Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge
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Abstract
Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies.
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Yolk-sac-derived microglia marker genes are highly enriched in microglia and are not upregulated in monocytes that engraft the brain in microglia-depleted mouse models.
“These genes are highly enriched in microglia and are not upregulated in monocytes that engraft the brain in microglia-depleted mouse models”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Shemer et al., 2018
The Results section (‘Engrafted cells have transcriptomes distinct from microglia’; page not provided) reports that several microglia signature genes are reduced or absent in engrafted cells. But it also reports expression of other signature genes, including Fcrls and Tgfbr, in those cells. The claim therefore overgeneralizes when it says the marker genes are not upregulated in engrafted monocytes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOnce 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 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [16]
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 measuredExperimentally 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 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [16]
Monocyte-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 ).”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [16]
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“Strong similarities between the transcriptomic profile of BM-derived BAM repopulating the brain and that of native BAM has also been reported [52], supporting the idea that local cues determine myeloid cell identity [98].”
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Chemically modified guide RNAs enhance CRISPR-Cas13 knockdown in human cells
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- Authors
- Shemer, A., Grozovski, J., Tay, T. L., Tao, J., Volaski, A., Süß, P., Ardura-Fabregat, A., Gross-Vered, M., Kim, J.-S., David, E., Chappell-Maor, L., Thielecke, L., Glass, C. K., Cornils, K., Prinz, M., & Jung, S.
- Affiliations
- Weizmann Institute of Science (IL)
- University of Freiburg (DE)
- University of California San Diego (US)
- Technische Universität Dresden (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Jung, Steffen
- ORCID
- Venue
- Nature Communications
- Published
- 2018-12-06
- Volume
- 9
- Issue
- 1
- Pages
- 5206-5206
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6284018
- OpenAlex
- W2902840690
- Cited by
- 1,052
- References
- 27
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 49 · 2023: 37 · 2022: 35 · 2021: 525 · 2020: 262 · 2019: 73 · 2018: 13
- FWCI
- 98.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- International Progressive MS Alliance
- Deutsche Forschungsgemeinschaft (SFB-1160, SFB 992, SFB/ TRR 167, CRC/TRR 167, TA1029/1-1, DFG, TA1029/1-1, TRR 167)
- Bundesministerium für Bildung und Forschung
- Albert-Ludwigs-Universität Freiburg (SFB/TRR167)
- Roman, Marga und Mareille Sobek Stiftung
- National Institutes of Health (NS096170, GM085764)
- Universitätsklinikum Hamburg-Eppendorf
- National Institute of General Medical Sciences (P50GM085764)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK091183)
- National Institute of Neurological Disorders and Stroke (R01NS096170)
- FP7 Ideas: European Research Council (340345)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, bone marrow-derived macrophages, hematopoietic stem cell transplantation, macrophage heterogeneity, transcriptome, chromatin accessibility, endotoxin challenge, clonal expansion, lysosomal storage disease, monogenic immunodeficiency
- MeSH terms
- Animals, Brain, Chromatin, Female, Humans, Lipopolysaccharides, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Hematopoietic Stem Cell Transplantation, Cell Proliferation, Transcriptome
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