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

Mayumi Mochizuki, Esra Güç, Anthony J. Park, Ziad Julier, Priscilla S. Briquez, Gisela A. Kuhn, Ralph Müller, Melody A. Swartz, Jeffrey A. Hubbell, Mikaël M. Martino

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)463-475
Number of pages13
JournalNature Biomedical Engineering
Volume4
Issue number4
DOIs
Publication statusPublished - Apr 2020

Keywords

  • molecular medicine
  • regenerative medicine

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