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


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: CD15CD163+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.


  1. 1

    Bessis, M. L'îlot érythroblastique, unité fonctionnelle de la moelle osseuse. Rev. Hematol. 13, 8–11 (1958).

    CAS  PubMed  Google Scholar 

  2. 2

    Mohandas, N. & Prenant, M. Three-dimensional model of bone marrow. Blood 51, 633–643 (1978).

    Article  CAS  Google Scholar 

  3. 3

    Lee, G. et al. Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation. Blood 108, 2064–2071 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Rhodes, M.M., Kopsombut, P., Bondurant, M.C., Price, J.O. & Koury, M.J. Adherence to macrophages in erythroblastic islands enhances erythroblast proliferation and increases erythrocyte production by a different mechanism than erythropoietin. Blood 111, 1700–1708 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Hanspal, M., Smockova, Y. & Uong, Q. Molecular identification and functional characterization of a novel protein that mediates the attachment of erythroblasts to macrophages. Blood 92, 2940–2950 (1998).

    Article  CAS  Google Scholar 

  6. 6

    Chasis, J.A. & Mohandas, N. Erythroblastic islands: niches for erythropoiesis. Blood 112, 470–478 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Chow, A. et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Chow, A., Brown, B.D. & Merad, M. Studying the mononuclear phagocyte system in the molecular age. Nat. Rev. Immunol. 11, 788–798 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Miyake, Y. et al. Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. J. Clin. Invest. 117, 2268–2278 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Crocker, P.R., Werb, Z., Gordon, S. & Bainton, D.F. Ultrastructural localization of a macrophage-restricted sialic acid binding hemagglutinin, SER, in macrophage-hematopoietic cell clusters. Blood 76, 1131–1138 (1990).

    Article  CAS  Google Scholar 

  11. 11

    Manwani, D. & Bieker, J.J. The erythroblastic island. Curr. Top. Dev. Biol. 82, 23–53 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Barbé, E., Huitinga, I., Dopp, E.A., Bauer, J. & Dijkstra, C.D. A novel bone marrow frozen section assay for studying hematopoietic interactions in situ: the role of stromal bone marrow macrophages in erythroblast binding. J. Cell Sci. 109, 2937–2945 (1996).

    PubMed  Google Scholar 

  13. 13

    Ramos, P. et al. Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis. Blood 117, 1379–1389 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Schroit, A.J., Madsen, J.W. & Tanaka, Y. In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J. Biol. Chem. 260, 5131–5138 (1985).

    CAS  PubMed  Google Scholar 

  15. 15

    Sadahira, Y. et al. Impaired splenic erythropoiesis in phlebotomized mice injected with CL2MDP-liposome: an experimental model for studying the role of stromal macrophages in erythropoiesis. J. Leukoc. Biol. 68, 464–470 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Cairo, G., Recalcati, S., Mantovani, A. & Locati, M. Iron trafficking and metabolism in macrophages: contribution to the polarized phenotype. Trends Immunol. 32, 241–247 (2011).

    Article  CAS  Google Scholar 

  17. 17

    Zhang, Z. et al. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118, 1912–1922 (2011).

    Article  CAS  Google Scholar 

  18. 18

    Harandi, O.F., Hedge, S., Wu, D.C., McKeone, D. & Paulson, R.F. Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors. J. Clin. Invest. 120, 4507–4519 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Paulson, R.F., Shi, L. & Wu, D.C. Stress erythropoiesis: new signals and new stress progenitor cells. Curr. Opin. Hematol. 18, 139–145 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Hashimoto, D. et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 208, 1069–1082 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Sadahira, Y., Mori, M. & Kimoto, T. Participation of radioresistant Forssman antigen-bearing macrophages in the formation of stromal elements of erythroid spleen colonies. Br. J. Haematol. 71, 469–474 (1989).

    Article  CAS  Google Scholar 

  22. 22

    Millot, S. et al. Erythropoietin stimulates spleen BMP4-dependent stress erythropoiesis and partially corrects anemia in a mouse model of generalized inflammation. Blood 116, 6072–6081 (2010).

    Article  CAS  Google Scholar 

  23. 23

    Sadahira, Y., Yoshino, T. & Monobe, Y. Very late activation antigen 4-vascular cell adhesion molecule 1 interaction is involved in the formation of erythroblastic islands. J. Exp. Med. 181, 411–415 (1995).

    Article  CAS  Google Scholar 

  24. 24

    Kohyama, M. et al. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457, 318–321 (2009).

    Article  CAS  Google Scholar 

  25. 25

    Gooi, H.C. et al. Marker of peripheral blood granulocytes and monocytes of man recognized by two monoclonal antibodies VEP8 and VEP9 involves the trisaccharide 3-fucosyl-N-acetyllactosamine. Eur. J. Immunol. 13, 306–312 (1983).

    Article  CAS  Google Scholar 

  26. 26

    Tippett, E. et al. Differential expression of CD163 on monocyte subsets in healthy and HIV-1 infected individuals. PLoS ONE 6, e19968 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Xing, S. et al. Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood 111, 5109–5117 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Tefferi, A. et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 110, 1092–1097 (2007).

    Article  CAS  Google Scholar 

  29. 29

    Scott, L.M., Priestley, G.V. & Papayannopoulou, T. Deletion of α4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol. Cell. Biol. 23, 9349–9360 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Ulyanova, T., Jiang, Y., Padilla, S., Nakamoto, B. & Papayannopoulou, T. Combinatorial and distinct roles of α and α integrins in stress erythropoiesis in mice. Blood 117, 975–985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Bungartz, G. et al. Adult murine hematopoiesis can proceed without β1 and β7 integrins. Blood 108, 1857–1864 (2006).

    Article  CAS  Google Scholar 

  32. 32

    Thiele, J. et al. Macrophages and their subpopulations following allogenic bone marrow transplantation for chronic myeloid leukaemia. Virchows Arch. 437, 160–166 (2000).

    Article  CAS  Google Scholar 

  33. 33

    Thiele, J. et al. Erythropoietic reconstitution, macrophages and reticulin fibrosis in bone marrow specimens of CML patients following allogeneic transplantation. Leukemia 14, 1378–1385 (2000).

    Article  CAS  Google Scholar 

  34. 34

    Hartnell, A. et al. Characterization of human sialoadhesin, a sialic acid binding receptor expressed by resident and inflammatory macrophage populations. Blood 97, 288–296 (2001).

    Article  CAS  Google Scholar 

  35. 35

    Lenox, L.E., Perry, J.M. & Paulson, R.F. BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood 105, 2741–2748 (2005).

    Article  CAS  Google Scholar 

  36. 36

    Coleman, D.L., Russell, E.S. & Levin, E.Y. Enzymatic studies of the hemopoietic defect in flexed mice. Genetics 61, 631–642 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Seggewiss, R. & Einsele, H. Hematopoietic growth factors including keratinocyte growth factor in allogeneic and autologous stem cell transplantation. Semin. Hematol. 44, 203–211 (2007).

    Article  CAS  Google Scholar 

  38. 38

    Miller, C.B. et al. Impaired erythropoietin response to anemia after bone marrow transplantation. Blood 80, 2677–2682 (1992).

    Article  CAS  Google Scholar 

  39. 39

    Heuser, M. & Ganser, A. Recombinant human erythropoietin in the treatment of nonrenal anemia. Ann. Hematol. 85, 69–78 (2006).

    Article  CAS  Google Scholar 

  40. 40

    Zhan, H. & Spivak, J.L. The diagnosis and management of polycythemia vera, essential thrombocythemia, and primary myelofibrosis in the JAK2 V617F era. Clin. Adv. Hematol. Oncol. 7, 334–342 (2009).

    PubMed  Google Scholar 

  41. 41

    Reddy, M.M., Deshpande, A. & Sattler, M. Targeting JAK2 in the therapy of myeloproliferative neoplasms. Expert Opin. Ther. Targets 16, 313–324 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Hume, D.A. & MacDonald, K.P. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 119, 1810–1820 (2012).

    Article  CAS  Google Scholar 

  43. 43

    Ramos, P. et al. Macrophages support pathological erythropoiesis in polycythemia vera and β-thalassemia. Nat. Med. advance online publication, doi:10.1038/nm.3126 (17 March 2013).

  44. 44

    Saito, M. et al. Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice. Nat. Biotechnol. 19, 746–750 (2001).

    Article  CAS  Google Scholar 

  45. 45

    Chen, K. et al. Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc. Natl. Acad. Sci. USA 106, 17413–17418 (2009).

    Article  Google Scholar 

  46. 46

    Reeves, J.P., Reeves, P.A. & Chin, L.T. Survival surgery: removal of the spleen or thymus. Curr. Protoc. Immunol. 2, 1.10 (2001).

    Google Scholar 

  47. 47

    Hoffmann-Fezer, G. et al. Biotin labeling as an alternative nonradioactive approach to determination of red cell survival. Ann. Hematol. 67, 81–87 (1993).

    Article  CAS  Google Scholar 

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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.).

Author information




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.

Corresponding authors

Correspondence to Miriam Merad or Paul S Frenette.

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The authors declare no competing financial interests.

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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).

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