Probing cellular response to topography in three dimensions

Abstract

Biophysical aspects of in vivo tissue microenvironments include microscale mechanical properties, fibrillar alignment, architecture or topography of the extracellular matrix (ECM), and the repertoire of ECM ligands present, all of which provide cues to drive cellular response. Cell-ECM interactions are important regulators of both normal tissue homeostasis and malignancy.Thus, understanding both extracellular cues and the cellular responses they elicit is fundamental to developing therapeutic strategies. Various in vitro platforms for 3D cell culture and tissue engineering have been used to study cellular response to the microenvironment. However, recapitulating the diversity of tissue architectures present in vivo in a controlled manner in threedimensional tissue mimetics is challenging using naturally derived ECM hydrogels. Here, we use a bottom-up approach to build fibrillar architecture into 3D amorphous hydrogels using selfassembly of magnetic colloidal particles functionalized with human ECM proteins. Human ECM proteins associated with organ-specific pathological states were used. We determined that, while the bulk tissue mechanics of hydrogels containing either aligned fibers or randomly distributed colloidal particles were similar, aligned hydrogels exhibited spatial heterogeneities in microscale mechanical properties near aligned fibers. We then used this platform in combination with 2D substrates of defined elastic modulus to decouple the role of topography from microscale tissue mechanics for normal and tumor cells. We determined that topographical cues dominate cellular response for human and normal cells, which responded independently of microscale mechanics and ECM composition in 3D hydrogels. These data suggest that topography alone can drive fundamental cellular responses such as polarization and migration for both normal and transformed cells.

Prognostic significance of abnormal matrix collagen remodeling in colorectal cancer based on histologic and bioinformatics analysis

“…Histologically, abnormal remodeling of collagen mainly results in excessive deposition, altered-proportions and changed-arrangement of collagen ( 10 – 12 ). In normal tissues, the collagen fibers of the tumor matrix are curly with an irregular arrangement, while in tumor tissues, especially those with metastasis, the fibers are linearized and dense with a directional arrangement ( 13 ). Tanjore and Kalluri ( 14 ) identified numerous hidden carcinogen-containing domains within collagen that were exposed following collagen remodeling, and which subsequently facilitated tumor metastasis.…”

Cell based strain stiffening of a non-fibrous matrix as organizing principle for morphogenesis

“…In fact, functionally blocking antibodies against integrins that mainly bind to laminin inhibits tube formation, while blocking other integrins has no significant effect. While laminin gels are per se amorphous, it has been shown that cell-sized fibrous structures can be induced by mechanical forces, like the external application of fluid flow (33) or exerting a force via paramagnetic particles in a magnetic field (34). Here, we observe that Matrigel is rearranged into fibres by the exposure to cells.…”

Mechanobiology of Collective Cell Migration in 3D Microenvironments

“…Such "designer biomaterials" may permit improved control over distinct mechanical and biochemical features of the cell microenvironment. For example, aligned ECM cues can be patterned within a homogeneous matrix using magnetic nanoparticle self-assembly, allowing for hydrogels with modulated alignment cues while maintaining comparable elastic moduli and ligand densities 123,124 .…”