Specification of tissue-resident macrophages during organogenesis
Open accessAbstract
INTRODUCTION: Embryonic development and tissue homeostasis depend on cooperation between specialized cell types. Resident macrophages are professional phagocytes that survey their surroundings; eliminate unfit cells, microorganisms, and metabolic waste; and produce a large range of bioactive molecules and growth factors. Resident macrophages also serve tissue-specific purposes: For example, microglia in the central nervous system support neuronal circuit development, Kupffer cells scavenge blood particles and dying red blood cells in the liver, and alveolar macrophages uptake surfactant and remove airborne pollutants and microbes from the airways. Resident macrophage diversity in adult mice is reflected in tissue-specific gene expression profiles, which may be due to responses to specific cues from their microenvironment, different developmental processes, and the contribution of distinct progenitors cell types. Altogether, the mechanisms responsible for the generation of tissue-resident macrophage diversity remain unclear. RATIONALE: Tissue-resident macrophages originate, at least in part, from mesodermal erythro-myeloid progenitors (EMPs) from the yolk sac, which invade the embryo proper at the onset of organogenesis. These tissue-resident macrophages are also self-maintained in postnatal tissues, independently of definitive hematopoietic stem cells (HSCs) in a steady state. We therefore hypothesized that resident macrophages represent a founding cell type within most organ anlagen. In this model, the generation of macrophage diversity, as observed in the tissues of postnatal mice, may be integral to organogenesis. RESULTS: To test this hypothesis and explore the molecular basis of macrophage diversity in mammals, we performed a spatiotemporal analysis of macrophage development in mice, from embryonic day 9 (E9) to 3 weeks after birth. Unbiased single-cell RNA sequencing (RNA-seq) analysis of CD45 + cells, combined with RNA-seq analyses of sorted cell populations, genetic fate mapping, and in situ analyses, revealed that EMPs give rise to a population of premacrophages (pMacs) that colonize the whole embryo from E9.5, as they acquire a core macrophage differentiation program that includes pattern recognition, scavengers, and cytokine receptors. The chemokine receptor Cx3cr1 is up-regulated in pMacs and is important for embryo colonization, which is delayed in Cx3cr1 -deficient embryos. Fate mapping of pMacs using a Tnfrsf11a –Cre reporter labels homogeneously fetal and adult tissue-resident macrophages but not HSCs and their progeny. Transcriptional regulators that identify postnatal tissue-resident macrophages in the brain, liver, kidney, skin, and lung were specifically up-regulated immediately after colonization. These dynamic changes mark the onset of diversification into adult macrophages. We identified Id3 as a Kupffer cell–specific transcriptional regulator. Deletion of Id3 in pMacs resulted in Kupffer cell deficiency but did not affect development of microglia and kidney macrophages. CONCLUSION: Our study shows that EMP-derived precursors colonize embryonic tissues and simultaneously acquire a full core macrophage program. This is followed by their diversification into tissue-specific macrophages during organogenesis, likely via the expression of distinct sets of transcriptional regulators. These results indicate that differentiation of tissue-resident macrophages is an integral part of organogenesis and identify a spatiotemporal molecular road map for the generation of macrophage diversity in vivo. Our findings provide a conceptual framework to analyze and understand the consequence(s) of genetic variation for macrophage contribution to development, homeostasis, and disease pathogenesis in different tissues and will support efforts to differentiate specialized macrophages in vitro.
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YS-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 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [4]
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 measuredCerebellar microglia show increased expression of genes characteristic of immature microglia and genes expressed in neurodegenerative disease-associated microglia.
“Furthermore, cbMg show an increase in the expression of genes characteristic of immature microglia9,10, as well as genes that are expressed in neurodegenerative disease-associated microglia (such as primed microglia, MGnD, and DAMs)11–13 (Supplementary Fig. 5c,d, Supplementary Table 4).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [9]
The cerebellar microglia phenotype resembles microglia during early brain development and microglia associated with neurodegenerative disease.
“The cerebellar microglia phenotype is reminiscent of microglia during early brain development9,10 as well as microglia associated with neurodegenerative disease11–13.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [9]
The cerebellar microglia-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration and early brain development.
“We found that the cbMg-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration11–13 and early brain development9,10, two stages of life characterized by enhanced neuronal attrition and heightened microglia clearance activity.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [9]
This reduction in homeostatic microglia genes is another key characteristic feature of early microglia progenitors and microglia exposed to dying neurons during different diseases.
“This is another key characteristic feature of early microglia progenitors9,10 as well as microglia exposed to dying neurons during different diseases11–13.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [9]
Comparison of C57BL/6 microglia with different resident tissue macrophage populations observed 900 mRNAs with levels of expression in microglia 10-fold greater than the integrated mean of expression levels in the other macrophage subsets at an FDR of 0.05.
“We compared the levels of mRNA transcripts in C57BL/6 microglia with different resident tissue macrophage populations (26, 56) and observed 900 mRNAs with levels of expression in microglia that were 10-fold greater than the integrated mean of expression levels in the other macrophage subsets at a FDR of 0.05 (Fig. 2B).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [56]
Intersecting developmentally determined and environment-dependent transcriptional networks establish microglia identity and function.
“Integration of these findings with recent studies of yolk sac and embryonic microglia (56, 63) suggests a model by which intersecting developmentally determined and environment-dependent transcriptional networks establish microglia identity and function (Fig. 6E).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [56]
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- Authors
- Mass, E., Ballesteros, I., Farlik, M., Halbritter, F., Günther, P., Crozet, L., Jacome-Galarza, C. E., Händler, K., Klughammer, J., Kobayashi, Y., Gomez-Perdiguero, E., Schultze, J. L., Beyer, M., Bock, C., & Geissmann, F.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
- Austrian Academy of Sciences (AT)
- University of Bonn (DE)
- Matsumoto Dental University (JP)
- Centre for Molecular and Cellular Biology of Inflammation, King’s College London, London SE1 1UL, UK.
- Corresponding author
- Mass, Elvira
- Farlik, Matthias
- Halbritter, Florian
- Günther, Patrick
- Beyer, Marc
- Bock, Christoph
- ORCID
- Venue
- Science
- Published
- 2016-09-09
- Volume
- 353
- Issue
- 6304
- Pages
- aaf4238-aaf4238
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5066309
- OpenAlex
- W2506892818
- Cited by
- 891
- References
- 55
- Citations by year
- 2026: 77 · 2025: 97 · 2024: 93 · 2023: 76 · 2022: 84 · 2021: 88 · 2020: 95 · 2019: 108 · 2018: 90 · 2017: 72 · 2016: 9 · 2014: 1
- FWCI
- 56.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- DZNE Pub (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Cancer Institute of the U.S. NIH (P30CA008748)
- Wellcome Trust (WT101853MA)
- European Research Council (2010-StG-261299)
- European Molecular Biology (ALTF 530-2015)
- Deutsche Forschungsgemeinschaft (HA 7723/1-1)
- Austrian Academy of Sciences
- DFG (BE 4427/3-1, SFB 704, SFB 645, INST 217/575-1, INST 217/576-1, INST 217/577-1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- tissue-resident macrophages, organogenesis, yolk sac, macrophage differentiation, CX3CR1, RANK, embryonic development, single-cell RNA sequencing, fate mapping, microenvironment, tissue-specific gene expression, Kupffer cells, microglia
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Cell Differentiation, Embryo, Mammalian, Embryonic Induction, Female, Hematopoiesis, Kupffer Cells, Macrophages, Mice, Mutant Strains, Organ Specificity, Erythroid Precursor Cells, Gene Expression Regulation, Developmental, Receptors, Chemokine, Myeloid Progenitor Cells, Organogenesis, Embryonic Development, Mice, Inhibitor of Differentiation Proteins, Transcriptome
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