Wounds heal using a cellular ‘tug-of-war’

Researchers at IBEC reveal in a Nature Communications paper some surprising mechanics that drive epithelial gap closure in the absence of underlying layers

In a collaboration with their colleagues at the Mechanobiology Institute in Singapore, IBEC researchers have demonstrated that a kind of ‘tug-of-war’ takes place after our skin or other epithelial layer is damaged, particularly in cases where the tissue is chronicly or deeply injured.

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Image: Forces exerted by the cells surrounding the gap (dotted blue line) extend away at first, then direct towards the gap during contraction of the purse-string cable (red).

Usually, in minor or surface wounds, cells begin crawling forward towards the gap, and contractile cables are formed in the cells surrounding the wound to help pull it closed. This mechanism relies on a layer underneath the crawling cells, the extracellular matrix (ECM), which provides a support for them to adhere to and crawl over.

However, in cases of chronic or severe wounds, the underlying layers could also be damaged, and surrounding cells could also be unable to replace the ECM proteins. The researchers wanted to find out how these types of wounds – known as non-adherent gaps – still close and heal, albeit at a slower rate and with an increased likelihood of infection.

“We found that closure of these types of gaps is driven exclusively by the mechanism known as ‘purse-string contraction’,” explains Xavier Trepat, head of IBEC’s Integrative Cell and Tissue Dynamics group. “Using a combination of cell culture, microfabrication and force measurements, we saw that the cells at the edge of the non-adherent gap are still attached to the ECM. They then spread themselves out as far as possible towards the centre of the gap – but measuring the direction of force revealed that they are actually pushing away from it.”

While this may sound counter-intuitive, it actually stabilises the cells, a bit like a cantilever bridge, where support at either end anchors the extension of the bridge into space until the two sides meet in the middle. Once the cells have spread as far as possible into the gap, the contractile ‘purse-string’ cable forms across the cells, encircling the gap. The force exerted by these cells is reversed and the cells begin to pull each other towards the centre of the gap, continually speeding up the contraction of the protein cable. “As the cells move inwards to close the empty space, more contractile cables can reach out over the gap and connect to the other side,” says Xavier. “These cables can contract rapidly, leading to the formation of a suspended cell sheet over the gap, and complete closure of the wound.”

The ‘tug-of-war’ mechanism identified in this study provides a solid demonstration of how cells exert directional forces to enhance biological processes. This new knowledge of the mechanical properties of skin and internal epithelial cells may lead to advances in wound repair, especially in cases where the ECM is compromised. With chronic wounds, sores and ulcers a common complication in several diseases, particularly those associated with ageing, it is imperative that researchers better understand the mechanisms at play in their repair.

Reference article: Vedula SR, Peyret G, Cheddadi I, Chen T, Brugués A, Hirata H, Lopez-Menendez H, Toyama Y, Neves de Almeida L, Trepat X, Lim CT & Ladoux B. (2015). Mechanics of epithelial closure over non-adherent environments. Nat Commun., 6:6111