Cells have an extra pair of “skin” on their surface, but for what?

The surface wrinkles are basically skin reserves that protect the cell from dying. "Maintaining a sufficient reservoir of the cell surface that can be immediately deployed in response to any environmental requirements is a matter of cell survival," Maryna Kapustina, lead author and a professor at UNC, told Interesting Engineering (IE).

She further explained that if a cell doesn’t have the extra cell surface, the cell integrity can be easily compromised by external forces. This will eventually delay cell shape transformation and motility.

Blebs and bumps assist cell movement

In general, there are two main approaches that cells employ to move; ameboid locomotion and mesenchymal locomotion. The UNC team claims that both these methods involve the use of the extra skin, also called cell surface excess (CSE). 

The researchers performed an interesting experiment to study cell surface protrusions. They studied the movement of cigar-shaped cells embedded in a 3D collagen matrix under an electron microscope. Moreover, to track the changes on their surfaces, they provided the cells with fluorescent tags and also recorded time-lapse videos using fluorescence microscopy.

At the beginning of the experiment, the researchers noticed that the surfaces of the cells were round in shape and looked rough because of the presence of bumps, microvilli, blebs, and various other kinds of wrinkles. However, after some time when the cells started to move, the wrinkles unfolded revealing the extra skin they were hiding all this time.

The extra skin enabled the cells to move and expand without overstretching their membranes. Plus, during the movement, the cell surface also turned smooth, especially in areas that were close to the unfolded CSE. 

Interestingly, the slow (mesenchyma locomotion) and fast (ameboid locomotion) morphological changes that a cell goes through during these movements demand CSE activity for different time durations. For instance, since mesenchymal locomotion is time taking, it is achieved through large protrusions that develop slowly and last longer.

However, “during ameboid locomotion—which allows for much faster movement—cells don’t rely on adhesions but are instead propelled by the rapid movements of smaller “blebby” protrusions,” the researchers note.

What’s inside the extra skin? 

The study authors suggest that cell surface protrusions are made up of microtubules and actin proteins. They are not sure but it is possible microtubules offer mechanical support and stability to the CSE. Actin on the other side might be deciding the spot on the cell surface where a stable wrinkle or a bleb will eventually develop.

They also assume that a wrinkle can arise from any point beneath the cell surface where microtubules trigger actin. “Microtubules might have something to do with activating actin beneath the cell membrane to create an active site for a stable protrusion,” said Kapustina.  

For many years, cell surface protrusions have been considered nothing more than just artifacts hanging out of a cell. This is probably because scientists have been studying them through 2D cell culture. 

However, this time the researchers examined the cells in a 3D matrix and demonstrated that wrinkles or CSE actually facilitate cell movement as well as ensure cell membrane integrity. This knowledge may lead to novel therapeutic strategies for treating diseases, especially for inhibiting amoeboid cell migration when metastatic cancer cells invade other tissue.

Moreover, the research work is also important for bioengineers who work in the area of tissue engineering and regenerative medicine where knowledge of the mechanism of cell responses to physical forces is a key factor in tissue design.

The study is published in the Biophysical Journal.

Study Abstract:

To facilitate rapid changes in morphology without endangering cell integrity, each cell possesses a substantial amount of cell surface excess (CSE) that can be promptly deployed to cover cell extensions. CSE can be stored in different types of small surface projections such as filopodia, microvilli, and ridges, with rounded bleb-like projections being the most common and rapidly achieved form of storage. We demonstrate that similar to rounded cells in 2D culture, rounded cells in 3D collagen contain large amounts of CSE and use it to cover developing protrusions. Upon retraction of a protrusion, the CSE this produces is stored over the cell body similar to the CSE produced by cell rounding. We present high-resolution imaging of F-actin and microtubules (MTs) for different cell lines in a 3D environment and demonstrate the correlated changes between CSE and protrusion dynamics. To coordinate CSE storage and release with protrusion formation and motility, we expect cells to have specific mechanisms for regulating CSE, and we hypothesize that MTs play a substantial role in this mechanism by reducing cell surface dynamics and stabilizing CSE. We also suggest that different effects of MT depolymerization on cell motility, such as inhibiting mesenchymal motility and enhancing ameboid, can be explained by this role of MTs in CSE regulation.