte ontogeny dictates their functions and fates as tissue macrophages
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“64 Furthermore, our results suggest that when MLBMs carry CH variants, they shift into pro-inflammatory and proliferative states, potentially contributing to neuronal loss during AD pathogen-esis—paralleling another study showing that brain-resident microglia carrying driver variants may also lead…”
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“We also recognize that our characterization of myeloid cells in tissue do not necessarily distinguish microglial cells from macrophages, which is challenging to do in situ 62 .”
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A microglia clonal inflammatory disorder in Alzheimer’s DiseasePreprint
Vicario, R., Fragkogianni, S., Weber, L., Lazarov, T., Hu, Y., Hayashi, S. Y., Craddock, B. P., Socci, N. D., Alberdi, A., Baako, A., et al. (2024) · eLife · doi:10.7554/elife.96519.2 · Cited by 2 · see citing works
Self-citationKlein, B. Y., Gofrit, O. N., & Greenblatt, C. L. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47080651 · Cited by 1 · see citing works
“According to animal [12] and human [13–16] studies, it is likely that peripheral immunocytes originating in the bone marrow infiltrate the brain.”
Charting human developmental hematopoiesis in vitro to open new routes for regenerative medicine
Castiglioni, C., Piussi, R., & Ditadi, A. (2026) · Blood · doi:10.1182/blood.2024028063 · Cited by 1 · see citing works
Gateways for myeloid cell entry into the central nervous system
Amann, L., & Prinz, M. (2026) · Neuron · doi:10.1016/j.neuron.2026.04.001 · Cited by 2 · see citing works
Self-citationPlasticity of the infant immune system during the perinatal period
Kierdorf, K., Sperandio, M., Hornef, M. W., & Henneke, P. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01354-7 · Cited by 2 · see citing works
Visualization, Fate Mapping, Ablation, and Mutagenesis of Microglia in the Mouse Brain
Kim, J., & Jung, S. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_4 · Cited by 1 · see citing works
Self-citationClonal haematopoiesis-associated, age-related motor deficits caused by monocyte-derived microglia
Balevičiūtė, A., & Keane, L. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-00997-8
Owens, T., & Włodarczyk, A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00145-9
Differential Tissue Macrophage Ontogeny and its Impact on Physiology
Jung, S. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00270-2
Self-citationPlot twist: TET2 clones save the brain
Telpoukhovskaia, M. A., & Trowbridge, J. J. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.07.001
The Neuroimmune Landscape of the Lysosomal Storage Disorder Sanfilippo Syndrome
Badell‐Grau, R. A., & Schlachetzki, J. C. M. (2025) · BioEssays · doi:10.1002/bies.70083
“Indeed, infiltration of peripheral myeloid cells from the blood into the brain may occur during aging [74] and in neurodegenerative diseases such as AD, but it remains controversial if MdMs show a protective or pathogenic phenotype [73, 75– 78].”
Macrophages conquer the glands
Nonaka, D., & Jung, S. (2026) · Nature Immunology · doi:10.1038/s41590-025-02364-8
Self-citationFebo, M., Sorcini, D., Mirarchi, A., et al. (2026) · HemaSphere · doi:10.1002/hem3.70341
“9 In contrast, DNMT3A ‐ mutant monocyte ‐ derived microglia accumulate in nigrostriatal regions and induce Parkinson's disease ‐ like motor deficits, 10 demonstrating that premalignant hematopoietic clones can modulate neuroinflammatory processes and neurological function.”
Somatic variation in multiple sclerosis: from blood to brain
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CSF1R-related leukoencephalopathy: experimental models and potential for treatment
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Self-citationSomatic Blood Mosaicism and Psychiatric Disease: Current Evidence and Causal Limits
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Self-citation
- Authors
- Kim, J.-S., Trzebanski, S., Shin, S.-H., Schori, L., Frumer Friedman, G. R., Ilani, N. C., Kadam, A., Vicario, R., Aust, O., Bugaeva, P., Piatek, S., Ismajli, L. K., Hoffmann, C. J., Scheller, M., Boura-Halfon, S., Kaushansky, N., Golani, O., Solomon, A., Liu, Z., Amann, L., Böhm-Sturm, P., Koch, S. P., Wenger, N., Ginhoux, F., Prinz, M., Avraham, R., Harms, C., Geissmann, F., Müller-Tidow, C., Uderhardt, S., Milenkovic, I., Shlush, L., & Jung, S.
- Affiliations
- Weizmann Institute of Science (IL)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Einstein Center for Neurosciences Berlin (DE)
- German Centre for Cardiovascular Research (DE)
- University Hospital Heidelberg (DE)
- Shanghai Jiao Tong University (CN)
- University of Freiburg (DE)
- Humboldt-Universität zu Berlin (DE)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Jung, Steffen
- ORCID
- Kim, Jung-Seok
- Trzebanski, Sébastien
- Shin, Sun-Hye
- Kadam, Aditee
- Bugaeva, Polina
- Hoffmann, Christian Johannes
- Scheller, Marina
- Kaushansky, Nathali
- Golani, Ofra
- Solomon, Aryeh
- Liu, Zhaoyuan
- Amann, Lukas
- Koch, Stefan Paul
- Wenger, Nikolaus
- Ginhoux, Florent
- Prinz, Marco
- Avraham, Roi
- Harms, Christoph
- Uderhardt, Stefan
- Shlush, Liran
- Jung, Steffen
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2025-05
- Volume
- 44
- Issue
- 5
- Pages
- 115609
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4409716212
- Cited by
- 33
- References
- 99
- Citations by year
- 2026: 18 · 2025: 10 · 2024: 5
- FWCI
- 10.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- National Institutes of Health (1 R01 HL138090-01, 1 R01 AI130345-01, P30 CA008748, 1R01NS115715-01)
- Deutsche Forschungsgemeinschaft (259373024 -TRR 167)
- European Research Council (ID 101039438, 261193037)
- Bundesministerium für Bildung und Forschung
- Deutsches Zentrum für Herz-Kreislaufforschung
- Einstein Center for Neurosciences Berlin
- Weizmann Institute of Science
- Memorial Sloan-Kettering Cancer Center (18-40-15 -VICA)
- Israel Science Foundation (448121430, 505539112, 447268119, 696/21)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- clonal hematopoiesis, microglia, aging, motor impairment, parkinsonism, hematopoietic stem cells, medulla, somatic mutations, brain macrophages
- MeSH terms
- Clonal Hematopoiesis, DNA Methyltransferase 3A, Aging, Animals, Brain, DNA (Cytosine-5-)-Methyltransferases, Hematopoietic Stem Cells, Humans, Macrophages, Mice, Inbred C57BL, Monocytes, Microglia, Mice
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 2026-10-28.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.
Cited sources are checked by gpt-6-sol.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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