How cells sense extracellular matrix stiffness: a material's perspective.

The mechanical properties of the extracellular matrix (ECM) in which cells reside have emerged as an important regulator of cell fate. While materials based on natural ECM have been used to implicate the role of substrate stiffness for cell fate decisions, it is difficult in these matrices to isolate mechanics from other structural parameters. In contrast, fully synthetic hydrogels offer independent control over physical and adhesive properties. New synthetic materials that also recreate the fibrous structural hierarchy of natural matrices are now being designed to study substrate mechanics in more complex ECMs. This perspective examines the ways in which new materials are being used to advance our understanding of how ECM stiffness impacts cell function.

[1]  P. Janmey,et al.  Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[2]  C. Wilkinson,et al.  The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder. , 2007, Nature materials.

[3]  J. Fallas,et al.  Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel. , 2011, Nature chemistry.

[4]  Fabrizio Gelain,et al.  Designer Self-Assembling Peptide Nanofiber Scaffolds for Adult Mouse Neural Stem Cell 3-Dimensional Cultures , 2006, PloS one.

[5]  Jason A Burdick,et al.  Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. , 2002, Biomaterials.

[6]  Ravi A. Desai,et al.  Mechanical regulation of cell function with geometrically modulated elastomeric substrates , 2010, Nature Methods.

[7]  David J. Mooney,et al.  Harnessing Traction-Mediated Manipulation of the Cell-Matrix Interface to Control Stem Cell Fate , 2010, Nature materials.

[8]  J. A. Hubbell,et al.  Cell‐Responsive Synthetic Hydrogels , 2003 .

[9]  Wesley R. Legant,et al.  Bioactive hydrogels made from step-growth derived PEG-peptide macromers. , 2010, Biomaterials.

[10]  Martin A. Schwartz,et al.  Networks and crosstalk: integrin signalling spreads , 2002, Nature Cell Biology.

[11]  M. Mrksich,et al.  The microenvironment of immobilized Arg-Gly-Asp peptides is an important determinant of cell adhesion. , 2001, Biomaterials.

[12]  J. Hubbell,et al.  Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing. , 1998, Journal of biomedical materials research.

[13]  Joachim P Spatz,et al.  Polymeric substrates with tunable elasticity and nanoscopically controlled biomolecule presentation. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[14]  B. Coller,et al.  Immobilized Arg-Gly-Asp (RGD) peptides of varying lengths as structural probes of the platelet glycoprotein IIb/IIIa receptor. , 1992, Blood.

[15]  Cynthia A. Reinhart-King,et al.  Tensional homeostasis and the malignant phenotype. , 2005, Cancer cell.

[16]  J L West,et al.  Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering. , 2001, Biomaterials.

[17]  A. Metters,et al.  Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Jason A. Burdick,et al.  Hyaluronic Acid Hydrogels for Biomedical Applications , 2011, Advanced materials.

[19]  D. G. T. Strange,et al.  Extracellular-matrix tethering regulates stem-cell fate. , 2012, Nature materials.

[20]  Jing Liu,et al.  Soft fibrin gels promote selection and growth of tumourigenic cells , 2012, Nature Materials.

[21]  David J. Pine,et al.  Rapidly recovering hydrogel scaffolds from self-assembling diblock copolypeptide amphiphiles , 2002, Nature.

[22]  Viola Vogel,et al.  Assay to mechanically tune and optically probe fibrillar fibronectin conformations from fully relaxed to breakage. , 2008, Matrix biology : journal of the International Society for Matrix Biology.

[23]  Kristi S. Anseth,et al.  Photodegradable Hydrogels for Dynamic Tuning of Physical and Chemical Properties , 2009, Science.

[24]  Photopolymerized, multilaminated matrix devices with optimized nonuniform initial concentration profiles to control drug release. , 2000, Journal of pharmaceutical sciences.

[25]  D E Ingber,et al.  Fibronectin controls capillary endothelial cell growth by modulating cell shape. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Julia A. Kornfield,et al.  Structure and mechanical properties of artificial protein hydrogels assembled through aggregation of leucine zipper peptide domains. , 2006, Soft matter.

[27]  Cynthia A Reinhart-King,et al.  Tuning three-dimensional collagen matrix stiffness independently of collagen concentration modulates endothelial cell behavior. , 2013, Acta biomaterialia.

[28]  A. Huc,et al.  Evaluation of different chemical methods for cros-linking collagen gel, films and sponges , 1996 .

[29]  Christopher S. Chen,et al.  Mechanotransduction in development: a growing role for contractility , 2009, Nature Reviews Molecular Cell Biology.

[30]  Joachim P Spatz,et al.  Cooperativity in adhesion cluster formation during initial cell adhesion. , 2008, Biophysical journal.

[31]  D. Wirtz,et al.  PEG-based hydrogels with collagen mimetic peptide-mediated and tunable physical cross-links. , 2010, Biomacromolecules.

[32]  Wesley R. Legant,et al.  Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels , 2013, Nature materials.

[33]  R. Tranquillo,et al.  Controlled compaction with ruthenium-catalyzed photochemical cross-linking of fibrin-based engineered connective tissue. , 2009, Biomaterials.

[34]  Y. Wang,et al.  Cell locomotion and focal adhesions are regulated by substrate flexibility. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Christopher S. Chen,et al.  Cells lying on a bed of microneedles: An approach to isolate mechanical force , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Dembo,et al.  Cell movement is guided by the rigidity of the substrate. , 2000, Biophysical journal.

[37]  Donald E Ingber,et al.  Mechanical control of tissue and organ development , 2010, Development.

[38]  Hans Clevers,et al.  Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth. , 2024, Cancer cell.

[39]  Jordi Alcaraz,et al.  Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia , 2008, The EMBO journal.

[40]  P. Janmey,et al.  Tissue Cells Feel and Respond to the Stiffness of Their Substrate , 2005, Science.

[41]  S. Sen,et al.  Matrix Elasticity Directs Stem Cell Lineage Specification , 2006, Cell.

[42]  P. Zandstra,et al.  Functional immobilization of signaling proteins enables control of stem cell fate , 2008, Nature Methods.

[43]  Murat Guvendiren,et al.  Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics , 2012, Nature Communications.

[44]  Jennifer L West,et al.  Cell adhesion peptides alter smooth muscle cell adhesion, proliferation, migration, and matrix protein synthesis on modified surfaces and in polymer scaffolds. , 2002, Journal of biomedical materials research.

[45]  Mikala Egeblad,et al.  Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling , 2009, Cell.

[46]  Vivian H. Fan,et al.  Tethered Epidermal Growth Factor Provides a Survival Advantage to Mesenchymal Stem Cells , 2007, Stem cells.

[47]  M. Shoichet,et al.  Synthesis of enzyme-degradable, peptide-cross-linked dextran hydrogels. , 2007, Bioconjugate chemistry.

[48]  Kristi S Anseth,et al.  In situ elasticity modulation with dynamic substrates to direct cell phenotype. , 2010, Biomaterials.

[49]  S. Stupp,et al.  Tuning supramolecular rigidity of peptide fibers through molecular structure. , 2010, Journal of the American Chemical Society.

[50]  Matthew J. Paszek,et al.  The Tension Mounts: Mechanics Meets Morphogenesis and Malignancy , 2004, Journal of Mammary Gland Biology and Neoplasia.