title: Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing.
abstract: Growth factors (GFs) are critical in tissue repair, but their translation to clinical use has been modest. Physiologically, GF interactions with extracellular matrix (ECM) components facilitate localized and spatially regulated signaling; therefore, we reasoned that the lack of ECM binding in their clinically used forms could underlie the limited translation. We discovered that a domain in placenta growth factor-2 (PlGF-2(123-144)) binds exceptionally strongly and promiscuously to ECM proteins. By fusing this domain to the GFs vascular endothelial growth factor-A, platelet-derived growth factor-BB, and bone morphogenetic protein-2, we generated engineered GF variants with super-affinity to the ECM. These ECM super-affinity GFs induced repair in rodent models of chronic wounds and bone defects that was greatly enhanced as compared to treatment with the wild-type GFs, demonstrating that this approach may be useful in several regenerative medicine applications.
authors.affiliation: Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Mikaël M
authors.initials: MM
authors.lastname: Martino
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Briquez
authors.forename: Esra
authors.initials: E
authors.lastname: Güç
authors.forename: Federico
authors.initials: F
authors.lastname: Tortelli
authors.forename: Witold W
authors.initials: WW
authors.lastname: Kilarski
authors.forename: Stephanie
authors.initials: S
authors.lastname: Metzger
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rice
authors.forename: Gisela A
authors.initials: GA
authors.lastname: Kuhn
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D000077214:Becaplermin; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D020574:Proto-Oncogene Proteins c-sis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: D000077214:Becaplermin; D055396:Bone Morphogenetic Protein 2; D016326:Extracellular Matrix Proteins; D006497:Heparan Sulfate; D036341:Intercellular Signaling Peptides and Proteins; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; C000608036:PGF protein, human; C000608037:Pgf protein, mouse