Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 330 (6005): 841-845

Copyright © 2010 by the American Association for the Advancement of Science

Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages

Florent Ginhoux,1,2,* Melanie Greter,1 Marylene Leboeuf,1 Sayan Nandi,3 Peter See,2 Solen Gokhan,4 Mark F. Mehler,4,5 Simon J. Conway,6 Lai Guan Ng,2 E. Richard Stanley,3 Igor M. Samokhvalov,7 Miriam Merad1,*

Abstract: Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor–deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

1 Department of Gene and Cell Medicine and the Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA.
2 Singapore Immunology Network (SIgN), 8A Biomedical Grove, IMMUNOS Building Nos. 3-4, BIOPOLIS, 138648, Singapore.
3 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
4 Institute for Brain Disorders and Neural Regeneration, Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, and Department of Neurology, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
5 Departments of Neuroscience, Psychiatry, and Behavioral Sciences, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
6 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202, USA.
7 Laboratory for Stem Cell Biology, Center for Developmental Biology (CDB), RIKEN Kobe, Kobe 6500047, Japan.

* To whom correspondence should be addressed. E-mail: Miriam.Merad{at}mssm.edu (M.M.); Florent_ginhoux{at}immunol.a-star.edu.sg (F.G.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cardioprotective function of cardiac macrophages.
K. Fujiu, J. Wang, and R. Nagai (2014)
Cardiovasc Res 102, 232-239
   Abstract »    Full Text »    PDF »
Cardiac macrophages and their role in ischaemic heart disease.
S. Frantz and M. Nahrendorf (2014)
Cardiovasc Res 102, 240-248
   Abstract »    Full Text »    PDF »
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity.
D. Gomez-Nicola and V. H. Perry (2014)
Neuroscientist
   Abstract »    Full Text »    PDF »
Cranial irradiation induces bone marrow-derived microglia in adult mouse brain tissue.
N. Okonogi, K. Nakamura, Y. Suzuki, N. Suto, K. Suzue, T. Kaminuma, T. Nakano, and H. Hirai (2014)
J Radiat Res
   Abstract »    Full Text »    PDF »
Distinct functional programming of human fetal and adult monocytes.
E. R. Krow-Lucal, C. C. Kim, T. D. Burt, and J. M. McCune (2014)
Blood 123, 1897-1904
   Abstract »    Full Text »    PDF »
Quantification of Entry Phenotypes of Macrophage-Tropic HIV-1 across a Wide Range of CD4 Densities.
S. B. Joseph, K. T. Arrildt, A. E. Swanstrom, G. Schnell, B. Lee, J. A. Hoxie, and R. Swanstrom (2014)
J. Virol. 88, 1858-1869
   Abstract »    Full Text »    PDF »
Microglia Enhance Neurogenesis and Oligodendrogenesis in the Early Postnatal Subventricular Zone.
Y. Shigemoto-Mogami, K. Hoshikawa, J. E. Goldman, Y. Sekino, and K. Sato (2014)
J. Neurosci. 34, 2231-2243
   Abstract »    Full Text »    PDF »
Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS.
T. Konno, M. Tada, M. Tada, A. Koyama, H. Nozaki, Y. Harigaya, J. Nishimiya, A. Matsunaga, N. Yoshikura, K. Ishihara, et al. (2014)
Neurology 82, 139-148
   Abstract »    Full Text »    PDF »
The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus.
M. Schwartz and K. Baruch (2014)
EMBO J. 33, 7-22
   Abstract »    Full Text »    PDF »
Protective Autoimmunity: A Unifying Model for the Immune Network Involved in CNS Repair.
M. Schwartz and C. Raposo (2014)
Neuroscientist
   Abstract »    Full Text »    PDF »
CSF-1 receptor-mediated differentiation of a new type of monocytic cell with B cell-stimulating activity: its selective dependence on IL-34.
F. Yamane, Y. Nishikawa, K. Matsui, M. Asakura, E. Iwasaki, K. Watanabe, H. Tanimoto, H. Sano, Y. Fujiwara, E. R. Stanley, et al. (2014)
J. Leukoc. Biol. 95, 19-31
   Abstract »    Full Text »    PDF »
Inhibition of Microglia Activation as a Phenotypic Assay in Early Drug Discovery.
M. Figuera-Losada, C. Rojas, and B. S. Slusher (2014)
J Biomol Screen 19, 17-31
   Abstract »    Full Text »    PDF »
Identification of a Unique Hybrid Macrophage-Polarization State following Recovery from Lipopolysaccharide Tolerance.
C. O'Carroll, A. Fagan, F. Shanahan, and R. J. Carmody (2014)
J. Immunol. 192, 427-436
   Abstract »    Full Text »    PDF »
De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
K. N. Karle, S. Biskup, R. Schule, K. J. Schweitzer, R. Kruger, P. Bauer, B. Bender, T. Nagele, and L. Schols (2013)
Neurology 81, 2039-2044
   Abstract »    Full Text »    PDF »
Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke.
T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang (2013)
Brain 136, 3578-3588
   Abstract »    Full Text »    PDF »
Neuron-glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage.
G. K. Sheridan and K. J. Murphy (2013)
Open Bio 3, 130181
   Abstract »    Full Text »    PDF »
Beyond Stem Cells: Self-Renewal of Differentiated Macrophages.
M. H. Sieweke and J. E. Allen (2013)
Science 342, 1242974
   Abstract »    Full Text »    PDF »
Cell biology in neuroscience: Architects in neural circuit design: Glia control neuron numbers and connectivity.
M. M. Corty and M. R. Freeman (2013)
J. Cell Biol. 203, 395-405
   Abstract »    Full Text »    PDF »
How Do Immune Cells Support and Shape the Brain in Health, Disease, and Aging?.
M. Schwartz, J. Kipnis, S. Rivest, and A. Prat (2013)
J. Neurosci. 33, 17587-17596
   Abstract »    Full Text »    PDF »
Macrophages: Gatekeepers of Tissue Integrity.
Y. Lavin and M. Merad (2013)
Cancer Immunology 1, 201-209
   Abstract »    Full Text »    PDF »
A deficiency in CCR2+ monocytes: the hidden side of Alzheimer's disease.
G. Naert and S. Rivest (2013)
J Mol Cell Biol 5, 284-293
   Abstract »    Full Text »    PDF »
Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF.
M. Guilliams, I. De Kleer, S. Henri, S. Post, L. Vanhoutte, S. De Prijck, K. Deswarte, B. Malissen, H. Hammad, and B. N. Lambrecht (2013)
J. Exp. Med. 210, 1977-1992
   Abstract »    Full Text »    PDF »
Learning and memory ... and the immune system.
I. Marin and J. Kipnis (2013)
Learn. Mem. 20, 601-606
   Abstract »    Full Text »    PDF »
Resident Renal Mononuclear Phagocytes Comprise Five Discrete Populations with Distinct Phenotypes and Functions.
T. Kawakami, J. Lichtnekert, L. J. Thompson, P. Karna, H. Bouabe, T. M. Hohl, J. W. Heinecke, S. F. Ziegler, P. J. Nelson, and J. S. Duffield (2013)
J. Immunol. 191, 3358-3372
   Abstract »    Full Text »    PDF »
Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice.
Y. Li, Q. Chen, D. Zheng, L. Yin, Y. H. Chionh, L. H. Wong, S. Q. Tan, T. C. Tan, J. K. Y. Chan, S. Alonso, et al. (2013)
J. Immunol. 191, 3192-3199
   Abstract »    Full Text »    PDF »
Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy.
A. Biffi, E. Montini, L. Lorioli, M. Cesani, F. Fumagalli, T. Plati, C. Baldoli, S. Martino, A. Calabria, S. Canale, et al. (2013)
Science 341, 1233158
   Abstract »    Full Text »    PDF »
Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer.
L. Bosurgi, J. H. Bernink, V. Delgado Cuevas, N. Gagliani, L. Joannas, E. T. Schmid, C. J. Booth, S. Ghosh, and C. V. Rothlin (2013)
PNAS 110, 13091-13096
   Abstract »    Full Text »    PDF »
Receptor-type Protein-tyrosine Phosphatase {zeta} Is a Functional Receptor for Interleukin-34.
S. Nandi, M. Cioce, Y.-G. Yeung, E. Nieves, L. Tesfa, H. Lin, A. W. Hsu, R. Halenbeck, H.-Y. Cheng, S. Gokhan, et al. (2013)
J. Biol. Chem. 288, 21972-21986
   Abstract »    Full Text »    PDF »
SARM Is Required for Neuronal Injury and Cytokine Production in Response to Central Nervous System Viral Infection.
Y.-J. Hou, R. Banerjee, B. Thomas, C. Nathan, A. Garcia-Sastre, A. Ding, and M. B. Uccellini (2013)
J. Immunol. 191, 875-883
   Abstract »    Full Text »    PDF »
Tumor-Associated Macrophages as a Paradigm of Macrophage Plasticity, Diversity, and Polarization: Lessons and Open Questions.
A. Mantovani and M. Locati (2013)
Arterioscler Thromb Vasc Biol 33, 1478-1483
   Abstract »    Full Text »    PDF »
JMML patient-derived iPSCs induce new hypotheses.
R. J. Chan and M. C. Yoder (2013)
Blood 121, 4815-4817
   Full Text »    PDF »
Monocyte and Macrophage Heterogeneity in the Heart.
M. Nahrendorf and F. K. Swirski (2013)
Circ. Res. 112, 1624-1633
   Abstract »    Full Text »    PDF »
Functional Macrophage Heterogeneity in a Mouse Model of Autoimmune Central Nervous System Pathology.
A. London, I. Benhar, M. J. Mattapallil, M. Mack, R. R. Caspi, and M. Schwartz (2013)
J. Immunol. 190, 3570-3578
   Abstract »    Full Text »    PDF »
Regulation of Microglial Proliferation during Chronic Neurodegeneration.
D. Gomez-Nicola, N. L. Fransen, S. Suzzi, and V. H. Perry (2013)
J. Neurosci. 33, 2481-2493
   Abstract »    Full Text »    PDF »
Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection.
M. F. Cusick, J. E. Libbey, D. C. Patel, D. J. Doty, and R. S. Fujinami (2013)
J. Virol. 87, 1849-1860
   Abstract »    Full Text »    PDF »
Systemic Circulation and Bone Recruitment of Osteoclast Precursors Tracked by Using Fluorescent Imaging Techniques.
M. Kotani, J. Kikuta, F. Klauschen, T. Chino, Y. Kobayashi, H. Yasuda, K. Tamai, A. Miyawaki, O. Kanagawa, M. Tomura, et al. (2013)
J. Immunol. 190, 605-612
   Abstract »    Full Text »    PDF »
Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.
J. Luo, F. Elwood, M. Britschgi, S. Villeda, H. Zhang, Z. Ding, L. Zhu, H. Alabsi, R. Getachew, R. Narasimhan, et al. (2013)
J. Exp. Med. 210, 157-172
   Abstract »    Full Text »    PDF »
Microglia: Scapegoat, Saboteur, or Something Else?.
A. Aguzzi, B. A. Barres, and M. L. Bennett (2013)
Science 339, 156-161
   Abstract »    Full Text »    PDF »
The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes.
W. Beumer, S. M. Gibney, R. C. Drexhage, L. Pont-Lezica, J. Doorduin, H. C. Klein, J. Steiner, T. J. Connor, A. Harkin, M. A. Versnel, et al. (2012)
J. Leukoc. Biol. 92, 959-975
   Abstract »    Full Text »    PDF »
Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells.
N. H. Varvel, S. A. Grathwohl, F. Baumann, C. Liebig, A. Bosch, B. Brawek, D. R. Thal, I. F. Charo, F. L. Heppner, A. Aguzzi, et al. (2012)
PNAS 109, 18150-18155
   Abstract »    Full Text »    PDF »
Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation.
A. Capotondo, R. Milazzo, L. S. Politi, A. Quattrini, A. Palini, T. Plati, S. Merella, A. Nonis, C. di Serio, E. Montini, et al. (2012)
PNAS 109, 15018-15023
   Abstract »    Full Text »    PDF »
How type I interferons shape myeloid cell function in CNS autoimmunity.
S. M. Brendecke and M. Prinz (2012)
J. Leukoc. Biol. 92, 479-488
   Abstract »    Full Text »    PDF »
Systemic Analysis of PPAR{gamma} in Mouse Macrophage Populations Reveals Marked Diversity in Expression with Critical Roles in Resolution of Inflammation and Airway Immunity.
E. L. Gautier, A. Chow, R. Spanbroek, G. Marcelin, M. Greter, C. Jakubzick, M. Bogunovic, M. Leboeuf, N. van Rooijen, A. J. Habenicht, et al. (2012)
J. Immunol. 189, 2614-2624
   Abstract »    Full Text »    PDF »
Innate Inflammation in Parkinson's Disease.
V. H. Perry (2012)
Cold Spring Harb Perspect Med 2, a009373
   Abstract »    Full Text »    PDF »
Regulation of Postnatal Forebrain Amoeboid Microglial Cell Proliferation and Development by the Transcription Factor Runx1.
M. Zusso, L. Methot, R. Lo, A. D. Greenhalgh, S. David, and S. Stifani (2012)
J. Neurosci. 32, 11285-11298
   Abstract »    Full Text »    PDF »
Evolution of Siglec-11 and Siglec-16 Genes in Hominins.
X. Wang, N. Mitra, P. Cruz, L. Deng, NISC Comparative Sequencing Program, N. Varki, T. Angata, E. D. Green, J. Mullikin, T. Hayakawa, et al. (2012)
Mol. Biol. Evol. 29, 2073-2086
   Abstract »    Full Text »    PDF »
Editorial: Route by which monocytes leave the brain is revealed.
J. D. Laman and R. O. Weller (2012)
J. Leukoc. Biol. 92, 6-9
   Full Text »    PDF »
Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages.
G. Hoeffel, Y. Wang, M. Greter, P. See, P. Teo, B. Malleret, M. Leboeuf, D. Low, G. Oller, F. Almeida, et al. (2012)
J. Exp. Med. 209, 1167-1181
   Abstract »    Full Text »    PDF »
HIV-1-Related Central Nervous System Disease: Current Issues in Pathogenesis, Diagnosis, and Treatment.
S. Spudich and F. Gonzalez-Scarano (2012)
Cold Spring Harb Perspect Med 2, a007120
   Abstract »    Full Text »    PDF »
A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells.
C. Schulz, E. G. Perdiguero, L. Chorro, H. Szabo-Rogers, N. Cagnard, K. Kierdorf, M. Prinz, B. Wu, S. E. W. Jacobsen, J. W. Pollard, et al. (2012)
Science 336, 86-90
   Abstract »    Full Text »    PDF »
Early Activation of Microglia Triggers Long-Lasting Impairment of Adult Neurogenesis in the Olfactory Bulb.
F. Lazarini, M.-M. Gabellec, N. Torquet, and P.-M. Lledo (2012)
J. Neurosci. 32, 3652-3664
   Abstract »    Full Text »    PDF »
Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia.
V. L. Jacobs, R. P. Landry, Y. Liu, E. A. Romero-Sandoval, and J. A. De Leo (2012)
Neuro Oncology 14, 119-131
   Abstract »    Full Text »    PDF »
The Fractalkine Receptor but Not CCR2 Is Present on Microglia from Embryonic Development throughout Adulthood.
M. Mizutani, P. A. Pino, N. Saederup, I. F. Charo, R. M. Ransohoff, and A. E. Cardona (2012)
J. Immunol. 188, 29-36
   Abstract »    Full Text »    PDF »
Adenosine Augments IL-10 Production by Microglial Cells through an A2B Adenosine Receptor-Mediated Process.
B. Koscso, B. Csoka, Z. Selmeczy, L. Himer, P. Pacher, L. Virag, and G. Hasko (2012)
J. Immunol. 188, 445-453
   Abstract »    Full Text »    PDF »
Gab2 Promotes Colony-Stimulating Factor 1-Regulated Macrophage Expansion via Alternate Effectors at Different Stages of Development.
A. W. Lee, Y. Mao, J. M. Penninger, and S. Yu (2011)
Mol. Cell. Biol. 31, 4563-4581
   Abstract »    Full Text »    PDF »
Microglia and Memory: Modulation by Early-Life Infection.
L. L. Williamson, P. W. Sholar, R. S. Mistry, S. H. Smith, and S. D. Bilbo (2011)
J. Neurosci. 31, 15511-15521
   Abstract »    Full Text »    PDF »
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development.
R. C. Paolicelli, G. Bolasco, F. Pagani, L. Maggi, M. Scianni, P. Panzanelli, M. Giustetto, T. A. Ferreira, E. Guiducci, L. Dumas, et al. (2011)
Science 333, 1456-1458
   Abstract »    Full Text »    PDF »
Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia.
M. R. Hutchinson, Y. Shavit, P. M. Grace, K. C. Rice, S. F. Maier, and L. R. Watkins (2011)
Pharmacol. Rev. 63, 772-810
   Abstract »    Full Text »    PDF »
Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain.
N. Anandasabapathy, G. D. Victora, M. Meredith, R. Feder, B. Dong, C. Kluger, K. Yao, M. L. Dustin, M. C. Nussenzweig, R. M. Steinman, et al. (2011)
J. Exp. Med. 208, 1695-1705
   Abstract »    Full Text »    PDF »
The Spatial and Developmental Relationships in the Macrophage Family.
F. K. Swirski (2011)
Arterioscler Thromb Vasc Biol 31, 1517-1522
   Abstract »    Full Text »    PDF »
Characterization of the mononuclear phagocyte system in zebrafish.
V. Wittamer, J. Y. Bertrand, P. W. Gutschow, and D. Traver (2011)
Blood 117, 7126-7135
   Abstract »    Full Text »    PDF »
Gene therapy for leukodystrophies.
A. Biffi, P. Aubourg, and N. Cartier (2011)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882