The cell migration stimulator not only identifies optimal stiffness conditions for motility of a specific type of cell, but also shows how altering the number of active molecular motors and clutches that cause cell movement can modify this environment. This research may help scientists identify how to stop the progression of cancer cells, or how to stimulate stem cells migration to regenerate destroyed or diseased tissues.

The cell migration stimulator utilizes a model of cellular force transmission based on the motor-clutch hypothesis that predicts biphastic stiffness. The movement of cells, similar to the operation of a motor vehicle, uses motors to generate force and a clutch to transfer that force to structures that grip tissue along the path of movement. The model of cellular force transmission predicts the force transmitted by intracellular molecular motors, such as myosin II, through rigid actin filament bundles. The motor-clutch model, however, does not directly predict cellular level features like cell area, shape and migration.

Principal investigator David Odde, professor of biomedical engineering, and colleagues, explained that "the motor-clutch model simulates cell migration in compliant microenvironments while enforcing force and mass balance. It predicts a stiffness optimum that can be shifted by altering the number of active molecular motors and clutches." The new simulator links multiple motor-clutch systems, a capability that the motor-clutch model does not have.

Migration simulation

The research team simulated cell migration at high and low motor and clutch numbers. The simulator predicted a stiffness optimum for the rate of F-actin retrograde flow, a process fundamental to forms of directed cell motility. It also predicted a stiffness optimum for cell traction force, which could be reduced when the numbers of active molecular motors and clutches were altered. A shift to a higher stiffness could be attained when the numbers of motors and clutches were increased.

"Cells don't like their environment too hard or too soft – it needs to be just right or they won't move," Odde explained. "If cells can be tricked into believing that the environment is not good for migration, they won't move. This capability would be of great benefit to stop the spread of cancer cells."

The researchers used the simulator to compare migration patterns of the U251 glioma cells with those of healthy embryonic chick forebrain neurons (ECFN). They performed five different experiments that included six different stiffnesses. The experiments tested a hypothesis that the ECFN cells have a lower optimal stiffness and fewer motors and clutches than the U251 glioma cells. Glioma cells have the ability to migrate long distances within the brain through white matter tracts, infiltrating the cortex and subcortical grey matter structures. This is a primary reason that curative treatment is not successful.

The researchers determined that the greater force transmission for U251 glioma cells suggests that they express at least two orders of magnitude more motors and clutches than the ECFN cells. They concluded that the large difference in stiffness optima between glioma cells and neurons is mainly due to glioma cells expressing roughly 100-fold greater numbers of motors and clutches than neurons.

Drug development

To determine whether drugs used for cancer treatment can impact cell movements, the researchers partially inhibited myosin II motors via blebbistatin. Myocin II is required for cell migration in the brain. They also partially inhibited integrin-mediated adhesions to the collagen-coated substrate via cyclo(RGDfV) competitive binding using the U251 glioma cells. This combined drug treatment impacted motility, decreasing traction strain energy by approximately fourfold.

"Motor-and clutch-inhibited drugs are still in development, and are not available for cancer treatment. We hope that our research from an engineer's perspective using a maths and physics-based approach will hopefully have a medical benefit," concluded Odde.

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