What happens to skin cells when they are confronted with blood? A team of researchers from Oslo University Hospital, led by Emma Lång and Stig Ove Bøe, performed experiments on blood-deprived cells that were subsequently exposed to blood serum. Remarkably, all the cells started to move and grow in the same direction as soon as the blood serum was added. Assistant Professor Liesbeth Janssen and student Marijke Valk from Eindhoven University of Technology (TU/e) developed a matching simulation model, revealing new insights into the mechanisms of wound healing. The results are published in the journal Nature Communications.

A person encounters approximately 10,000 injuries during a normal lifespan, ranging from small cuts to traumatic injuries and surgery. In most cases, wounds are miraculously repaired, but in some cases, the healing process is defective and leads to chronic wounds. This is commonly associated with ageing and certain pathologies such as diabetes and obesity.

Wound healing without a wound
It is well established that blood plays an important role in wound healing, and various molecular components in the blood are known to trigger tissue repair processes after injury. In the Nature Communications paper, the authors investigate what happens when dormant skin cells are brought into contact with blood when no wound is present. They find that the blood serum induces spontaneous movement (migration) and growth (proliferation) of cells—two processes that are important in wound healing. Furthermore, they demonstrate that the cell divisions are polarized and aligned with the direction of cell migration, a new insight that may potentially be relevant in tissue repair. The study shows that the presence of blood serum is sufficient to activate dormant skin cells into a migratory and proliferative state and that a wound edge—previously believed to trigger cell migration and growth—is not necessarily required.

Making cells talk to each other
The team from Oslo subsequently studied how the movement and growth of cells are affected by the connectivity between cells. Interestingly, they saw that disconnected cells undergo only random individual motion, but that strong cell-cell connectivities lead to much more pronounced collective and coordinated cell migration, spanning distances of micro- and even millimetre length scales.

To understand this phenomenon, Valk and Janssen of TU/e developed a numerical simulation model that mimics the shape and movement of the cells both in the presence and absence of blood. In their model, blood-deprived cells remain in a quiescent state, while the addition of blood activates cells to undergo spontaneous motion. The simulations indicate that enhanced cell-cell connectivity causes cells to align more strongly with their neighbours, ultimately giving rise to the large-scale collective motion observed in experiments.

Healing bruises
It is known that inflammation and increased blood flow to a wound site can be activated without having an open wound, for example by bruising. The scientists involved think their results may be relevant in this field. “One may speculate, based on our data, that cell migration is also activated in these situations”, says Professor Bøe. “We may also speculate that our skin cells are much more active and dynamic than previously thought and that blood-regulated skin dynamics occur in many different situations.”
“The next step now is to understand why the presence of blood triggers the active forces inside the cells, and why the cells divide asymmetrically in the direction of cell migration”, says Janssen.

Excellent graduation
Master student Marijke Valk performed the major part of the Eindhoven research. She graduated recently with a 9.5/10 grade. “That was a nice surprise, but I am even more delighted with this publication in Nature Communications”, says Valk. “I like to simulate results of real experiments to gain more understanding of what is happening and why. If we can reproduce the movements seen in experiments, we can study which physical mechanisms are needed to describe the observed behaviour. ”

The publication:

Coordinated collective migration and asymmetric cell division in confluent human keratinocytes without wounding, Emma Lång, Anna Połeć, Anna Lång, Marijke Valk, Pernille Blicher, Alexander D. Rowe, Kim A. Tønseth, Catherine J. Jackson, Tor P. Utheim, Liesbeth M. C. Janssen, Jens Eriksson, and Stig Ove Bøe, Nature Communications DOI 10.1038/s41467-018-05578-7

Source: press release TU/e