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C-Myb+ Erythro-Myeloid Progenitor-Derived Fetal Monocytes Give Rise to Adult Tissue-Resident Macrophages
Open accessAbstract
Although classified as hematopoietic cells, tissue-resident macrophages (MFs) arise from embryonic precursors that seed the tissues prior to birth to generate a self-renewing population, which is maintained independently of adult hematopoiesis. Here we reveal the identity of these embryonic precursors using an in utero MF-depletion strategy and fate-mapping of yolk sac (YS) and fetal liver (FL) hematopoiesis. We show that YS MFs are the main precursors of microglia, while most other MFs derive from fetal monocytes (MOs). Both YS MFs and fetal MOs arise from erythro-myeloid progenitors (EMPs) generated in the YS. In the YS, EMPs gave rise to MFs without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal MOs that then seeded embryonic tissues and differentiated into MFs. Thus, adult tissue-resident MFs established from hematopoietic stem cell-independent embryonic precursors arise from two distinct developmental programs.
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“The transcription factors Spi1 and Irf8 have been shown to be the core orchestrators for microglia development”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Hoeffel et al., 2015
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“consistent with microglia emerging from PU.1 and IRF8-dependent, but MYB-independent cells 34–37.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [36]
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“…from fetal monocytes or hematopoietic stem cells, leading to either complete replacement of yolk sack–derived macrophages or mixed populations that are dominated by cells of the fetal monocyte or hematopoietic stem cell lineage (Epelman et al., 2014; Hoeffel et al., 2015; Sheng et al., 2015).”
BackgroundInfluentialAmit, I., Winter, D. R., & Jung, S. (2015) · Nature Immunology · doi:10.1038/ni.3325 · Cited by 416
Does niche competition determine the origin of tissue-resident macrophages?
Guilliams, M., & Scott, C. L. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.42 · Cited by 409
Liver macrophages in health and disease
Guilliams, M., & Scott, C. L. (2022) · Immunity · doi:10.1016/j.immuni.2022.08.002 · Cited by 395
Tran, S., Baba, I., Poupel, L., Dussaud, S., Moreau, M., Gélineau, A., Marcelin, G., Magréau-Davy, E., Ouhachi, M., Lesnik, P., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.003 · Cited by 400
Fetal monocytes and the origins of tissue-resident macrophages
Hoeffel, G., & Ginhoux, F. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.01.001 · Cited by 431
Self-citationOntogeny and homeostasis of CNS myeloid cells
Prinz, M., Erny, D., & Hagemeyer, N. (2017) · Nature Immunology · doi:10.1038/ni.3703 · Cited by 413
Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression
Shaw, T. N., Houston, S. A., Wemyss, K., Bridgeman, H. M., Barbera, T. A., Zangerle-Murray, T., Strangward, P., Ridley, A. J. L., Wang, P., Tamoutounour, S., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20180019 · Cited by 397
“…often arising from embryonic or perinatal precursors that are maintained locally and independently of blood monocytes at homeostasis (Ginhoux et al., 2010; Hoeffel et al., 2012, 2015; Schulz et al., 2012; Hashimoto et al., 2013; Yona et al., 2013; Sheng et al., 2015; Ginhoux and Guilliams, 2016).”
BackgroundImmune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies
Beers, D. R., & Appel, S. H. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30394-6 · Cited by 396
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Macrophage Polarization and Osteoporosis: A Review
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Neuroinflammation: Microglia and T Cells Get Ready to Tango
Schetters, S. T. T., Gómez‐Nicola, D., García-Vallejo, J. J., & van Kooyk, Y. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01905 · Cited by 400
“This could have two important consequences: (1) the insoluble antigen is unable to drain to secondary lymphoid structures where T cells are primed and (2) the insoluble antigen may harbor neo-antigens that can be presented by microglia on MHCII.”
BackgroundInfluentialEnsan, S., Li, A., Besla, R., Degousee, N., Cosme, J., Roufaiel, M., Shikatani, E. A., El-Maklizi, M., Williams, J. W., Robins, L., et al. (2016) · Nature Immunology · doi:10.1038/ni.3343 · Cited by 372
Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design
Ogle, M. E., Segar, C. E., Sridhar, S., & Botchwey, E. A. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370216650293 · Cited by 378
Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Guan, F., Wang, R., Yi, Z., Luo, P., Liu, W., Xie, Y., Liu, Z., Xia, Z., Zhang, H., & Cheng, Q. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02124-y · Cited by 371
Macrophages in intestinal homeostasis and inflammatory bowel disease
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Macrophage-Mediated Inflammation in Skin Wound Healing
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Ontogeny of Tissue-Resident Macrophages
Hoeffel, G., & Ginhoux, F. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00486 · Cited by 364
“The use of the S100a4-Cre fate-mapping model in our hands supports these observations and similar conclusions were obtained for BM and peritoneal macrophages (15).”
BackgroundMethodResultInfluentialSelf-citationMacrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis
Corliss, B. A., Azimi, M. S., Munson, J. M., Peirce, S. M., & Murfee, W. L. (2016) · Microcirculation · doi:10.1111/micc.12259 · Cited by 356
“Early EMPs give rise to YS-Mac that eventually populate the brain to become microglia, the tissue-resident macrophage for that organ [113].”
BackgroundThe Cytokine TGF-β Promotes the Development and Homeostasis of Alveolar Macrophages
Yu, X., Buttgereit, A., Lelios, I., Utz, S. G., Cansever, D., Becher, B., & Greter, M. (2017) · Immunity · doi:10.1016/j.immuni.2017.10.007 · Cited by 370
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Self-citationOrigin, Differentiation, and Function of Intestinal Macrophages
Bain, C. C., & Schridde, A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02733 · Cited by 366
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Roles of macrophages in tumor development: a spatiotemporal perspective
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Self-citationHemogenic Endothelial Fate Mapping Reveals Dual Developmental Origin of Mast Cells
Gentek, R., Ghigo, C., Hoeffel, G., Bulle, M. J., Msallam, R., Gautier, G., Launay, P., Chen, J., Ginhoux, F., & Bajénoff, M. (2018) · Immunity · doi:10.1016/j.immuni.2018.04.025 · Cited by 334
Self-citationPrimitive Embryonic Macrophages are Required for Coronary Development and Maturation
Leid, J. M., Carrelha, J., Boukarabila, H., Epelman, S., Jacobsen, S. E. W., & Lavine, K. J. (2016) · Circulation Research · doi:10.1161/circresaha.115.308270 · Cited by 336
“sac–derived erythromyeloid progenitor that migrates from the yolk sac to the liver during midgestation.(13) For example,”
Molecular and epigenetic basis of macrophage polarized activation
Porta, C., Riboldi, E., Ippolito, A., & Sica, A. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.10.003 · Cited by 334
Epigenetic regulation of macrophages: from homeostasis maintenance to host defense
Chen, S., Yang, J., Wei, Y., & Wei, X. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0315-0 · Cited by 331
“Fetal monocytes differentiate into macrophages when recruited to fetal tissues, replacing the main components of the existing yolk-sac-derived macrophages gradually with the exception of microglia.(35) With the growth of host tissues, these primitive macrophages differentiate through proliferating in their respective…”
BackgroundTumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies
Kumari, N., & Choi, S. H. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02272-x · Cited by 331
Pulmonary Macrophages: A New Therapeutic Pathway in Fibrosing Lung Disease?
Byrne, A. J., Maher, T. M., & Lloyd, C. M. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.02.004 · Cited by 326
“Subsequently, this work was confirmed using depletion and fate-mapping mouse models of yolk sac and fetal liver macrophages, respectively [26,27].”
Revisiting Mouse Peritoneal Macrophages: Heterogeneity, Development, and Function
Cassado, A. D. A., D’Império Lima, M. R., & Bortoluci, K. R. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00225 · Cited by 315
Neuroinflammation in Alzheimer’s Disease
Onyango, I. G., Jauregui, G. V., Čarná, M., Bennett, J. P., & Stokin, G. B. (2021) · Biomedicines · doi:10.3390/biomedicines9050524 · Cited by 330
“Other tissue macrophages develop from precursors that emerge later in life [103,104].”
BackgroundMacrophages as Key Drivers of Cancer Progression and Metastasis
Nielsen, S. R., & Schmid, M. C. (2017) · Mediators of Inflammation · doi:10.1155/2017/9624760 · Cited by 308
“Fate mapping has identified yolk sac-derived macrophages as the main precursor for brain microglia [11], whereas fetal liverderived monocytes are the main precursor of liver Kupffer cells and lung alveolar macrophages [12, 13], while bone marrow-derived monocytes replenish intestinal and cardiac macrophages in the ste…”
Background
Metadata
- Authors
- Hoeffel, G., Chen, J., Lavin, Y., Low, D., Almeida, F. F., See, P., Beaudin, A. E., Lum, J., Low, I., Forsberg, E. C., Poidinger, M., Zolezzi, F., Larbi, A., Ng, L. G., Chan, J. K. Y., Greter, M., Becher, B., Samokhvalov, I. M., Merad, M., & Ginhoux, F.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Tisch Cancer Institute (US)
- University of California, Santa Cruz (US)
- University of Zurich (CH)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Ginhoux, Florent
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 42
- Issue
- 4
- Pages
- 665-678
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4545768
- OpenAlex
- W2023666964
- Cited by
- 1,135
- References
- 55
- Citations by year
- 2026: 64 · 2025: 84 · 2024: 111 · 2023: 99 · 2022: 135 · 2021: 122 · 2020: 118 · 2019: 102 · 2018: 107 · 2017: 81 · 2016: 67 · 2015: 44
- FWCI
- 77.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- National University of Singapore (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL086899, R01HL086899)
- National Cancer Institute (R01CA173861, R01CA112100, CA112100, R01CA190400)
- National Institute of Allergy and Infectious Diseases (AI080884, R01AI080884)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100917)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- tissue-resident macrophages, erythro-myeloid progenitors, microglia, yolk sac hematopoiesis, fetal liver hematopoiesis, MYB, fate mapping
- MeSH terms
- Aging, Animals, Cell Differentiation, Embryo, Mammalian, Female, Fetus, Hematopoietic Stem Cells, Kidney, Liver, Lung, Macrophages, Monocytes, Pregnancy, Skin, Yolk Sac, Biomarkers, Microglia, Cell Lineage, Proto-Oncogene Proteins c-myb, Myeloid Progenitor Cells, Mice, Cell Tracking, Primary Cell Culture
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