Abstract
Directing specific, complex cell behaviors, such as differentiation, in response to biomaterials for regenerative medicine applications is, at present, a mostly unrealized goal. To date, current technological advances have been inspired by the reductionist point of view, focused on developing simple and merely adequate environments that facilitate simple cellular adhesion. However, even if extracellular matrix (ECM)-derived peptides, such as Arg–Gly–Asp (RGD), have largely demonstrated their utility in supporting cell adhesion, their lack of biological specificity is simply not optimal for controlling more integrated processes, such as cell differentiation. These more complex cellular processes require specific integrin-signaling scaffolds and presumably synergistic integrin and growth factor-receptor signaling. This article will introduce some current efforts to engineer ECM variants that incorporate additional levels of complexity for directing greater integrin specificity and synergistic ECM growth factor signaling toward directing cell phenotype.
Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest
Bibliography
- 1 Hubbell JA: Bioactive biomaterials. Curr. Opin. Biotechnol.10,123–129 (1999).Crossref, Medline, CAS, Google Scholar
- 2 Hubbell JA: Materials as morphogenetic guides in tissue engineering. Curr. Opin. Biotechnol.14,551–558 (2003).Crossref, Medline, CAS, Google Scholar
- 3 Ruoslahti E: RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol.12,697–715 (1996).Crossref, Medline, CAS, Google Scholar
- 4 Petrie TA, Capadona JR, Reyes CD, Garcia AJ: Integrin specificity and enhanced cellular activities associated with surfaces presenting a recombinant fibronectin fragment compared with RGD supports. Biomaterials27,5459–5470 (2006).▪ Highlights the importance of integrin specificity in directing cell fate.Crossref, Medline, CAS, Google Scholar
- 5 Pankov R, Yamada KM: Fibronectin at a glance. J. Cell Sci.115,3861–3863 (2002).Crossref, Medline, CAS, Google Scholar
- 6 Beattie J, Kreiner M, Allan GJ, Flint DJ, Domingues D, van der Walle CF: IGFBP-3 and IGFBP-5 associate with the cell binding domain (CBD) of fibronectin. Biochem. Biophys. Res. Commun.381,572–576 (2009).Crossref, Medline, CAS, Google Scholar
- 7 Goerges AL, Nugent MA: pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release. J. Biol. Chem.279,2307–2315 (2004).Crossref, Medline, CAS, Google Scholar
- 8 Taipale J, Saharinen J, Hedman K, Keski-Oja J: Latent transforming growth factor-β1 and its binding protein are components of extracellular matrix microfibrils. J. Histochem. Cytochem.44,875–889 (1996).Crossref, Medline, CAS, Google Scholar
- 9 Schenk S, Quaranta V: Tales from the crypt[ic] sites of the extracellular matrix. Trends Cell Biol.13,366–375 (2003).Crossref, Medline, CAS, Google Scholar
- 10 Metcalfe AD, Ferguson MW: Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration. J. R. Soc. Interface4,413–437 (2007).Crossref, Medline, CAS, Google Scholar
- 11 Davis GE, Bayless KJ, Davis MJ, Meininger GA: Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am. J. Pathol.156,1489–1498 (2000).Crossref, Medline, CAS, Google Scholar
- 12 Mott JD, Werb Z: Regulation of matrix biology by matrix metalloproteinases. Curr. Opin. Cell Biol.16,558–564 (2004).Crossref, Medline, CAS, Google Scholar
- 13 Tran KT, Lamb P, Deng JS: Matrikines and matricryptins: implications for cutaneous cancers and skin repair. J. Dermatol. Sci.40,11–20 (2005).Crossref, Medline, CAS, Google Scholar
- 14 Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V: Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science277,225–228 (1997).Crossref, Medline, CAS, Google Scholar
- 15 Koshikawa N, Minegishi T, Sharabi A, Quaranta V, Seiki M: Membrane-type matrix metalloproteinase-1 (MT1-MMP) is a processing enzyme for human laminin γ2-chain. J. Biol. Chem.280,88–93 (2005).▪ Describes and highlights the importance of proteolytic processing of laminin in directing time-resolved integrin specificity.Crossref, Medline, CAS, Google Scholar
- 16 Miner JH, Yurchenco PD: Laminin functions in tissue morphogenesis. Annu. Rev. Cell Dev. Biol.20,255–284 (2004).Crossref, Medline, CAS, Google Scholar
- 17 Litjens SH, de Pereda JM, Sonnenberg A: Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol.16,376–383 (2006).Crossref, Medline, CAS, Google Scholar
- 18 Kim JM, Park WH, Min BM: The PPFLMLLKGSTR motif in globular domain 3 of the human laminin-5 α3-chain is crucial for integrin-α3β1 binding and cell adhesion. Exp. Cell Res.304,317–327 (2005).Crossref, Medline, CAS, Google Scholar
- 19 Nguyen BP, Gil SG, Carter WG: Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling. J. Biol. Chem.275,31896–31907 (2000).Crossref, Medline, CAS, Google Scholar
- 20 Goldfinger LE, Hopkinson SB, deHart GW, Collawn S, Couchman JR, Jones JC: The α3 laminin subunit, α6β4- and α3β1-integrin coordinately regulate wound healing in cultured epithelial cells and in the skin. J. Cell Sci.112(Pt 16),2615–2629 (1999).Crossref, Medline, CAS, Google Scholar
- 21 Hintermann E, Bilban M, Sharabi A, Quaranta V: Inhibitory role of α6β4-associated erbB-2 and phosphoinositide 3-kinase in keratinocyte haptotactic migration dependent on α 3 β 1 integrin. J. Cell Biol.153,465–478 (2001).Crossref, Medline, CAS, Google Scholar
- 22 Nguyen BP, Ryan MC, Gil SG, Carter WG: Deposition of laminin 5 in epidermal wounds regulates integrin signaling and adhesion. Curr. Opin. Cell Biol.12,554–562 (2000).Crossref, Medline, CAS, Google Scholar
- 23 O’Toole EA, Marinkovich MP, Hoeffler WK, Furthmayr H, Woodley DT: Laminin-5 inhibits human keratinocyte migration. Exp. Cell Res.233,330–339 (1997).Crossref, Medline, Google Scholar
- 24 Baudoin C, Fantin L, Meneguzzi G: Proteolytic processing of the laminin α3 G domain mediates assembly of hemidesmosomes but has no role on keratinocyte migration. J. Invest. Dermatol.125,883–888 (2005).Crossref, Medline, CAS, Google Scholar
- 25 Li J, Tzu J, Chen Y et al.: Laminin-10 is crucial for hair morphogenesis. EMBO J.22,2400–2410 (2003).Crossref, Medline, CAS, Google Scholar
- 26 Mao Y, Schwarzbauer JE: Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol.24,389–399 (2005).Crossref, Medline, CAS, Google Scholar
- 27 Baneyx G, Baugh L, Vogel V: Coexisting conformations of fibronectin in cell culture imaged using fluorescence resonance energy transfer. Proc. Natl Acad. Sci. USA98,14464–14468 (2001).Crossref, Medline, CAS, Google Scholar
- 28 Barker TH, Baneyx G, Cardo-Vila M et al.: SPARC regulates extracellular matrix organization through its modulation of integrin-linked kinase activity. J. Biol. Chem.280,36483–36493 (2005).Crossref, Medline, CAS, Google Scholar
- 29 Baneyx G, Baugh L, Vogel V: Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension. Proc. Natl Acad. Sci. USA99,5139–5143 (2002).▪▪ Demonstrates a direct link between cell contractile forces via the cytoskeleton and conformational changes in fibronectin protein within fibronectin fibers. This enables the concept of force-mediated exposure of cryptic sites in fibronectin.Crossref, Medline, CAS, Google Scholar
- 30 Davidson LA, Dzamba BD, Keller R, Desimone DW: Live imaging of cell protrusive activity, and extracellular matrix assembly and remodeling during morphogenesis in the frog, Xenopus laevis.Dev. Dyn.237,2684–2692 (2008).Crossref, Medline, Google Scholar
- 31 Smith ML, Gourdon D, Little WC et al.: Force-induced unfolding of fibronectin in the extracellular matrix of living cells. PLoS Biol.5,e268 (2007).Crossref, Medline, Google Scholar
- 32 Krammer A, Craig D, Thomas WE, Schulten K, Vogel V: A structural model for force regulated integrin binding to fibronectin’s RGD-synergy site. Matrix Biol.21,139–147 (2002).Crossref, Medline, CAS, Google Scholar
- 33 Grant RP, Spitzfaden C, Altroff H, Campbell ID, Mardon HJ: Structural requirements for biological activity of the ninth and tenth FIII domains of human fibronectin. J. Biol. Chem.272,6159–6166 (1997).Crossref, Medline, CAS, Google Scholar
- 34 Altroff H, Schlinkert R, van der Walle CF et al.: Interdomain tilt angle determines integrin-dependent function of the ninth and tenth FIII domains of human fibronectin. J. Biol. Chem.279,55995–56003 (2004).Crossref, Medline, CAS, Google Scholar
- 35 Khew ST, Zhu XH, Tong YW: An integrin-specific collagen-mimetic peptide approach for optimizing Hep3B liver cell adhesion, proliferation, and cellular functions. Tissue Eng.13,2451–2463 (2007).Crossref, Medline, CAS, Google Scholar
- 36 Zhu C, Bao G, Wang N: Cell mechanics: mechanical response, cell adhesion, and molecular deformation. Annu. Rev. Biomed. Eng.2,189–226 (2000).Crossref, Medline, CAS, Google Scholar
- 37 Niimi T, Osawa M, Yamaji N et al.: NMR structure of human fibronectin EDA. J. Biomol. NMR21,281–284 (2001).Crossref, Medline, CAS, Google Scholar
- 38 Johnson KJ, Sage H, Briscoe G, Erickson HP: The compact conformation of fibronectin is determined by intramolecular ionic interactions. J. Biol. Chem.274,15473–15479 (1999).Crossref, Medline, CAS, Google Scholar
- 39 Manabe R, Ohe N, Maeda T, Fukuda T, Sekiguchi K: Modulation of cell-adhesive activity of fibronectin by the alternatively spliced EDA segment. J. Cell Biol.139,295–307 (1997).Crossref, Medline, CAS, Google Scholar
- 40 Gronthos S, Simmons PJ, Graves SE, Robey PG: Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix. Bone28,174–181 (2001).Crossref, Medline, CAS, Google Scholar
- 41 Stephansson SN, Byers BA, Garcia AJ: Enhanced expression of the osteoblastic phenotype on substrates that modulate fibronectin conformation and integrin receptor binding. Biomaterials23,2527–2534 (2002).Crossref, Medline, CAS, Google Scholar
- 42 Koistinen P, Pulli T, Uitto VJ, Nissinen L, Hyypia T, Heino J: Depletion of αV integrins from osteosarcoma cells by intracellular antibody expression induces bone differentiation marker genes and suppresses gelatinase (MMP-2) synthesis. Matrix Biol.18,239–251 (1999).Crossref, Medline, CAS, Google Scholar
- 43 Cheng SL, Lai CF, Blystone SD, Avioli LV: Bone mineralization and osteoblast differentiation are negatively modulated by integrin-αvβ3. J. Bone Miner. Res.16,277–288 (2001).Crossref, Medline, CAS, Google Scholar
- 44 Garcia AJ, Vega MD, Boettiger D: Modulation of cell proliferation and differentiation through substrate-dependent changes in fibronectin conformation. Mol. Biol. Cell10,785–798 (1999).Crossref, Medline, CAS, Google Scholar
- 45 Aota S, Nomizu M, Yamada KM: The short amino acid sequence Pro-His-Ser-Arg-Asn in human fibronectin enhances cell-adhesive function. J. Biol. Chem.269,24756–24761 (1994).Crossref, Medline, CAS, Google Scholar
- 46 Bowditch RD, Hariharan M, Tominna EF et al.: Identification of a novel integrin binding site in fibronectin. Differential utilization by β3 integrins. J. Biol. Chem.269,10856–10863 (1994).Crossref, Medline, CAS, Google Scholar
- 47 Nagai T, Yamakawa N, Aota S et al.: Monoclonal antibody characterization of two distant sites required for function of the central cell-binding domain of fibronectin in cell adhesion, cell migration, and matrix assembly. J. Cell Biol.114,1295–1305 (1991).Crossref, Medline, CAS, Google Scholar
- 48 Mao Y, Schwarzbauer JE: Accessibility to the fibronectin synergy site in a 3D matrix regulates engagement of α5β1- versus αvβ3-integrin receptors. Cell. Commun. Adhes.13,267–277 (2006).Crossref, Medline, CAS, Google Scholar
- 49 Petrie TA, Raynor JE, Reyes CD, Burns KL, Collard DM, Garcia AJ: The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration. Biomaterials29,2849–2857 (2008).Crossref, Medline, CAS, Google Scholar
- 50 Martino MM, Mochizuki M, Rothenfluh DA, Rempel SA, Hubbell JA, Barker TH: Controlling integrin specificity and stem cell differentiation in 2D and 3D environments through regulation of fibronectin domain stability. Biomaterials30,1089–1097 (2009).▪▪ Realizes the functional significance of engineering structural changes into extracellular matrix domains to direct integrin specificity and cell fate.Crossref, Medline, CAS, Google Scholar
- 51 Richards J, Miller M, Abend J, Koide A, Koide S, Dewhurst S: Engineered fibronectin type III domain with a RGDWXE sequence binds with enhanced affinity and specificity to humanαvβ3 integrin. J. Mol. Biol.326,1475–1488 (2003).Crossref, Medline, CAS, Google Scholar
- 52 van der Walle CF, Altroff H, Mardon HJ: Novel mutant human fibronectin FIII9–10 domain pair with increased conformational stability and biological activity. Protein Eng.15,1021–1024 (2002).▪▪ Exemplifies finding ‘new’ biology in unique places. By comparing mouse with human fibronectin, van der Walle et al. were able to identify a single point mutation capable of conferring enhanced conformational stability to intergrin-binding fibronectin domains.Crossref, Medline, CAS, Google Scholar
- 53 Knight CG, Morton LF, Onley DJ et al.: Identification in collagen type I of an integrin-α2β1-binding site containing an essential GER sequence. J. Biol. Chem.273,33287–33294 (1998).Crossref, Medline, CAS, Google Scholar
- 54 Knight CG, Morton LF, Peachey AR, Tuckwell DS, Farndale RW, Barnes MJ: The collagen-binding A-domains of integrins α1β1 and α2β1 recognize the same specific amino acid sequence, GFOGER, in native (triple-helical) collagens. J. Biol. Chem.275,35–40 (2000).Crossref, Medline, CAS, Google Scholar
- 55 Reyes CD, Garcia AJ: α2β1 integrin-specific collagen-mimetic surfaces supporting osteoblastic differentiation. J. Biomed. Mater. Res. A69,591–600 (2004).Crossref, Medline, Google Scholar
- 56 Hennessy KM, Pollot BE, Clem WC et al.: The effect of collagen I mimetic peptides on mesenchymal stem cell adhesion and differentiation, and on bone formation at hydroxyapatite surfaces. Biomaterials30,1898–1909 (2009).Crossref, Medline, CAS, Google Scholar
- 57 Reyes CD, Garcia AJ: Engineering integrin-specific surfaces with a triple-helical collagen-mimetic peptide. J. Biomed. Mater. Res. A65,511–523 (2003).Crossref, Medline, Google Scholar
- 58 Giancotti FG, Tarone G: Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu. Rev. Cell Dev. Biol.19,173–206 (2003).Crossref, Medline, CAS, Google Scholar
- 59 Ross RS: Molecular and mechanical synergy: cross-talk between integrins and growth factor receptors. Cardiovasc. Res.63,381–390 (2004).Crossref, Medline, CAS, Google Scholar
- 60 Yamada KM, Even-Ram S: Integrin regulation of growth factor receptors. Nat. Cell Biol.4,E75–E76 (2002).Crossref, Medline, CAS, Google Scholar

