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Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans

Nature Cell Biology volume 27, pages 720–735 (2025)Cite this article

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Abstract

Fibroblasts, once perceived as a uniform cell type, are now recognized as a mosaic of distinct populations with specialized roles in tissue homeostasis and pathology. Here we provide a global overview of the expanding compendium of fibroblast cell types and states, their diverse lineage origins and multifaceted functions across various human organs. By integrating insights from developmental biology, lineage tracing and single-cell technologies, we highlight the complex nature of fibroblasts. We delve into their origination from embryonic mesenchyme and tissue-resident populations, elucidating lineage-specific behaviours in response to physiological cues. Furthermore, we highlight the pivotal role of fibroblasts in orchestrating tissue repair, connective tissue remodelling and immune modulation across diverse pathologies. This knowledge is essential to develop novel fibroblast-targeted therapies to restore steady-state fibroblast function and advance regenerative medicine strategies across multiple diseases.

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Fig. 1: Overview of different fibroblast populations throughout embryo development.
Fig. 2: Stromal cells in health and disease.

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Acknowledgements

This project was funded by the German Federal Ministry of Education and Research under code 03ZU1111GA as part of the Clusters4Future cluster SaxoCell. Y.R. is supported by a European Research Council Consolidator Grant (ERC-CoG 819933), the LEO Foundation (LF-OC-21-000835) and the EFSD Anniversary Fund Programme (CRC/TRR 359; Perinatal Development of Immune Cell Topology (PILOT)). J.C.S. and S.F. are supported by the 3D4D2 project carried out under the M-ERA.NET 2 scheme (the European Union’s Horizon 2020 research and innovation programme; grant number 685451) and co-funded by the Saxon State Ministry for Science, Culture and Tourism (grant number 100579959), as well as tax funds from the Saxon State Parliament. S.F. is supported by the German Research Foundation (FR2671/5-1). Some of the ideas presented in this Review were initiated at a fibroblast symposium at the University of Toronto. We thank B. Hinz, N. Henderson, G. Gabbiani, C. Philippeos, J. Duffield, R. Schwabe and F. Rossi for critical discussions throughout this meeting, as well as S. Miyara for interesting talks on cardiac fibroblasts.

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Author notes

  1. These authors contributed equally: Sandra Franz, Yuval Rinkevich.

Authors and Affiliations

  1. Department of Dermatology, Venereology and Allergology, Leipzig University Medical Faculty, Leipzig, Germany

    Marta Torregrossa, Jan C. Simon & Sandra Franz

  2. Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden

    Lindsay Davies

  3. Department for Plastic Surgery and Hand Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany

    Machens Hans-Günther

  4. Chinese Institutes for Medical Research, Beijing, China

    Yuval Rinkevich

  5. Capital Medical University, Beijing, China

    Yuval Rinkevich

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  4. Jan C. Simon
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M.T. wrote the article with guidance from Y.R. and S.F. All authors discussed the manuscript content. M.T., S.F. and Y.R. reviewed and edited the manuscript before submission.

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Torregrossa, M., Davies, L., Hans-Günther, M. et al. Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans. Nat Cell Biol 27, 720–735 (2025). https://doi.org/10.1038/s41556-025-01638-5

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