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CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress

Nature Medicine volume 19, pages 429–436 (2013)Cite this article

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Abstract

A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169+ macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169+ macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2V617F-driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169+ macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.

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Figure 1: Depletion of bone marrow CD169+ macrophages results in reduced erythroblast numbers without peripheral blood anemia.
Figure 2: Depletion of macrophages impairs erythroid recovery after hemolytic anemia and acute blood loss.
Figure 3: Depletion of macrophages impairs erythroid recovery after myeloablation.
Figure 4: VCAM1 blockade abrogates bone marrow erythroblast recovery.
Figure 5: CD15−CD163+CD169+ marks a population of human macrophages expressing VCAM1.
Figure 6: Depletion of macrophages normalizes the erythroid compartment in a JAK2V617F-driven mouse model of polycythemia vera.

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Acknowledgements

We thank C. Prophete, N. Dholakia, the Mount Sinai School of Medicine (MSSM) Microscopy Shared Resource Facility, J. Qi and S. Kim-Schulze at the MSSM Human Immune Monitoring Center, J. Ochando and X. Qiao at the MSSM Flow Cytometry Shared Resource Center and L. Tesfa at the Albert Einstein College of Medicine Flow Cytometry Sorting Facility for providing reagents, technical assistance and guidance. This work was supported by US National Institutes of Health grants (R01 grants HL097700, HL069438 and DK056638 to P.S.F., R01CA112100 to M.M. and R01HL116340 to P.S.F. and M.M.). A.C., J.A., D.L. and Y.K. were supported by fellowships from the National Heart, Lung and Blood Institute (5F30HL099028, A.C.), the National Institute of General Medical Sciences (T32GM062754, J.A.), Fundación Ramón Areces (D.L.) and the Japan Society for the Promotion of Science (Y.K.).

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Author notes

  1. Miriam Merad and Paul S Frenette: These authors contributed equally to this work.

Authors and Affiliations

  1. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA

    Andrew Chow, Matthew Huggins, Jalal Ahmed, Daniel Lucas, Yuya Kunisaki, Sandra Pinho & Paul S Frenette

  2. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA

    Andrew Chow, Jalal Ahmed, Daigo Hashimoto, Marylene Leboeuf, Clara Noizat & Miriam Merad

  3. Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

    Andrew Chow, Jalal Ahmed, Daigo Hashimoto, Marylene Leboeuf, Clara Noizat & Miriam Merad

  4. Department of Medicine, Universite Pierre et Marie Curie, Paris, France

    Clara Noizat

  5. Department of Immunology, Pasteur Institute, Paris, France

    Clara Noizat

  6. Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands

    Nico van Rooijen

  7. Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.,

    Masato Tanaka

  8. Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Hachiouji, Tokyo, Japan.,

    Masato Tanaka

  9. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Zhizhuang Joe Zhao

  10. Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, USA

    Aviv Bergman

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Contributions

A.C. designed the experiments, conducted experiments, analyzed data and wrote the manuscript. M.M. and P.S.F. designed the experiments and wrote the manuscript. M.H., J.A., D.H., D.L., Y.K., S.P., M.L. and C.N. conducted experiments, analyzed data and provided feedback on the manuscript. N.v.R. provided clodronate liposomes and feedback on the manuscript. M.T. and Z.J.Z. provided mice and feedback on the manuscript. A.B. designed the mathematical model of steady-state erythropoiesis and provided feedback on the manuscript.

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Correspondence to Miriam Merad or Paul S Frenette.

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Chow, A., Huggins, M., Ahmed, J. et al. CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med 19, 429–436 (2013). https://doi.org/10.1038/nm.3057

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