A softer touch to understand how cells function in different environments

It has long been believed that cells grow better on stiff surfaces when grown outside the body. This is like how walking on a firm, stable concrete sidewalk feels easier compared to walking in soft, slippery mud. For this reason, researchers often grow cells, including stem cells, on very stiff plastic or glass surfaces in the lab.

However, the body’s tissues vary in stiffness. For example, bones are very hard, while the brain is soft; yet cells in both environments are able to function effectively. You might assume then that this is because the cells in these different tissues are specialised to function in these environments. If we consider neurons, which are typically found in the soft environment of the brain, we find that they can still be grown on stiff surfaces in the lab. Even more surprising is how skin cells, such as fibroblasts, change their behaviour when grown on stiff surfaces, acting as if they are near a cancerous tumour. This disparity between the stiffness of our tissues and the standard conditions used to culture cells in the lab has confounded research for many years and limits the efficacy of disease modelling.

To tackle this confounding factor of tissue stiffness, we set about to better understand how cells work in soft environments inside the body by developing a new way to grow cells on different mixtures of extracellular proteins, like those found in the brain, bone, liver, or kidney, on both soft and stiff surfaces. When we grew cancer and normal skin cells on these different surfaces, we found that certain protein combinations made the cells behave as though they were on a stiff surface, even when it was actually soft. Thus, it became clear that the right combination of extracellular proteins was key to supporting cell growth on a softer surface, and that these proteins are present in the native tissue environment in precisely defined combinations to support cellular functions.

Next, we looked at how these extracellular proteins are able to help cells survive and grow on soft surfaces. Cells use special "hands" called integrins to grab onto the proteins around them and sense their environment. These integrins have a “lock and key” mechanism to allow them to specifically bind to certain extracellular proteins, such as collagens, to help cells stick to their surroundings. However, they also send signals into the cell to tell it how to behave when they encounter these specific extracellular proteins.

To see how the number of these "hands" affects cell behaviour, we used a computer simulation and found that increasing the number of integrins helped cells survive and spread even in softer environments. If we come back to the analogy of mud and concrete, it makes sense that you can drive easily on concrete, but to drive in mud you need more traction, like a four-wheel drive. Thus, having more integrins on the cell’s surface helps cells to grip and move. But interestingly cells can only do this when particular extracellular matrix proteins are present. It is possible that these specific proteins also allow cells to gain more traction too, like having grit or sand present in mud.

This research helps us understand how the physical properties of tissues affect cell behaviour. It’s important because it could change how we think about diseases and how we design experimental models to test new drugs prior to progressing to clinical trials. Thinking about tissue stiffness is especially relevant for conditions like fibrosis and cancer, where the disease leads to an increase in stiffness, and this supports disease progression. Thus, the extracellular protein mixtures that support cell growth on soft surfaces give us a clue as to how cells in a normal soft tissue are able to function, as well as clarifying the disparity between laboratory culture conditions and that of the more complex human body.