Abstract
Cells sense and respond to the rigidity of their microenvironment by altering their morphology and migration behavior. To examine this response, hydrogels with a range of moduli or mechanical gradients have been developed. Here, we show that edge effects inherent in hydrogels supported on rigid substrates also influence cell behavior. A Matrigel hydrogel was supported on a rigid glass substrate, an interface which computational techniques revealed to yield relative stiffening close to the rigid substrate support. To explore the influence of these gradients in 3D, hydrogels of varying Matrigel content were synthesized and the morphology, spreading, actin organization, and migration of glioblastoma multiforme (GBM) tumor cells were examined at the lowest (<50 µm) and highest (>500 µm) gel positions. GBMs adopted bipolar morphologies, displayed actin stress fiber formation, and evidenced fast, mesenchymal migration close to the substrate, whereas away from the interface, they adopted more rounded or ellipsoid morphologies, displayed poor actin architecture, and evidenced slow migration with some amoeboid characteristics. Mechanical gradients produced via edge effects could be observed with other hydrogels and substrates and permit observation of responses to multiple mechanical environments in a single hydrogel. Thus, hydrogel-support edge effects could be used to explore mechanosensitivity in a single 3D hydrogel system and should be considered in 3D hydrogel cell culture systems.
Highlights
Cell migration is a complex, broad-ranging phenomenon strongly influenced by cues from the external environment such as its chemical nature, topographical architecture, and rigidity [1]
We explored the response of glioblastoma multiforme (GBM) cells, a type of brain cancer previously shown to be sensitive to stiffness in 2D [23] and 3D [24], in this system, characterizing cell spreading and morphology, intracellular actin organization, and migration capacity
We further hypothesized that these inherent mechanical gradients might influence cell behavior in a single, 3D hydrogel construct
Summary
Cell migration is a complex, broad-ranging phenomenon strongly influenced by cues from the external environment such as its chemical nature, topographical architecture, and rigidity [1]. Investigators have begun to incorporate stiffness gradients into hydrogel systems [10,11,12,13,14,15,16,17,18] These gradients have been shown to better mimic in vivo cell response compared to culture in a single modulus mechanical environment [19]. They can induce directed cell migration (referred to as ‘‘durotaxis’’ or ‘‘mechanotaxis’’), in contrast to the random migration that occurs in uniformly rigid microenvironments. There are very few studies in 3D exploring the effects of mechanical gradients on cell behaviors [14,20]
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