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

Nat Biomed Eng. 2020 Apr;4(4):463-475. doi: 10.1038/s41551-019-0469-1. Epub 2019 Nov 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin / metabolism
  • Bone Regeneration / drug effects
  • Capillary Permeability / drug effects
  • Cell Membrane / drug effects
  • Cell Proliferation / drug effects
  • Extracellular Matrix / drug effects
  • Heparan Sulfate Proteoglycans / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Microfluidics
  • Models, Animal
  • Neuropilin-1
  • Receptors, Growth Factor / drug effects
  • Signal Transduction / drug effects*
  • Syndecans / pharmacology*
  • Vascular Endothelial Growth Factor A / metabolism
  • Wound Healing / drug effects*


  • Heparan Sulfate Proteoglycans
  • Intercellular Signaling Peptides and Proteins
  • Receptors, Growth Factor
  • Syndecans
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1
  • Becaplermin