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A roadmap for delivering a human musculoskeletal cell atlas

Nature Reviews Rheumatology volume 19, pages 738–752 (2023)Cite this article

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Abstract

Advances in single-cell technologies have transformed the ability to identify the individual cell types present within tissues and organs. The musculoskeletal bionetwork, part of the wider Human Cell Atlas project, aims to create a detailed map of the healthy musculoskeletal system at a single-cell resolution throughout tissue development and across the human lifespan, with complementary generation of data from diseased tissues. Given the prevalence of musculoskeletal disorders, this detailed reference dataset will be critical to understanding normal musculoskeletal function in growth, homeostasis and ageing. The endeavour will also help to identify the cellular basis for disease and lay the foundations for novel therapeutic approaches to treating diseases of the joints, soft tissues and bone. Here, we present a Roadmap delineating the critical steps required to construct the first draft of a human musculoskeletal cell atlas. We describe the key challenges involved in mapping the extracellular matrix-rich, but cell-poor, tissues of the musculoskeletal system, outline early milestones that have been achieved and describe the vision and directions for a comprehensive musculoskeletal cell atlas. By embracing cutting-edge technologies, integrating diverse datasets and fostering international collaborations, this endeavour has the potential to drive transformative changes in musculoskeletal medicine.

Key points

  • Musculoskeletal diseases present a large, and growing, global burden and delivery of effective treatments for these diseases requires improved understanding of the cellular basis of musculoskeletal tissue health and disease.

  • The advent of single-cell sequencing methods allows us to build a ‘human cell atlas’ that identifies and maps every cell of the human body.

  • The application of single-cell technologies in the study of musculoskeletal tissue has historically been difficult owing to the low cellularity and extracellular matrix-rich composition of these tissues.

  • Advances in laboratory and computational methodologies and sharing of knowledge and data among the research community should make it possible to deliver a musculoskeletal cell atlas.

  • Future expansion of the atlas, incorporating a greater number of ancestrally diverse donors, more tissue types and life stages, and diseased samples, will help to accelerate the development of improved diagnostic and therapeutic capabilities.

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Fig. 1: Complexity of the musculoskeletal system.
Fig. 2: Generalized workflow for generating a single-cell musculoskeletal atlas.
Fig. 3: Utility of a single-cell atlas of the musculoskeletal system.

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Acknowledgements

This publication is part of the Human Cell Atlas (HCA): www.humancellatlas.org/publications. The authors would like to thank the Musculoskeletal Bionetwork of the Human Cell Atlas for their discussions and input into this roadmap, particularly T. Herpelinck, L. Geris, P. Tylzanowski, (J.) S. Lawrence, J. Mimpen, C. Cohen, T. Boakye-Serebour and S. Teichmann. A.P.C. is funded by Medical Research Council Career Development Fellowship (MR/V010182/1). S.S. and M.B. are funded by the Chan Zuckerberg Initiative (CZIF2019–002426 and CZIF2021–240342) and supported by the National Institute for Health Research Oxford Biomedical Research Centre.

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Authors and Affiliations

  1. The Botnar Institute for Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK

    Mathew Baldwin, Philippa Hulley, Adam P. Cribbs & Sarah Snelling

  2. The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK

    Christopher D. Buckley

  3. Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, USA

    Farshid Guilak

  4. Shriners Hospitals for Children, St. Louis, MO, USA

    Farshid Guilak

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  1. Mathew Baldwin
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Contributions

S.S., M.B., F.G., A.P.C. and P.H. wrote the article. All authors researched data for the article, contributed substantially to discussion of content and reviewer and/or edited the manuscript before submission.

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Correspondence to Sarah Snelling.

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Competing interests

A.P.C. is listed as an inventor on several patents filed by Oxford University Innovations concerning single-cell sequencing technologies. The remaining authors declare no competing interests.

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Nature Reviews Rheumatology thanks Nidhi Bhutani, Deepak Rao, Gabriela Loots and Hui Shen for their contribution to the peer review of this work.

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Related links

Cellxgene: https://cellxgene.cziscience.com/

GitHub: https://github.com/humancellatlas; https://github.com/

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The Musculoskeletal Knowledge Portal: https://msk.hugeamp.org/

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Baldwin, M., Buckley, C.D., Guilak, F. et al. A roadmap for delivering a human musculoskeletal cell atlas. Nat Rev Rheumatol 19, 738–752 (2023). https://doi.org/10.1038/s41584-023-01031-2

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