Scar-free wound healing

Scar-free wound healing

Tue, 18/10/2016


LBMC Publication in Nature Cell Biology

Dorsal view of a Drosophila mutant embryo defective for the Zasp52 gene and marked for the adhesion molecule E-Cadherin (green) and the tubulin (red). Closure is complete, but cell shape is irregular. Scale bar= 10 microns. © Antoine Ducuing.
Two researchers from the Laboratoire de Biologie et Modélisation de la Cellule (LBMC) demonstrated that a structure, called the actin cable mediates scar-free wound healing. Surprisingly they show that the cable does not enhance the dynamics of closure, but rather equilibrates tension forces at the wound edge, thus protecting cellular integrity. These results are published in Nature Cell Biology dated October 17th, 2016
Embryos undergo perfect wound healing, but this property is progressively lost during development. While this spectacular feature is exploited during in utero surgery to repair cleft palate, we do not understand its molecular basis. Still, scar-free wound healing correlates with the presence of an actin cable that surrounds embryonic-but not adult wounds. This cable is made of actin, a prime component of our muscles. Actin generates a tread within each cell that borders the wound, and adhesion molecules bind the tread present in adjacent cells. Thus, the actin cable provides coherence to the tissue.
An attractive hypothesis is that the cable acts as a purse-string that enhances closure dynamics, thus leading to fast and perfect healing. This model is based on a number of studies, including work performed on the Drosophila embryo during dorsal closure, where a naturally-occurring hole is eliminated at the end of embryogenesis. This system provides an elegant setting to visualize closure dynamics in vivo thanks to fluorescent proteins while benefitting from the availability of a number of mutants. Interestingly, some mutant strains do not form the actin cable during dorsal closure, while the rest of the actin cytoskeleton appears intact. These strains thus provide a specific tool to assess the function of the cable and test the purse-string hypothesis.
The first surprise came at the PLATIM facility when the two researchers noticed that the mutants that do not form the cable close. In addition, no delay was observed in these mutants and closure proceeded with wild type dynamics. Thus the cable does not drive closure and does not act as a purse-string. Still, detailed analysis revealed that in the absence of the cable, the cells of the leading edge are stretched, compressed, and do not resume their rectangular shape. Their organization is affected and planar cell polarity is defective. During epidermis differentiation these defects persist, producing a characteristic scar.
These results demonstrate that the cable prevents scarring and suggest that this occurs through a novel mechanism: repair forces act at the tissue level, at a level of magnitude that is far superior to what a cell can sustain. If only a few cells support these tensions, their structure will be altered and their ability to generate a coherent tissue will be compromised. On the other hand, the cable allows the homogenization of the forces across the tissue so that cells remain well coordinated and polarized.
One open question is to verify that these findings can be extended to vertebrate embryos, with the perspective to induce cable formation in adult patients to prevent scar formation after wounding or surgery.

Références :
The actin cable is dispensable in directing dorsal closure dynamics but neutralizes mechanical stress to prevent scarring in the Drosophila embryo. Antoine Ducuing and Stéphane Vincent. Nature Cell Biology. doi:10.1038/ncb3421
Stéphane Vincent and Antoine Ducuing are part of the team Epithelial differentiation and morphogenesis in Drosophila (LBMC) lead by Muriel Grammont.