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Stem and progenitor cells in the synovial joint as targets for regenerative therapy

Nature Reviews Rheumatology volume 21, pages 211–220 (2025)Cite this article

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Abstract

Damage to articular cartilage, tendons, ligaments and entheses as a result of trauma, degeneration or inflammation in rheumatic diseases is prevalent. Regenerative medicine offers promising strategies for repairing damaged tissues, with the aim of restoring both their structure and function. While these strategies have traditionally relied on tissue engineering approaches using exogenous cells, interventions based on the activation of endogenous repair mechanisms are an attractive alternative. Key to advancing such approaches is a comprehensive understanding of the diversity of the stem and progenitor cells that reside in the adult synovial joint and how they function to repair damaged tissues. Advances in developmental biology have provided a lens through which to understand the origins, identities and functions of these cells, and insights into the roles of stem and progenitor cells in joint tissue repair, as well as their complex relationship with fibroblasts, have emerged. Integration of knowledge obtained through studies using advanced single-cell technologies will be crucial to establishing unified models of cell populations, lineage hierarchies and their molecular regulation. Ultimately, a more complete understanding of how cells repair tissues in adult life will guide the development of innovative pro-regenerative drugs, which are poised to enter clinical practice in musculoskeletal medicine.

Key points

  • Joint tissues are susceptible to damage that often does not adequately heal without intervention and can predispose to osteoarthritis.

  • Understanding the regenerative biology of the synovial joint will guide the development of therapeutic strategies to activate endogenous repair mechanisms and improve outcomes.

  • In adult joint tissues, stem and progenitor cell niches are present in the synovial lining and sublining, the paratenon and tendon sheath, the superficial zone of cartilage and the subchondral bone marrow.

  • The identity and functions of the different stem and progenitor cell populations in adult joint tissues can be understood in the context of their diverse developmental origins.

  • The synovium could be a reservoir of joint-repairing cells, and cells from bone marrow can contribute to the repair of osteochondral defects.

  • Single-cell technologies offer the opportunity to establish integrated models of cell populations and lineage hierarchies and their molecular regulation.

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Fig. 1: Overview of limb development and synovial joint formation.
Fig. 2: Overview of skeletal stem and progenitor cell populations in the synovial joint.

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Authors and Affiliations

  1. Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK

    Anke J. Roelofs, Jessica J. McClure & Cosimo De Bari

  2. Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, Aberdeen, UK

    Anke J. Roelofs, Jessica J. McClure, Elizabeth A. Hay & Cosimo De Bari

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  1. Anke J. Roelofs
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  2. Jessica J. McClure
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  4. Cosimo De Bari
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All authors researched data for and wrote the article. C.D.B. and A.J.R. contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Cosimo De Bari.

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Competing interests

A.J.R. and C.D.B. have received research grant funding through their institution from Biosplice Therapeutics (formerly Samumed). C.D.B. declares that he has received consultancy fees from Celltrion Healthcare, Galapagos and UCB. J.J.M. and E.A.H. declare no competing interests.

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Roelofs, A.J., McClure, J.J., Hay, E.A. et al. Stem and progenitor cells in the synovial joint as targets for regenerative therapy. Nat Rev Rheumatol 21, 211–220 (2025). https://doi.org/10.1038/s41584-025-01222-z

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