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Kinetic behaviour of the cells touching substrate: the interfacial stiffness guides cell spreading.

ABSTRACT: To describe detailed behaviour of cell spreading under the influence of substrate stiffness, A549 cells cultured on the surfaces of polydimethylsiloxane (PDMS) and polyacrylamide (PAAm) with bulk rigidities ranging from 0.1?kPa to 40?kPa were in situ observed. The spreading behaviour of cells on PAAm presented a positive correlation between spreading speed and substrate stiffness. After computing the deformations of PAAm gels and collagen, the bulk stiffness of PAAm, rather than matrix tethering, determined the cell behaviour. On the other hand, spreading behaviour of the cells was unaffected by varying the bulk stiffness of PDMS. Based on simulation analyses, the elasticity of silica-like layer induced by UV radiation on PDMS surface dominated cell-substrate interaction, rather than the bulk stiffness of the material, indicating that it is the interfacial stiffness that mainly guided the cell spreading. And then the kinetics of cell spreading was for the first time modeled based on absolute rate theory.

SUBMITTER: Li J

PROVIDER: S-EPMC5379211 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Kinetic behaviour of the cells touching substrate: the interfacial stiffness guides cell spreading.

Li Jianjun J Han Dong D Zhao Ya-Pu YP

Scientific reports 20140128

To describe detailed behaviour of cell spreading under the influence of substrate stiffness, A549 cells cultured on the surfaces of polydimethylsiloxane (PDMS) and polyacrylamide (PAAm) with bulk rigidities ranging from 0.1 kPa to 40 kPa were in situ observed. The spreading behaviour of cells on PAAm presented a positive correlation between spreading speed and substrate stiffness. After computing the deformations of PAAm gels and collagen, the bulk stiffness of PAAm, rather than matrix tethering ...[more]

PMID: 24468681

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Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.

Dataset Information

Kinetic behaviour of the cells touching substrate: the interfacial stiffness guides cell spreading.

Publications

Kinetic behaviour of the cells touching substrate: the interfacial stiffness guides cell spreading.

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