P53 protein plays a critical role in tissue repair

An artistic depiction of a leader cell that directs the migration of its neighbors (followers) to repair a wound. Author: Ella Marushenko Studio

New research led by[{” attribute=””>University of Bristol has found the protein p53 plays a key role in epithelial migration and tissue repair. The findings could improve our understanding of the processes used by cells to repair tissues, and be used to identify interventions that could accelerate and improve wound repair.

Epithelial tissues are the linings that protect the body’s external skin and internal cavities, and their ability to repair themself is important. It is known that wounded epithelia repair themself thanks to the ability of the remaining cells to start migrating, collectively, to seal the breach. Specialized migratory cells called leader cells arise from damaged epithelia, promoting epithelial migration. However, it’s unclear what molecules and signals in epithelial cells make them become migratory leaders and how some wounded cells develop leader behavior whilst some do not.

The study, funded by CRUK and Wellcome Trust and published in Science on February 11, 2022, found that, when epithelial cells are damaged, the damage activates a molecular program that turns cells into migratory leader cells so that the breach can be repaired quickly. The same molecular program also makes sure that these highly migratory cells are removed when the breach is closed, so that the tissue restores its normal epithelial tissue structure.

Leaders That Are Not Eliminated Compromise Tissue Architecture

Once the collective migration of cells has closed the breach, the damaged leader cells need to be cleared from the tissue. When the leaders (blue nuclei) cannot be eliminated by their neighbours (green nuclei) their permanence in the epithelium compromises its regular architecture. Credit: University of Bristol

Using a simplified model of a wound, epithelial sheets that were scratched in vitro to injure the epithelial monolayer, the researchers identified the molecular signal that makes leader cells emerge.

The study found that, following injury, cells at the border of the epithelial gap elevate p53 and p21, suggesting that the injury triggers the migratory program. Once the breach was repaired, leader cells were eliminated from the population by their healthy epithelial neighbors. The cells damaged by the wound were able to cause wound closure, but are then sacrificed to maintain a functional tissue with normal epithelial morphology.

Frame-by-frame video of a model wound up in a test tube. The cell-leader, who emerges from the population, pushes the collective migration of followers into the gap to close the gap. Once the tissue is restored, the leader cell is surrounded by neighbors and eliminated. Credit: University of Bristol

Eugenia Pidini, professor of cell biology and senior fellow at the Wellcome Trust School of Cellular and Molecular Medicine (CMM) at the University of Bristol and lead senior author of this paper, said: “Our findings improve our understanding of the mechanisms used by cells to repair tissues and can be that accelerate wound healing.

“P53 plays two critical roles in epithelial regeneration. It begins a closure of the leader-led epithelium, and as soon as the epithelium recovers, p53 induces clearance from the leader cells. ”

Dr Julia Pilia, a CMM researcher at the University of Bristol and one of the first authors, added: “Collective migration is important in other areas, such as cancer, when groups of cells move together from the primary tumor to metastasize. It would be important to know if the same proteins that we identified in the wound model work in this situation so that current therapeutic treatments can be changed. ”

The next steps for research will be to check whether the mechanisms that have been found in are working in vitro also apply the epithelium in vivo. If so, the research team would like to test whether they can selectively and safely challenge leaders in vivo, to promote migration and tissue repair. This new knowledge of how leaders work can also be used to develop new therapeutic approaches that can help block the unwanted migration of metastatic cells.

Help: “p53 controls the behavior of leader cells, migration and cleansing during epithelial regeneration” from Kasia Kozyrskaya, Julia Pilia, Medhavi Vishvakarma, Lori Wagstaff, Mai Gashora, Sylvia Cyril, Saad Mohammad, Calai Galla. , February 11, 2022, Science.
DOI: 10.1126 / science.abl8876 P53 protein plays a critical role in tissue repair

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