Universität zu Köln

Martino, Mikael M., Tortelli, Federico, Mochizuki, Mayumi, Traub, Stephanie, Ben-David, Dror, Kuhn, Gisela A., Mueller, Ralph, Livne, Erella, Eming, Sabine A. and Hubbell, Jeffrey A. (2011). Engineering the Growth Factor Microenvironment with Fibronectin Domains to Promote Wound and Bone Tissue Healing. Sci. Transl. Med., 3 (100). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

Although growth factors naturally exert their morphogenetic influences within the context of the extracellular matrix microenvironment, the interactions among growth factors, their receptors, and other extracellular matrix components are typically ignored in clinical delivery of growth factors. We present an approach for engineering the cellular microenvironment to greatly accentuate the effects of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) for skin repair, and of bone morphogenetic protein-2 (BMP-2) and PDGF-BB for bone repair. A multifunctional recombinant fragment of fibronectin (FN) was engineered to comprise (i) a factor XIIIa substrate fibrin-binding sequence, (ii) the 9th to 10th type III FN repeat (FN III9-10) containing the major integrin-binding domain, and (iii) the 12th to 14th type III FN repeat (FN III12-14), which binds growth factors promiscuously, including VEGF-A165, PDGF-BB, and BMP-2. We show potent synergistic signaling and morphogenesis between alpha(5)beta(1) integrin and the growth factor receptors, but only when FN III9-10 and FN III12-14 are proximally presented in the same polypeptide chain (FN III9-10/12-14). The multifunctional FN III9-10/12-14 greatly enhanced the regenerative effects of the growth factors in vivo in a diabetic mouse model of chronic wounds (primarily through an angiogenic mechanism) and in a rat model of critical-size bone defects (through a mesenchymal stem cell recruitment mechanism) at doses where the growth factors delivered within fibrin only had no significant effects.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Martino, Mikael M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tortelli, Federico UNSPECIFIED UNSPECIFIED UNSPECIFIED Mochizuki, Mayumi UNSPECIFIED UNSPECIFIED UNSPECIFIED Traub, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Ben-David, Dror UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuhn, Gisela A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Ralph UNSPECIFIED UNSPECIFIED UNSPECIFIED Livne, Erella UNSPECIFIED UNSPECIFIED UNSPECIFIED Eming, Sabine A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hubbell, Jeffrey A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-489067
DOI:	10.1126/scitranslmed.3002614
Journal or Publication Title:	Sci. Transl. Med.
Volume:	3
Number:	100
Date:	2011
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	1946-6242
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FACTOR-BINDING; MORPHOGENETIC PROTEINS; ANIMAL-MODELS; REPAIR; DIFFERENTIATION; BECAPLERMIN; DELIVERY; MATRIX; SAFETY Multiple languages Cell Biology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48906