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Growth factors with enhanced syndecan binding generate tonic signalling and promote tissue healing

Nature Biomedical Engineering volume 4, pages 463–475 (2020)Cite this article

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Abstract

Growth factors can stimulate tissue regeneration, but the side effects and low effectiveness associated with suboptimal delivery systems have impeded their use in translational regenerative medicine. Physiologically, growth factor interactions with the extracellular matrix control their bioavailability and spatiotemporal cellular signalling. Growth factor signalling is also controlled at the cell surface level via binding to heparan sulfate proteoglycans, such as syndecans. Here we show that vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) that were engineered to have a syndecan-binding sequence trigger sustained low-intensity signalling (tonic signalling) and reduce the desensitization of growth factor receptors. We also show in mouse models that tonic signalling leads to superior morphogenetic activity, with syndecan-binding growth factors inducing greater bone regeneration and wound repair than wild-type growth factors, as well as reduced tumour growth (associated with PDGF-BB delivery) and vascular permeability (triggered by VEGF-A). Tonic signalling via syndecan binding may also enhance the regenerative capacity of other growth factors.

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Fig. 1: Enhancing growth factor binding to syndecans.
Fig. 2: Enhancing growth factor binding to syndecans triggers tonic signalling.
Fig. 3: Syndecan-binding growth factors have enhanced morphogenetic capacity.
Fig. 4: Syndecan-binding VEGF-A has enhanced capacity to induce EC assembly.
Fig. 5: Syndecan-binding PDGF-BB improves bone regeneration.
Fig. 6: Syndecan-binding VEGF-A promotes impaired wound healing and angiogenesis.
Fig. 7: Syndecan-binding growth factors induce fewer side effects.

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Data availability

All the data supporting the results in this study are available in the Article and Supplementary Information. The datasets generated and analysed during the study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank the Bioimaging and the histology platform of Ecole Polytechnique Fédérale de Lausanne and Monash University. This work was partially funded by the European Community’s Seventh Framework Programme in the project Angioscaff (grant no. NMP-LA-2008-214402) to J.A.H. and M.A.S., by the Swiss National Science Foundation (grant no. P2ELP3_1750 71) to Z.J., by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (grant no. DP3DK108215) to J.A.H. and by the National Health and Medical Research Council (grant no. APP1140229) to M.M.M. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government.

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Authors and Affiliations

  1. European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia

    Mayumi Mochizuki, Anthony J. Park, Ziad Julier & Mikaël M. Martino

  2. Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Mayumi Mochizuki, Esra Güç, Priscilla S. Briquez, Melody A. Swartz & Jeffrey A. Hubbell

  3. MRC Centre for Reproductive Health, Queen’s Medical Research Institute, Edinburgh, UK

    Esra Güç

  4. Institute for Molecular Engineering, University of Chicago, Chicago, IL, USA

    Priscilla S. Briquez, Melody A. Swartz & Jeffrey A. Hubbell

  5. Institute for Biomechanics, ETH Zurich, Zürich, Switzerland

    Gisela A. Kuhn & Ralph Müller

  6. Laboratory of Host Defense, Immunology Frontier Research Centre, Osaka University, Suita, Japan

    Mikaël M. Martino

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Contributions

M.M., J.A.H. and M.M.M. designed the research. M.M., E.G., A.J.P., Z.J., P.S.B. and M.M.M. conducted the experiments and analysed the data. G.A.K. and R.M. conducted the microCT measurements and analyses. M.A.S. supervised the flow chamber and microvascular permeability experiments. M.M., E.G. and M.M.M. wrote the manuscript. J.A.H. and M.M.M. supervised the research.

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Correspondence to Mikaël M. Martino.

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Monash University and Ecole Polytechnique Fédérale de Lausanne have filed for patent protection on the molecular design described herein; M.M., J.A.H. and M.M.M. are named as inventors.

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Supplementary Information

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Supplementary Video 1

Syndecan-binding VEGF-A induces low vascular permeability (example 1).

Supplementary Video 2

Syndecan-binding VEGF-A induces low vascular permeability (example 2).

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Mochizuki, M., Güç, E., Park, A.J. et al. Growth factors with enhanced syndecan binding generate tonic signalling and promote tissue healing. Nat Biomed Eng 4, 463–475 (2020). https://doi.org/10.1038/s41551-019-0469-1

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