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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
Experimental — accuracy not yet measuredIn the citing paper
“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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Self-citationCD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages
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“Inmice, fetal liver monocytes migrate into tissues in a CCR2-independent manner (Hoeffel et al., 2015; Rantakari et al., 2016), in contrast with adult monocytes (Ly6Chi *, P < 0.”
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Movahedi, K., & Ginderachter, J. A. V. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6704 · Cited by 53
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“In fact, LCs are replenished by a small number of proliferative LC precursors residing in the skin, although circulating precursors do contribute to LCs when a severe injury occurs (Chorro et al., 2009; Collin et al., 2006; Ghigo et al., 2013; Gomez Perdiguero et al., 2015; Hoeffel et al., 2015; Hoeffel et al., 2012;…”
BackgroundMethodResultInfluentialSelf-citationKit ligand has a critical role in mouse yolk sac and aorta–gonad–mesonephros hematopoiesis
Azzoni, E., Frontera, V., McGrath, K. E., Harman, J. R., Carrelha, J., Nerlov, C., Palis, J., Jacobsen, S. E. W., & Bruijn, M. F. T. R. D. (2018) · EMBO Reports · doi:10.15252/embr.201745477 · Cited by 57
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Human‐induced pluripotent stem cell‐derived blood products: state of the art and future directions
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“differentiate from an early precursor in the yolk-sac blood islands or the fetal liver, but independently fromHSCs (Gomez Perdiguero et al., 2015; Guilliams et al., 2013; Hoeffel et al., 2015).”
Thymic macrophages consist of two populations with distinct localization and origin
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Self-citationOrigin and Emergence of Microglia in the CNS—An Interesting (Hi)story of an Eccentric Cell
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“As the progenitors of microglia were identified to be the EMPs of YS, the vast majority of other tissue-resident macrophages arise from fetal monocytes that derive from late c-MYB+ EMPs of the YS [51].”
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Nelson, B. N., Hawkins, A. N., & Wozniak, K. L. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00037 · Cited by 49
Role of Macrophages and Microglia in Zebrafish Regeneration
Var, S. R., & Byrd-Jacobs, C. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134768 · Cited by 52
“Unlike peripheral macrophages, microglial cells are believed to be the only adult macrophage population with early erythroid myeloid progenitor origin (eEMP) [56,57].”
BackgroundHematopoiesis: A Layered Organization Across Chordate Species
Elsaid, R., Soares‐da‐Silva, F., Peixoto, M. M., Amiri, D., Mackowski, N., Pereira, P., Bandeira, A., & Cumano, A. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.606642 · Cited by 51
Mendes, M. S., Le, L., Atlas, J., Brehm, Z., Ladron-de-Guevara, A., Matei, E., Lamantia, C., McCall, M. N., & Majewska, A. K. (2021) · eLife · doi:10.7554/elife.61173 · Cited by 46
Recent Advances in Developmental Hematopoiesis: Diving Deeper With New Technologies
Weijts, B. G. M. W., Yvernogeau, L., & Robin, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.790379 · Cited by 45
Zhao, D., Yang, F., Wang, Y., Li, S., Li, Y., Hou, F., Yang, W., Liu, D., Tao, Y., Li, Q., et al. (2022) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 46
Lineage tracing clarifies the cellular origin of tissue-resident macrophages in the developing heart
Liu, K., Jin, H., Tang, M., Zhang, S., Tian, X., Zhang, M., Han, X., Liu, X., Tang, J., Pu, W., et al. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202108093 · Cited by 49
“It is acknowledged that endothelial cells contribute to the three distinct waves of hematopoiesis during embryogenesis (Ginhoux and Guilliams, 2016; Gomez Perdiguero et al., 2015; Hoeffel et al., 2015; Shalaby et al., 1997).”
BackgroundResultInfluentialTargeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils
Russo, M., & Nastasi, C. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.871513 · Cited by 45
“Furthermore, the yolk sac-derived macrophages of the heart are replaced by fetal liver monocytes (118, 123).”
BackgroundMicroglia: A Unique Versatile Cell in the Central Nervous System
Masuda, T., & Prinz, M. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00317 · Cited by 46
Barreiro, O., Cibrián, D., Clemente, C., Álvarez, D., Moreno, V., Valiente, Í., Bernad, A., Vestweber, D., Arroyo, A. G., Martı́n, P., et al. (2016) · eLife · doi:10.7554/elife.15251 · Cited by 46
“A certain degree of heterogeneity among skin-resident macrophages has been previously reported relative to their ontogeny as well as to the functional specialization of specific subsets (Abtin et al., 2014; Hoeffel et al., 2015; Schulz et al., 2012; Tamoutounour et al., 2013).”
BackgroundMechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview
Pinheiro, D., Dias, I., Ribeiro Silva, K., Stumbo, A. C., Thole, A., Cortez, E., de Carvalho, L., Weiskirchen, R., & Carvalho, S. (2019) · Cells · doi:10.3390/cells8111339 · Cited by 46
Perinatal development of innate immune topology
Henneke, P., Kierdorf, K., Hall, L. J., Sperandio, M., & Hornef, M. W. (2021) · RWTH Publications (RWTH Aachen) · Cited by 45
Gao, X., Zhu, B., Wu, Y., Li, C., Zhou, X., Tang, J., & Sun, J. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2100741 · Cited by 45
The diversity of myeloid immune cells shaping wound repair and fibrosis in the lung
Florez‐Sampedro, L., Song, S., & Melgert, B. N. (2018) · Regeneration · doi:10.1002/reg2.97 · Cited by 46
“…tissue-resident macrophages, including alveolar macrophages, originate from yolk sac macrophages or from erythro-myeloid progenitors in the fetal liver (Ginhoux & Guilliams, 2016; Ginhoux et al., 2010; Guilliams et al., 2013; Hoeffel et al., 2012, 2015; McGrath et al., 2015; Schulz et al., 2012).”
BackgroundLi, F., Okreglicka, K. M., Pohlmeier, L. M., Schneider, C., & Köpf, M. (2020) · The EMBO Journal · doi:10.15252/embj.2019103205 · Cited by 43
“EV4B) suggests that their expansion and tissue-specific differentiation are driven by PPAR c rather than by the balance of c-Myb and MafB that drives expansion and differentiation of definitive EMP and fetal liver monocytes.”
InfluentialLiver macrophages: development, dynamics, and functions
Nusse, Y., & Kubes, P. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01298-3 · Cited by 50
“Upon seeding, EMPs begin differentiating towards a Kupffer cell speci fi c state, featuring the several canonical transcription factors (such as Id3 ), extra-cellular receptors, and functional components discussed above [112, 113].”
Autophagy drives plasticity and functional polarization of tumor‐associated macrophages
Kuo, W., Chang, J., Chen, C., Tsao, N., & Chang, C. (2021) · IUBMB Life · doi:10.1002/iub.2543 · Cited by 47
Liver macrophages in healthy and diseased liver
Abdullah, Z., & Knolle, P. A. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1954-6 · Cited by 46
Nenasheva, T. A., Gerasimova, T., Serdyuk, Y. V., Grigor’eva, E. V., Kosmiadi, G. A., Nikolaev, A., Dashinimaev, E. B., & Lyadova, I. V. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01016 · Cited by 45
Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis
Yao, Y., Liu, Q., Adrianto, I., Wu, X., Glassbrook, J. E., Khalasawi, N., Yin, C., Yi, Q., Dong, Z., Geissmann, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17630-6 · Cited by 46
Yahara, Y., Ma, X., Gracia, L., & Alman, B. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.622035 · Cited by 47
“Early c-Myb-independent EMPs that give rise to primitive yolk sac macrophages without passing through monocyte intermediates and a late c-Myb-dependent EMPs that seed the fetal liver to produce fetal monocytes (Hoeffel et al., 2015).”
BackgroundResultVascular deficiencies in renal organoids and ex vivo kidney organogenesis
Ryan, A. R., England, A. R., Chaney, C. P., Cowdin, M. A., Hiltabidle, M. S., Daniel, E., Gupta, A., Oxburgh, L. H., Carroll, T. J., & Cleaver, O. B. (2021) · Developmental Biology · doi:10.1016/j.ydbio.2021.04.009 · Cited by 49
“Additionally, these factors—ECM, pericytes, and macrophages—are already present in kidney explants, which still experience extensive vascular regression (Hoeffel et al., 2015).”
BackgroundImmune and vascular contributions to organogenesis of the testis and ovary
Gu, X., Li, S., & DeFalco, T. (2021) · FEBS Journal · doi:10.1111/febs.15848 · Cited by 45
The molecular determinants of microglial developmental dynamics
Barry-Carroll, L., & Gómez‐Nicola, D. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00813-1 · Cited by 49
“Interestingly, however, genetic deletion of Trem2 does not inhibit microglia expansion to the same extent as CSF1R inhibition, suggesting that it might be less important for the development of microglia.”
Monocyte, Macrophage, and Dendritic Cell Development: the Human Perspective
Collin, M. P., & Bigley, V. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.mchd-0015-2015 · Cited by 45
“As alluded to previously, it is now appreciated that primitive myelopoiesis contributes almost exclusively to microglia, which arise directly from yolk sac macrophages, and that LCs and most tissue macrophages also have a primitive origin via fetal liver monocytes (12, 17, 18).”
BackgroundThe multifaceted role of the renal mononuclear phagocyte system
Viehmann, S. F., Böhner, A. M. C., Kurts, C., & Brähler, S. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.04.009 · Cited by 43
The Formation and Therapeutic Update of Tumor-Associated Macrophages in Cervical Cancer
Wang, Q., Steger, A., Mahner, S., Jeschke, U., & Heidegger, H. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133310 · Cited by 43
“Tissue-resident macrophage maintenance and homeostasis depend on its origin in the steady state, which can be disturbed by pathological or physiological inflammation [8,14].”
BackgroundmiR‐124 Contributes to the functional maturity of microglia
Svahn, A. J., Giacomotto, J., Graeber, M. B., Rinkwitz, S., & Becker, T. S. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22328 · Cited by 42
“The development of yolk-sac derived primitive myeloid cells precedes the onset of hematopoietic monocyte differentiation and a subset of the former migrate to become the self-sustaining microglial population (Ginhoux et al., 2010; Kierdorf et al., 2013; Hoeffel et al., 2015).”
BackgroundUpdate on macrophages and innate immunity in scleroderma
Chia, D. J., & Lu, T. T. (2015) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000218 · Cited by 43
Leuschner, F., & Nahrendorf, M. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz159 · Cited by 43
Nguyen, Q.-H. L., Witt, R. G., Wang, B., Eikani, C. K., Shea, J. M., Smith, L. K., Boyle, G., Cadaoas, J., Sper, R. B., MacKenzie, J. D., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay8980 · Cited by 43
The multifaceted role of macrophages in homeostatic and injured skeletal muscle
Wang, X., & Zhou, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1274816 · Cited by 45
“Fetal monocytes gradually outcompete yolk sac macrophages to seed all embryonic tissues except for brain (27).”
BackgroundMicroglia heterogeneity in health and disease
Dadwal, S., & Heneka, M. T. (2023) · FEBS Open Bio · doi:10.1002/2211-5463.13735 · Cited by 48
“Microglia remain in the brain throughout life and self-renew [15 – 19,22”
BackgroundClaeys, W., Verhaege, D., Imschoot, G. V., Wonterghem, E. V., Acker, L. V., Amelinck, L., Ponti, F. F. D., Scott, C. L., Geerts, A. M., Steenkiste, C. V., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1283711 · Cited by 42
Cai, P., Li, W., Xu, Y., & Wang, H. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106561 · Cited by 43
“…studies showed that microglia originate from early erythroid lineage progenitors (EMP) in the extra-embryonic yolk sac, migrate to the embryonic CNS (Gomez Perdiguero et al., 2015), and eventually differentiate into mature microglia through a stepwise developmental program (Hoeffel et al., 2015).”
BackgroundOrigin and function of synovial macrophage subsets during inflammatory joint disease
Culemann, S., Grüneboom, A., & Krönke, G. (2019) · Advances in immunology · doi:10.1016/bs.ai.2019.08.006 · Cited by 44
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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