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 language | English |
|---|---|
| Article number | 100ra89 |
| Journal | Science Translational Medicine |
| Volume | 3 |
| Issue number | 100 |
| DOIs | |
| State | Published - Sep 14 2011 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing
AU - Martino, Mikaël M.
AU - Tortelli, Federico
AU - Mochizuki, Mayumi
AU - Traub, Stephanie
AU - Ben-David, Dror
AU - Kuhn, Gisela A.
AU - Müller, Ralph
AU - Livne, Erella
AU - Eming, Sabine A.
AU - Hubbell, Jeffrey A.
PY - 2011/9/14
Y1 - 2011/9/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052951552&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052951552&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3002614
DO - 10.1126/scitranslmed.3002614
M3 - Article
C2 - 21918106
AN - SCOPUS:80052951552
VL - 3
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 100
M1 - 100ra89
ER -