title: Biphasic response of cell invasion to matrix stiffness in three-dimensional biopolymer networks.
abstract: When cells come in contact with an adhesive matrix, they begin to spread and migrate with a speed that depends on the stiffness of the extracellular matrix. On a flat surface, migration speed decreases with matrix stiffness mainly due to an increased stability of focal adhesions. In a three-dimensional (3-D) environment, cell migration is thought to be additionally impaired by the steric hindrance imposed by the surrounding matrix. For porous 3-D biopolymer networks such as collagen gels, however, the effect of matrix stiffness on cell migration is difficult to separate from effects of matrix pore size and adhesive ligand density, and is therefore unknown. Here we used glutaraldehyde as a crosslinker to increase the stiffness of self-assembled collagen biopolymer networks independently of collagen concentration or pore size. Breast carcinoma cells were seeded onto the surface of 3-D collagen gels, and the invasion depth was measured after 3 days of culture. Cell invasion in gels with pore sizes >5 μm increased with higher gel stiffness, whereas invasion in gels with smaller pores decreased with higher gel stiffness. These data show that 3-D cell invasion is enhanced by higher matrix stiffness, opposite to cell behavior in two dimensions, as long as the pore size does not fall below a critical value where it causes excessive steric hindrance. These findings may be important for optimizing the recellularization of soft tissue implants or for the design of 3-D invasion models in cancer research.
authors.affiliation: Department of Physics, University of Erlangen-Nuremberg, Germany. Electronic address: nlang@biomed.uni-erlangen.de.
authors.forename: Nadine R
authors.initials: NR
authors.lastname: Lang
authors.affiliation: Department of Physics, University of Erlangen-Nuremberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Skodzek
authors.affiliation: Department of Physics, University of Erlangen-Nuremberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hurst
authors.affiliation: Department of Physics, University of Erlangen-Nuremberg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Mainka
authors.affiliation: Department of Physics, University of Erlangen-Nuremberg, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Steinwachs
authors.affiliation: Department of Physics, University of Erlangen-Nuremberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Department of Civil Engineering and Engineering Mechanics, University of Arizona, Tucson, AR, USA.
authors.forename: Katerina E
authors.initials: KE
authors.lastname: Aifantis
authors.affiliation: Department of Physics, University of Erlangen-Nuremberg, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Fabry
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry*; D005109:Extracellular Matrix / Q000737:chemistry*; D005260:Female; D006801:Humans; D015233:Models, Statistical; D009361:Neoplasm Invasiveness
chemical_list: D003094:Collagen
keywords: Cell migration; Crosslinking; Matrix mechanics; Matrix metalloproteinase; Pore size