Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing

Mikaël M. Martino, Federico Tortelli, Mayumi Mochizuki, Stephanie Traub, Dror Ben-David, Gisela A. Kuhn, Ralph Müller, Erella Livne, Sabine A. Eming, Jeffrey A. Hubbell

Research output: Contribution to journalArticle

230 Citations (Scopus)

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 α5β 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.

Original languageEnglish
Article number100ra89
JournalScience Translational Medicine
Volume3
Issue number100
DOIs
StatePublished - Sep 14 2011
Externally publishedYes

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Fibronectins
Intercellular Signaling Peptides and Proteins
Bone and Bones
Wounds and Injuries
Bone Morphogenetic Protein 2
Growth Factor Receptors
Fibrin
Integrins
Vascular Endothelial Growth Factor A
Extracellular Matrix
Factor XIIIa
Cellular Microenvironment
Mesenchymal Stromal Cells
Morphogenesis
Skin
Peptides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Martino, M. M., Tortelli, F., Mochizuki, M., Traub, S., Ben-David, D., Kuhn, G. A., ... Hubbell, J. A. (2011). Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. Science Translational Medicine, 3(100), [100ra89]. https://doi.org/10.1126/scitranslmed.3002614

Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. / Martino, Mikaël M.; Tortelli, Federico; Mochizuki, Mayumi; Traub, Stephanie; Ben-David, Dror; Kuhn, Gisela A.; Müller, Ralph; Livne, Erella; Eming, Sabine A.; Hubbell, Jeffrey A.

In: Science Translational Medicine, Vol. 3, No. 100, 100ra89, 14.09.2011.

Research output: Contribution to journalArticle

Martino, MM, Tortelli, F, Mochizuki, M, Traub, S, Ben-David, D, Kuhn, GA, Müller, R, Livne, E, Eming, SA & Hubbell, JA 2011, 'Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing', Science Translational Medicine, vol. 3, no. 100, 100ra89. https://doi.org/10.1126/scitranslmed.3002614
Martino, Mikaël M. ; Tortelli, Federico ; Mochizuki, Mayumi ; Traub, Stephanie ; Ben-David, Dror ; Kuhn, Gisela A. ; Müller, Ralph ; Livne, Erella ; Eming, Sabine A. ; Hubbell, Jeffrey A. / Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. In: Science Translational Medicine. 2011 ; Vol. 3, No. 100.
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