Editors' ChoiceDevelopment

Engineering Tissue Repair

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Sci. Signal.  25 Feb 2014:
Vol. 7, Issue 314, pp. ec53
DOI: 10.1126/scisignal.2005206

Growth factors direct tissue development and repair, and the activities of these ligands are often modulated by interactions with components of the extracellular matrix (ECM). Although growth factors have potential for use in regenerative medicine, large quantities of soluble growth factors are required to stimulate healing. Martino et al. engineered growth factors to interact strongly with the ECM and demonstrated that the engineered proteins stimulated tissue repair better than did their wild-type counterparts. The heparin-binding motif of placenta growth factor-1 (PlGF-2123-144) mediated high-affinity binding of PlGF-2 to the ECM proteins fibronectin, fibrinogen, tenascin, vitronectin, and osteopontin in vitro. The authors replaced the heparin-binding domain of vascular endothelial growth factor A (VEGF-A) with PlGF-2123-144 and fused PlGF-2123-144 to the C termini of platelet-derived growth factor­–BB (PDGF-BB) and bone morphogenetic protein 2 (BMP-2). These engineered growth factors (VEGF-A/PlGF-2123-144, PDGF-BB/PlGF-2123-144, and BMP-2/ PlGF-2123-144) were active in cell culture assays and bound to ECM proteins with high affinity in vitro. In rodent bone healing and skin wound healing assays, low concentrations of these engineered high-affinity ECM-binding growth factors were more effective at promoting healing than were the same concentrations of the wild-type growth factors. Furthermore, VEGF-A/PlGF-2123-144 induced substantially less leakage than did wild-type VEGF-A in an in vivo vascular permeability assay. Targeted delivery of these and other similarly engineered growth factors may improve the prospects for using growth factors to stimulate healing and tissue repair.

M. M. Martino, P. S. Briquez, E. Güç, F. Tortelli, W. W. Kilarski, S. Metzger, J. J. Rice, G. A. Kuhn, R. Müller, M. A. Swartz, J. A. Hubbell, Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing. Science 343, 885–888 (2014). [Abstract] [Full Text]