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Matriz Extracelular PDF
Matriz Extracelular PDF
Fibrous collagens
and biophysical dialogue between the
various cellular components (e.g. epithelial,
Core protein
Decorin Lumican Fibronectin Tenascin Elastins Laminin
Glycosamino- Cell membrane
glycan chains Perlecan Aggrecan
Loss of cell−cell adhesion Loss of apical−basal polarity Loss of apical–basal polarity microenvironment. Indeed, the physical,
topological, and biochemical composition of the
Cell proliferation
Cell migration
Journal of Cell Science
Thinner BM
BM
ECM is not only tissue-specific, but is also
Metastatic
cell migration
markedly heterogeneous. Cell adhesion to the
Epithelial cell
(apical−basal polarity)
Inflammatory cell
(infiltration from blood
Senescent fibroblast (growth arrest,
resistant to apoptotic signals)
EMT
ECM is mediated by ECM receptors, such as
integrins, discoidin domain receptors and
and lymph vessels) Fibrin blood clot
Fibroblast (secreting ECM Growth factors
precursors and reorganizing MMP
Myofibroblast
the ECM) Non-enzymatic crosslinking (differentiated fibroblast)
Col I Fibronectin Elastin Degenerated elastin network ↑ Fibronectin ↑ Col types I, III ↑ Fibronectin ↑ Col types I, III and IV ↑ Fibronectin ↑ Elastin
mediates cytoskeletal coupling to the ECM and
is involved in cell migration through the ECM
PGs (examples)
↓ Tensile strength
G
G G
Unbound TGFβ, VGEF,
recruits inflammatory cells G
G
CH
TGF-β and VEGF
promote vessel
growth and inflammation
molecular components are subjected to a myriad
of post-translational modifications. Through
PAI G ↑ TGF-β, PDGF, bFGF, G
G GFs: EGF, TGF-β, bFGF G ↑ Stiffness VEGF ↑ TGF-β, VEGF, PDGF,
S
ROS ROS G EGF, bFGF, HGF
CH G G
G
G
G CH PAI G ↓ Mechanical stability,
G
500 Pa
Increased stiffness
3000 Pa
and also mediates protection by a buffering
Extrinsic and intrinsic forces
action that maintains extracellular homeostasis
Tensional
homeostasis
ECM resistance Reciprocal ECM resistance
Migrating and
dividing cells
Reciprocal ECM resistance
Stiff crosslinked
and water retention. In addition, the ECM
directs essential morphological organization
PG-modified ECM-contracting
myofibroblast collagen fibers
collagen and
elastin fibers
Stiff crosslinked
3 Natural and synthetic engineered ECMs regulate gene transcription. The biochemical
and biomechanical, protective and
Natural Modified or synthetic
Soft rBM gel (e.g. Matrigel™) (Kleinman et al., Col I (Friess, 1998) Functionalized HA (Serban and Prestwich, 2008) PEG hydrogels
1986; Kleinman and Martin, 2005) (Lutolf and Hubbell, 2005) Self-assembling peptides (Hauser and Zhang, 2010)
Thrombin mg/ml
(See accompanying article for full citations.) renal medulla), as well as from one
Abbreviations: bFGF, basic fibroblast growth factor; BM, basement membrane; CH, chemokines;
physiological state to another (normal versus
cancerous). In this Cell Science at a Glance
Col, collagen; EGF, endothelial growth factor; HGH, human growth hormone; HA, hyaluronic acid;
MMP, matrix metalloproteinase; LDV, Leu-Asp-Val; PAI, plasminogen activator inhibitor; PDGF,
platelet-derived growth factor; PEG, polyethyleneglycol; rBM, reconstituted basement membrane; RGD,
Arg-Gly-Asp; ROS, reactive oxygen species; SIS, small intestinal submucosa; SRLPs, small leucine-
rich proteoglycans; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor; © Journal of Cell Science 2010 (123, pp. 4195–4200)
YIGSR,
functionally competent normal tissue can also arrested and resistant to apoptotic cues, which is degradation products and cytokines, monocytes
easily resist compressive stresses because of the indicative of senescence (Campisi and d’Adda rapidly differentiate into macrophages (Clark,
binding of the hydrated glycosaminoglycan di Fagagna, 2007). Indeed, senescent fibroblasts 2001). These activated macrophages, in turn,
(GAG) network to the fibrous ECM molecules typically express elevated levels of FN, MMPs, secrete and release multiple GFs, MMPs
(Scott, 2003). Thus, the tissue ECM is a highly GFs, interleukins and cytokines, as well as high and cytokines that promote angiogenesis and
dynamic entity that continuously undergoes levels of the plasminogen activator inhibitor stimulate fibroblast migration and proliferation
regulated remodeling, whose precise (PAI) (Coppe et al., 2010) and mitochondrial- (Schultz and Wysocki, 2009). Thereafter,
orchestration is crucial to the maintenance of related reactive oxygen species (ROS) recruited fibroblasts begin to synthesize and
normal function (Egeblad et al., 2010; Kass et (Untergasser et al., 2005) and, as a result, are deposit large quantities of ECM proteins,
al., 2007). Tissue homeostasis is mediated by the frequently in a state of chronic inflammation. including collagen type I and III, FN and
coordinated secretion of fibroblast metallopro- Indeed, the combination of chronic hyaluronic acid. The elevated mechanical stress
teinases (MMPs) (Mott and Werb, 2004); this is inflammation and elevated MMPs, PAI and associated with this profound ECM deposition
counterbalanced by tissue inhibitors of metallo- ROS destroy the integrity of the elastin network can induce the transdifferentiation of fibroblasts
proteinases (TIMPs) (Cruz-Munoz and Khokha, and modify the collagen fiber network, whereas and other tissue-resident cells – i.e. epithelial-to-
2008) and the controlled activity of other reduced levels of tissue-associated GAGs mesenchymal transition (EMT) of epithelial
enzymes, such as LOX, and also transglutami- compromise the integrity of the BM (Callaghan cells – or of circulating bone marrow-derived
nases that crosslink and, consequently, stiffen and Wilhelm, 2008; Calleja-Agius et al., 2007; mesenchymal stem cells into myofibroblasts
the ECM (Lucero and Kagan, 2006). A plethora Nomura, 2006). Nevertheless, and somewhat (Schultz and Wysocki, 2009; Velnar et al.,
of GFs that are bound to the ECM direct these paradoxically, in an aging tissue, collagen fibers 2009). Myofibroblasts, which have a high
processes (Friedl, 2010; Hynes, 2009; Macri et are frequently – inappropriately – crosslinked capacity to synthesize ECM components and are
al., 2007; Murakami et al., 2008; Oehrl and through glycation, by byproducts of lipid highly contractile, can promote the formation of
Panayotou, 2008). These ECM-bound GFs oxidation and through exposure to UV light large, rigid collagen bundles that, if crosslinked
differentially modulate cell growth and (Robins, 2007). The combination of elevated and by LOX enzymes, mechanically strengthen and
migration and, when released, comprise part of a inappropriate collagen crosslinking contributes stiffen the tissue (Szauter et al., 2005). This
tightly controlled feedback circuit that is to tissue stiffening so that an aged tissue is wounded ‘stiffened’ microenvironment disrupts
essential for normal tissue homeostasis (Hynes, mechanically weaker and less elastic but also the BM that surrounds the epithelium and
2009). more rigid than a young tissue (Calleja-Agius compromises tissue integrity with loss of
et al., 2007; Robins, 2007). This aberrant apical–basal polarity and destabilized cell–cell
Stiffening up – the ECM and tissue mechanical state can severely compromise ECM adhesions. The remodeled ECM also promotes
aging organization, and modify epithelial organization the directional migration of cells within the
As a tissue ages the levels of junctional proteins and function, potentially promoting age-related tissue towards the wound site (Schafer and
such as cadherin, catenin or occludin decrease diseases such as cancer (Coppe et al., 2010; Werner, 2008). In some instances, the release of
and this loss can compromise junctional Freund et al., 2010; Sprenger et al., 2008). transforming growth factor (TGF-) by
integrity as revealed by the appearance of gaps tension and MMPs induces EMT of the resident
between the epithelial cells (Akintola et al., Tensional homeostasis and fibrosis epithelium (Schultz and Wysocki, 2009; Wipff
2008; Bolognia, 1995). Old tissue is also Acute injury activates the fibrogenic machinery et al., 2007; Xu et al., 2009). In a healthy tissue,
characterized by a thinning of the BM, probably and induces wound healing. One of the first once the wound has been repopulated, strict
4198 Journal of Cell Science 123 (24)
feedback mechanisms are initiated that ensure ECM-embedded GFs (Bosman and epithelial or endothelial behavior and to
restoration of tissue homeostasis and resolution Stamenkovic, 2003; Kessenbrock et al., 2010). distinguish between the ‘normal’ and
of fibrosis (Schultz and Wysocki, 2009; Velnar The release of GFs, including vascular ‘malignant’ behavior of some tissues, has a
et al., 2009). Under extreme conditions, such as endothelial growth factor (VEGF), enhances complex and rudimentarily defined
repeated injury or when normal feedback vascular permeability and promotes new vessel composition, and fails to reconstruct the
mechanisms are compromised, continuous growth, which generates interstitial tissue physical state of the native interstitial ECM.
ECM synthesis, deposition and remodeling pressure. Thus, an amplifying circuitry between Fibrin has also been used as natural
ensue and myofibroblasts remain, in which tumor-associated ECM stiffening, an ensuing biodegradable scaffold with reasonable success
TIMP production prevails over MMP synthesis. reciprocal ECM resistance that is induced by in vascular tissue engineering, but lacks the
These aberrant conditions promote chronic resident tumor cells, and myoepithelial and cell- mechanical strength and durability of native
vascular remodeling and enhanced ECM generated contractility act as a vicious, positive- interstitial ECM (Blomback and Bark, 2004;
crosslinking that eventually leads to aberrant feedback loop to potentiate tumor growth Shaikh et al., 2008). By contrast, type I collagen
fibrosis and an inability of the tissue to heal and survival. This induces angiogenesis and is reasonably useful and can be combined with
properly. This aberrant wound healing scenario invasion and, eventually, fosters metastasis rBM, purified laminin or FN to reconstitute
is characterized by the altered mechanical (Butcher et al., 2009; Erler and Weaver, 2009; some of the biological aspects of normal and
stability and reduced elasticity that is typical of Paszek and Weaver, 2004; Paszek et al., 2005). diseased interstitial ECM (Friess, 1998;
scarred tissue (Kisseleva and Brenner, 2008). In Gudjonsson et al., 2002). Moreover, collagen
extreme cases, a chronic wound can also Where do we go from here? type I readily assembles into a mechanically
promote a tumor phenotype (De Wever et al., Challenges encountered with natural tense network of fibrils that can be oriented,
2008). and synthetic ECMs functionally modified, and enzymatically or
Considering the importance of the ECM to so chemically crosslinked and stiffened. Thus
Tumors – a tough situation many fundamental cellular processes, a myriad collagen I gels are useful substrates to assess
Cancer is the loss of tissue organization and of tissue-culture models have been developed to the role of collagen and FN stiffness, and
aberrant behavior of the cellular components. study the interplay between its biochemical and organization on the pathogenesis of tumor
Journal of Cell Science
Cell transformation results from genetic biophysical properties, and to understand the progression and invasion (Levental et al., 2009;
mutations and epigenetic alterations. Yet, molecular origins of cellular behaviors Provenzano et al., 2009). Nevertheless, collagen
tumors have also been likened to wounds that regulated by ECM ligation. With respect to gels are quite heterogeneous, and modifying
fail to heal (Schafer and Werner, 2008). Thus, assessing the fundamental nature of cell their architecture changes their organization,
the tumor stroma exhibits some of the character- adhesion and its effects on cell behavior, the pore size and ligand concentration, thereby
istics found in an unresolved wound (Bissell and majority of cancer researchers have relied on complicating the interpretation of data
Radisky, 2001). For example, tumors are char- coating tissue culture dishes (whether plastic or generated from experiments conducted by using
acteristically stiffer than the surrounding normal glass) with purified preparations or mixtures of this natural scaffold (Johnson et al., 2007). To
tissue. The stiffening of tumors is induced by ECM proteins in order to obtain 2D monolayers overcome this issue, tissue engineers and
ECM deposition and remodeling by resident (Kuschel et al., 2006). To address the issue of biomaterial specialists have generated denuded
fibroblasts, and by increased contractility of the ECM rigidity, functionalized polyacrylamide ECM scaffold from various tissues (Macchiarini
transformed epithelium (Butcher et al., 2009; (PA) gels crosslinked with reconstituted et al., 2008). These scaffolds, combined with
Levental et al., 2009). Moreover, chemokines basement membrane (rBM) – generated from colonies of seeded stem cells, can reconstitute
and GFs (De Wever et al., 2008) induce Engelbreth-Holm-Swarm mouse carcinoma normal tissues with reasonable fidelity (Lutolf et
inflammation and modify the repertoire of (commercially available as Matrigel™), al., 2009). ECMs have also been isolated and
infiltrating T lymphocytes (Tan and Coussens, collagen type I, FN or ECM peptides – has extracted from various tissues, such as small
2007). Tissue inflammation potentiates stromal become the standard approach (Johnson et al., intestine, skin (from cadavers), pancreas and
fibroblast activation and induces their trans- 2007; Pelham and Wang, 1997). Yet, none of breast (Rosso et al., 2005), and these ECMs have
differentiation into myofibroblasts, thus these strategies faithfully recapitulates the been used to engineer skin grafts (Badylak,
exacerbating and promoting tissue desmoplasia behavior of cells within tissues, which demand 2007), enhance wound healing and to study
(De Wever et al., 2008; Desmouliere et al., not only a 3D format, but an ECM that can be tumor progression. One such example is given
2004). Myofibroblasts deposit copious readily remodeled. To address the aspect of 3D by porcine-derived small intestinal submucosa
quantities of ECM proteins, secrete GFs and and ECM remodeling, researchers have used (SIS), which has proven clinical success for
exert strong contraction forces on the ECM (De natural ECM and reconstituted ECM gels to treating patients with hernias (Franklin et al.,
Wever et al., 2008; Desmouliere et al., 2004). As recapitulate specific aspects of tissue-specific 2002) (reviewed in Badylak, 2007). Although
a consequence, newly deposited and remodeled differentiation and architecture (see poster, these purified ECMs certainly have useful
collagen and elastin fibers are reoriented and, panel 3). For instance, the rBM, which mimics applications, their use is limited in scope owing
thereafter, crosslinked by LOX and transglutam- some of the biochemical and biophysical to the need for well-defined microenvironments
inase, thus generating larger, more-rigid fibrils properties of endogenous epithelial basement in tissue regeneration and stem cell transplanta-
that further stiffen the tissue ECM (Butcher et membranes, has been used frequently in 3D tion in which animal byproducts and
al., 2009; Erler and Weaver, 2009; Levental organotypic culture assays, for xenograft contaminants are limited. Moreover, to
et al., 2009; Lucero and Kagan, 2006; Payne et manipulations or tissue engineering, and to understand the molecular and biophysical
al., 2007; Rodriguez et al., 2008). MMPs, which study tissue-specific morphogenesis (e.g. mechanisms by which the ECM elicits diverse
are secreted and activated by tumor cells and branching, acini formation) and differentiation effects on cellular differentiation and
by myofibroblasts (De Wever et al., 2008; (Kleinman and Martin, 2005; Kleinman et al., morphogenesis it is crucial to use chemically
Kessenbrock et al., 2010), also remodel the BM 1986). Unfortunately, BM preparations such as and physically defined, modular ECMs that can
surrounding the tumor and release and activate Matrigel™, although useful for studying normal be reliably reproduced. In this respect, synthetic
Journal of Cell Science 123 (24) 4199
that recapitulate the collagen triple helix, and scaffold material. Biomaterials 28, 3587-3593. signalling at a glance. J. Cell Sci. 122, 159-163.
readily support stem cell growth and viability, Barsky, S. H. and Karlin, N. J. (2005). Myoepithelial Harvey, S. J. and Miner, J. H. (2008). Revisiting the
cells: autocrine and paracrine suppressors of breast cancer glomerular charge barrier in the molecular era. Curr. Opin.
and direct multicellular morphogenesis progression. J. Mammary Gland Biol. Neoplasia 10, 249- Nephrol. Hypertens. 17, 393-398.
(Hauser and Zhang, 2010; Sieminski et al., 260. Hauser, C. A. and Zhang, S. (2010). Designer self-
assembling peptide nanofiber biological materials. Chem.
2008; Smith and Ma, 2004; Ulijn and Bissell, M. J. and Radisky, D. (2001). Putting tumours in
Soc. Rev. 39, 2780-2790.
context. Nat. Rev. Cancer 1, 46-54.
Smith, 2008). These peptides-amphiphiles are Blombäck, B. and Bark, N. (2004). Fibrinopeptides and Humphries, J. D., Byron, A. and Humphries, M. J.
amenable to modification by covalent binding of fibrin gel structure. Biophys. Chem. 112, 147-151. (2006). Integrin ligands at a glance. J. Cell Sci. 119, 3901-
3903.
native proteins and MMP-degradable ECM Bolognia, J. L. (1995). Aging skin. Am. J. Med. 98, 99S-
Hynes, R. O. (2009). The extracellular matrix: not just
103S.
peptides. Alternatively, poly(lactic-co-glycolic Bosman, F. T. and Stamenkovic, I. (2003). Functional pretty fibrils. Science 326, 1216-1219.
acid) (PLGA), a copolymer of glycolic acid and structure and composition of the extracellular matrix. J. Iozzo, R. V. and Murdoch, A. D. (1996). Proteoglycans of
Pathol. 200, 423-428. the extracellular environment: clues from the gene and
lactic acid (McCullen et al., 2009) that is protein side offer novel perspectives in molecular diversity
Butcher, D. T., Alliston, T. and Weaver, V. M. (2009). A
inherently biodegradable as it is hydrolyzed into tense situation: forcing tumour progression. Nat. Rev. and function. FASEB J. 10, 598-614.
lactic acid and glycolic acid, has been developed Cancer 9, 108-122. Iozzo, R. V., Zoeller, J. J. and Nystrom, A. (2009).
Callaghan, T. M. and Wilhelm, K. P. (2008). A review of Basement membrane proteoglycans: modulators Par
and can be readily conjugated to various ECM Excellence of cancer growth and angiogenesis. Mol. Cells
ageing and an examination of clinical methods in the
ligands and peptides, or coated with collagen or assessment of ageing skin. Part 2, Clinical perspectives and 27, 503-513.
chitosan to support cell adhesion, viability and clinical methods in the evaluation of ageing skin. Int. J. Jarvelainen, H., Sainio, A., Koulu, M., Wight, T. N. and
Cosmet. Sci. 30, 323-332. Penttinen, R. (2009). Extracellular matrix molecules:
growth. Indeed, one of the most exciting recent Calleja-Agius, J., Muscat-Baron, Y. and Brincat, M. P. potential targets in pharmacotherapy. Pharmacol. Rev. 61,
advances in the field has been the development (2007). Skin ageing. Menopause Int. 13, 60-64. 198-223.
of modular biocompatible ECMs, which contain Campisi, J. and d’Adda di Fagagna, F. (2007). Cellular Johnson, K. R., Leight, J. L. and Weaver, V. M. (2007).
senescence: when bad things happen to good cells. Nat. Rev. Demystifying the effects of a three-dimensional
ligand-binding cassettes and have tunable Mol. Cell Biol. 8, 729-740. microenvironment in tissue morphogenesis. Methods Cell
stiffness features that permit a precise patterning Clark, R. A. (2001). Fibrin and wound healing. Ann. NY Biol. 83, 547-583.
Acad. Sci. 936, 355-367. Kass, L., Erler, J. T., Dembo, M. and Weaver, V. M.
of cell adhesion in 2D and 3D formats (Serban (2007). Mammary epithelial cell: influence of extracellular
Coppe, J. P., Desprez, P. Y., Krtolica, A. and Campisi, J.
and Prestwich, 2008). The realization that ECM (2010). The senescence-associated secretory phenotype: the matrix composition and organization during development
organization is a crucial aspect of cellular dark side of tumor suppression. Annu. Rev. Pathol. 5, 99- and tumorigenesis. Int. J. Biochem. Cell Biol. 39, 1987-
118. 1994.
behavior has led to the development of new Kessenbrock, K., Plaks, V. and Werb, Z. (2010). Matrix
Cruz-Munoz, W. and Khokha, R. (2008). The role of
methodologies and generated ECMs whose tissue inhibitors of metalloproteinases in tumorigenesis and metalloproteinases: regulators of the tumor
fiber size, orientation, stiffness, ligand-binding metastasis. Crit. Rev. Clin. Lab. Sci. 45, 291-338. microenvironment. Cell 141, 52-67.
De Wever, O., Demetter, P., Mareel, M. and Bracke, M. Kim, D. H., Lipke, E. A., Kim, P., Cheong, R.,
function and remodeling potential can be strictly (2008). Stromal myofibroblasts are drivers of invasive Thompson, S., Delannoy, M., Suh, K. Y., Tung, L. and
controlled and monitored – including cancer growth. Int. J. Cancer 123, 2229-2238. Levchenko, A. (2010). Nanoscale cues regulate the
electrospun silk, and lactic-acid polymer Desmouliere, A., Guyot, C. and Gabbiani, G. (2004). The structure and function of macroscopic cardiac tissue
stroma reaction myofibroblast: a key player in the control constructs. Proc. Natl. Acad. Sci. USA 107, 565-570.
(PLLA) and PLGA scaffolds (Zhang et al., of tumor cell behavior. Int. J. Dev. Biol. 48, 509-517. Kisseleva, T. and Brenner, D. A. (2008). Mechanisms of
2009). Anisotropically nanofabricated Dutta, R. C. and Dutta, A. K. (2009). Cell-interactive 3D- fibrogenesis. Exp. Biol. Med. (Maywood) 233, 109-122.
substrates formed from scalable biocompatible scaffold; advances and applications. Biotechnol. Adv. 27, Kleinman, H. K. and Martin, G. R. (2005). Matrigel:
334-339. basement membrane matrix with biological activity. Semin.
PEG (Kim et al., 2010; Smith et al., 2009) are Egeblad, M., Rasch, M. G. and Weaver, V. M. (2010). Cancer Biol. 15, 378-386.
exciting new developments in the biomaterials Dynamic interplay between the collagen scaffold and tumor Kleinman, H. K., McGarvey, M. L., Hassell, J. R., Star,
field, whose only major impediment to their evolution. Curr. Opin. Cell Biol. 22, 697-706. V. L., Cannon, F. B., Laurie, G. W. and Martin, G. R.
Ehrbar, M., Rizzi, S. C., Schoenmakers, R. G., Miguel, (1986). Basement membrane complexes with biological
biological application appears to be a lack of B. S., Hubbell, J. A., Weber, F. E. and Lutolf, M. P. activity. Biochemistry 25, 312-318.
4200 Journal of Cell Science 123 (24)
Kuschel, C., Steuer, H., Maurer, A. N., Kanzok, B., Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Smith, L. A. and Ma, P. X. (2004). Nano-fibrous scaffolds
Stoop, R. and Angres, B. (2006). Cell adhesion profiling Rozenberg, G. I., Gefen, A., Reinhart-King, C. A., for tissue engineering. Colloids Surf. B Biointerfaces 39,
using extracellular matrix protein microarrays. Margulies, S. S., Dembo, M., Boettiger, D. et al. (2005). 125-131.
Biotechniques 40, 523-531. Tensional homeostasis and the malignant phenotype. Smith, M. L., Gourdon, D., Little, W. C., Kubow, K. E.,
LeBleu, V. S., Macdonald, B. and Kalluri, R. (2007). Cancer Cell 8, 241-254. Eguiluz, R. A., Luna-Morris, S. and Vogel, V. (2007).
Structure and function of basement membranes. Exp. Biol. Payne, S. L., Hendrix, M. J. and Kirschmann, D. A. Force-induced unfolding of fibronectin in the extracellular
Med. (Maywood) 232, 1121-1129. (2007). Paradoxical roles for lysyl oxidases in cancer-a matrix of living cells. PLoS Biol. 5, e268.
Leiss, M., Beckmann, K., Giros, A., Costell, M. and prospect. J. Cell Biochem. 101, 1338-1354. Sprenger, C. C., Plymate, S. R. and Reed, M. J. (2008).
Fassler, R. (2008). The role of integrin binding sites in Pelham, R. J., Jr and Wang, Y. (1997). Cell Extracellular influences on tumour angiogenesis in the aged
fibronectin matrix assembly in vivo. Curr. Opin. Cell Biol. locomotion and focal adhesions are regulated by host. Br. J. Cancer 98, 250-255.
20, 502-507. substrate flexibility. Proc. Natl. Acad. Sci. USA 94, Szauter, K. M., Cao, T., Boyd, C. D. and Csiszar, K.
Leitinger, B. and Hohenester, E. (2007). Mammalian 13661-13665. (2005). Lysyl oxidase in development, aging and
collagen receptors. Matrix Biol. 26, 146-155. Provenzano, P. P., Eliceiri, K. W. and Keely, P. J. (2009). pathologies of the skin. Pathol. Biol. 53, 448-456.
Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, Shining new light on 3D cell motility and the metastatic Tan, T. T. and Coussens, L. M. (2007). Humoral immunity,
M., Erler, J. T., Fong, S. F., Csiszar, K., Giaccia, A., process. Trends Cell. Biol. 19, 638-648. inflammation and cancer. Curr. Opin. Immunol. 19, 209-
Weninger, W. et al. (2009). Matrix crosslinking forces Robins, S. P. (2007). Biochemistry and functional 216.
tumor progression by enhancing integrin signaling. Cell significance of collagen cross-linking. Biochem. Soc. Trans. Trebaul, A., Chan, E. K. and Midwood, K. S. (2007).
139, 891-906. 35, 849-852. Regulation of fibroblast migration by tenascin-C. Biochem.
Lucero, H. A. and Kagan, H. M. (2006). Lysyl oxidase: Rodriguez, C., Rodriguez-Sinovas, A. and Martinez- Soc. Trans. 35, 695-697.
an oxidative enzyme and effector of cell function. Cell. Mol. Gonzalez, J. (2008). Lysyl oxidase as a potential Tsang, K. Y., Cheung, M. C., Chan, D. and Cheah, K. S.
Life Sci. 63, 2304-2316. therapeutic target. Drug News Perspect. 21, 218-224. (2010). The developmental roles of the extracellular matrix:
Lutolf, M. P. and Hubbell, J. A. (2005). Synthetic Ronnov-Jessen, L., Petersen, O. W. and Bissell, M. J. beyond structure to regulation. Cell Tissue Res. 339, 93-110.
biomaterials as instructive extracellular microenvironments (1996). Cellular changes involved in conversion of normal Tucker, R. P. and Chiquet-Ehrismann, R. (2009). The
for morphogenesis in tissue engineering. Nat. Biotechnol. to malignant breast: importance of the stromal reaction. regulation of tenascin expression by tissue
23, 47-55. Physiol. Rev. 76, 69-125. microenvironments. Biochim. Biophys. Acta 1793, 888-892.
Lutolf, M. P., Gilbert, P. M. and Blau, H. M. (2009). Rosso, F., Marino, G., Giordano, A., Barbarisi, M., Ulijn, R. V. and Smith, A. M. (2008). Designing peptide
Designing materials to direct stem-cell fate. Nature 462, Parmeggiani, D. and Barbarisi, A. (2005). Smart based nanomaterials. Chem. Soc. Rev. 37, 664-675.
433-441. materials as scaffolds for tissue engineering. J. Cell Physiol. Untergasser, G., Madersbacher, S. and Berger, P. (2005).
Macchiarini, P., Jungebluth, P., Go, T., Asnaghi, M. A., 203, 465-470. Benign prostatic hyperplasia: age-related tissue-remodeling.
Rees, L. E., Cogan, T. A., Dodson, A., Martorell, J., Rozario, T. and DeSimone, D. W. (2010). The extracellular Exp. Gerontol. 40, 121-128.
Bellini, S., Parnigotto, P. P. et al. (2008). Clinical matrix in development and morphogenesis: a dynamic view. Vakonakis, I. and Campbell, I. D. (2007). Extracellular
transplantation of a tissue-engineered airway. Lancet 372, Dev. Biol. 341, 126-140. matrix: from atomic resolution to ultrastructure. Curr. Opin.
2023-2030. Schaefer, L. and Iozzo, R. V. (2008). Biological functions Cell Biol. 19, 578-583.
Journal of Cell Science
Macri, L., Silverstein, D. and Clark, R. A. (2007). Growth of the small leucine-rich proteoglycans: from genetics to Velnar, T., Bailey, T. and Smrkolj, V. (2009). The wound
factor binding to the pericellular matrix and its importance signal transduction. J. Biol. Chem. 283, 21305-21309. healing process: an overview of the cellular and molecular
in tissue engineering. Adv. Drug Deliv. Rev. 59, 1366-1381. Schaefer, L. and Schaefer, R. M. (2010). Proteoglycans: mechanisms. J. Int. Med. Res. 37, 1528-1542.
Mao, Y. and Schwarzbauer, J. E. (2005). Fibronectin from structural compounds to signaling molecules. Cell Wipff, P. J., Rifkin, D. B., Meister, J. J. and Hinz, B.
fibrillogenesis, a cell-mediated matrix assembly process. Tissue Res. 339, 237-246. (2007). Myofibroblast contraction activates latent TGF-
Matrix Biol. 24, 389-399. Schafer, M. and Werner, S. (2008). Cancer as an beta1 from the extracellular matrix. J. Cell Biol. 179, 1311-
McCullen, S. D., Ramaswamy, S., Clarke, L. I. and overhealing wound: an old hypothesis revisited. Nat. Rev. 1323.
Gorga, R. E. (2009). Nanofibrous composites for tissue Mol. Cell Biol. 9, 628-638. Wise, S. G. and Weiss, A. S. (2009). Tropoelastin. Int. J.
engineering applications. Wiley Interdiscip. Rev. Nanomed. Schmidt, S. and Friedl, P. (2010). Interstitial cell Biochem. Cell Biol. 41, 494-497.
Nanobiotechnol. 1, 369-390. migration: integrin-dependent and alternative adhesion Xian, X., Gopal, S. and Couchman, J. R. (2010).
Morita, H., Yoshimura, A., Inui, K., Ideura, T., mechanisms. Cell Tissue Res. 339, 83-92. Syndecans as receptors and organizers of the extracellular
Watanabe, H., Wang, L., Soininen, R. and Tryggvason, Schultz, G. S. and Wysocki, A. (2009). Interactions matrix. Cell Tissue Res. 339, 31-46.
K. (2005). Heparan sulfate of perlecan is involved in between extracellular matrix and growth factors in wound Xu, J., Lamouille, S. and Derynck, R. (2009). TGF-beta-
glomerular filtration. J. Am. Soc. Nephrol. 16, 1703-1710. healing. Wound Repair Regen. 17, 153-162. induced epithelial to mesenchymal transition. Cell Res. 19,
Mott, J. D. and Werb, Z. (2004). Regulation of matrix Scott, J. E. (2003). Elasticity in extracellular matrix ‘shape 156-172.
biology by matrix metalloproteinases. Curr. Opin. Cell Biol. modules’ of tendon, cartilage, etc. A sliding proteoglycan- Zhang, X., Reagan, M. R. and Kaplan, D. L. (2009).
16, 558-564. filament model. J. Physiol. 553, 335-343. Electrospun silk biomaterial scaffolds for regenerative
Murakami, M., Elfenbein, A. and Simons, M. (2008). Serban, M. A. and Prestwich, G. D. (2008). Modular medicine. Adv. Drug Deliv. Rev. 61, 988-1006.
Non-canonical fibroblast growth factor signalling in extracellular matrices: solutions for the puzzle. Methods 45, Zisch, A. H., Lutolf, M. P. and Hubbell, J. A. (2003).
angiogenesis. Cardiovasc. Res. 78, 223-231. 93-98. Biopolymeric delivery matrices for angiogenic growth
Myllyharju, J. and Kivirikko, K. I. (2004). Collagens, Shaikh, F. M., Callanan, A., Kavanagh, E. G., Burke, P. factors. Cardiovasc. Pathol. 12, 295-310.
modifying enzymes and their mutations in humans, flies and E., Grace, P. A. and McGloughlin, T. M. (2008). Fibrin:
worms. Trends Genet. 20, 33-43. a natural biodegradable scaffold in vascular tissue
Nomura, Y. (2006). Structural change in decorin with skin engineering. Cells Tissues Organs 188, 333-346.
aging. Connect. Tissue Res. 47, 249-255. Sieminski, A. L., Semino, C. E., Gong, H. and
Oehrl, W. and Panayotou, G. (2008). Modulation of Kamm, R. D. (2008). Primary sequence of ionic self-
growth factor action by the extracellular matrix. Connect. assembling peptide gels affects endothelial cell adhesion
Cell Science at a Glance on the Web
Tissue Res. 49, 145-148. and capillary morphogenesis. J. Biomed. Mater. Res. A 87, Electronic copies of the poster insert are
Pankov, R. and Yamada, K. M. (2002). Fibronectin at a 494-504. available in the online version of this article
glance. J. Cell Sci. 115, 3861-3863. Smith, I. O., Liu, X. H., Smith, L. A. and Ma, P. X. at jcs.biologists.org. The JPEG images can
Paszek, M. J. and Weaver, V. M. (2004). The tension (2009). Nanostructured polymer scaffolds for tissue be downloaded for printing or used as
mounts: mechanics meets morphogenesis and malignancy. engineering and regenerative medicine. Wiley Interdiscip. slides.
J. Mammary Gland Biol. Neoplasia 9, 325-342. Rev. Nanomed. Nanobiotechnol. 1, 226-236.