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Monocytes-macrophages that express α-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow

Nature Immunology volume 13, pages 1072–1082 (2012)Cite this article

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Abstract

Hematopoietic stem and progenitor cells (HSPCs) are regulated by various bone marrow stromal cell types. Here we identified rare activated bone marrow monocytes and macrophages with high expression of α-smooth muscle actin (α-SMA) and the cyclooxygenase COX-2 that were adjacent to primitive HSPCs. These myeloid cells resisted radiation-induced cell death and further upregulated COX-2 expression under stress conditions. COX-2-derived prostaglandin E2 (PGE2) prevented HSPC exhaustion by limiting the production of reactive oxygen species (ROS) via inhibition of the kinase Akt and higher stromal-cell expression of the chemokine CXCL12, which is essential for stem-cell quiescence. Our study identifies a previously unknown subset of α-SMA+ activated monocytes and macrophages that maintain HSPCs and protect them from exhaustion during alarm situations.

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Figure 1: Bone marrow α-SMA+ macrophages are adjacent to primitive SLAM+ hematopoietic cells.
Figure 2: The α-SMA+ macrophages are migratory and respond to LPS stimulation.
Figure 3: High expression of COX-2 by α-SMA+ macrophages in the steady state maintains HSPCs.
Figure 4: COX-2 expression is transiently increased in α-SMA+ macrophages after sublethal irradiation; this results in the preservation of bone marrow primitive HSPCs.
Figure 5: The α-SMA+ macrophages maintain primitive LSK CD34−ROSlo cells via COX-2 activity.
Figure 6: COX-2 activity preserves primitive HSPCs by maintaining a low abundance of ROS in an Akt-dependent manner.
Figure 7: PGE2 diminishes ROS and phosphorylated Akt in HSPCs and increases CXCL12 expression on nestin-GFP+ reticular stromal cells.

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Acknowledgements

We thank G.N. Enikolopov (Cold Spring Harbor Laboratory) for nestin-GFP mice; Y. Yarden (Weizmann Institute of Science) for the 3T3 cell line; N. Iscove for guidance during the study and for critical review of the manuscript; H. Perlman for help in the characterization of myeloid cells; J. Hanna for use of the FACSAria; and D. Shafritz, J. Canaani, K. Lapid and Y. Ovadia for critical review of the manuscript. Supported by the Israeli Science Foundation (ISF 544/09), the European Commission (CELL-PID FP7-261387) and the Leona M. and Harry B. Helmsley Charitable Trust.

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Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Aya Ludin, Tomer Itkin, Shiri Gur-Cohen, Alexander Mildner, Elias Shezen, Karin Golan, Orit Kollet, Alexander Kalinkovich, Gabriele D'Uva, Amir Schajnovitz, Steffen Jung & Tsvee Lapidot

  2. Department of Biological Services, Flow Cytometry Unit, Weizmann Institute of Science, Rehovot, Israel

    Ziv Porat

  3. Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University, Be'er Sheva, Israel

    Elena Voronov & Ron N Apte

  4. Department of Medicine, University of California, San Diego, California, USA

    David A Brenner

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Contributions

A.L. designed and did experiments, analyzed data and wrote the manuscript; T.I. and S.G.-C. helped in the design and execution of experiments and analyzed data; A.M. identified the myeloid characteristics of the α-SMA+ population; E.S. helped with the immunohistochemical staining; K.G., A.K., G.D. and A.S. helped with experiments; O.K. helped in writing the manuscript; Z.P. helped in the design and analysis of the flow cytometry–based single-cell imaging; E.V. designed and did IL-1β-related experiments; R.N.A. helped in the design of IL-1β-related experiments; D.A.B. provided α-SMA–RFP mice; S.J. provided advice and guided characterization of the α-SMA+ cells; and T.L. designed the research and wrote the manuscript.

Corresponding author

Correspondence to Tsvee Lapidot.

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Supplementary Figures 1–7 (PDF 1794 kb)

Supplementary Video 1

Three dimensional view of α-SMA+ two cell complex adjacent to Nestin+ reticular cell. (AVI 122 kb)

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Ludin, A., Itkin, T., Gur-Cohen, S. et al. Monocytes-macrophages that express α-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow. Nat Immunol 13, 1072–1082 (2012). https://doi.org/10.1038/ni.2408

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