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A population of nonneuronal GFRα3-expressing cells in the bone marrow resembles nonmyelinating Schwann cells

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Abstract

Artemin is a neurotrophic factor that plays a crucial role in the regulation of neural development and regeneration and has also been implicated in the pathogenesis of inflammatory pain. The receptor for artemin, GFRα3, is expressed by sympathetic and nociceptive sensory neurons, including some that innervate the bone marrow, but it is unclear if it is also expressed in other cell types in the bone marrow. Our goal in the present study was to characterise the expression of GFRα3 in nonneuronal cells in the bone marrow. Immunohistochemical studies revealed that GFRα3-expressing cells in the bone marrow are spatially associated with blood vessels and are in intimate contact with nerve fibres. We used various combinations of markers to distinguish different cell types and found that the GFRα3-expressing cells expressed markers of nonmyelinating Schwann cells (e.g. GFAP, p75NTR, nestin). Analysis of bone marrow sections of Wnt1-reporter mice also demonstrated that they originate from the neural crest. Further characterisation using flow cytometry revealed that GFRα3 is expressed in a population of CD51+Sca1−PDGFRα− cells, reinforcing the notion that they are neural crest-derived, nonmyelinating Schwann cells. In conclusion, there is a close association between peripheral nerve terminals and a population of nonneuronal cells that express GFRα3 in the bone marrow. The nonneuronal cells have characteristics consistent with a neural crest-derived, nonmyelinating Schwann cell phenotype. Our findings provide a better understanding of the expression pattern of GFRα3 in the bone marrow microenvironment.

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Acknowledgements

The authors acknowledge Professor Roberto Cappai and Phan Truong for generously providing us with tissue from C57BL/6 mice. Louise E. Purton was an NHMRC Senior Research Fellow.

Funding

This work was supported by funding from the National Health and Medical Research Council and the Operational Infrastructure Support Program from the Victorian Government (to St. Vincent’s Institute).

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  1. Alanna C. Green

    Present address: Department of Oncology and Metabolism and Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK

Authors and Affiliations

  1. Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia

    Jenny Thai, Lincon A. Stamp & Jason Ivanusic

  2. St. Vincent’s Institute of Medical Research and Department of Medicine at St. Vincent’s Hospital, University of Melbourne, Melbourne, Victoria, Australia

    Alanna C. Green & Louise E. Purton

  3. College of Medicine and Public Health, Center for Neuroscience, Flinders University, Adelaide, South Australia, Australia

    Nick J. Spencer

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Correspondence to Jason Ivanusic.

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All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors. All experiments performed were in accordance with ethical standards of the University of Melbourne Animal Experimentation Ethics Committee, St. Vincent’s Health Animal Ethics Committee and the Animal Welfare Committee of Flinders University of South Australia.

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Thai, J., Green, A.C., Stamp, L.A. et al. A population of nonneuronal GFRα3-expressing cells in the bone marrow resembles nonmyelinating Schwann cells. Cell Tissue Res 378, 441–456 (2019). https://doi.org/10.1007/s00441-019-03068-w

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