Northwestern Medicine investigators have discovered new mechanisms underlying cellular adhesion and repair, findings that could inform the development of new therapeutics that boost cellular repair after tissue injury, according to a recent study published in the Journal of Cell Biology.

Cara J. Gottardi, PhD, associate professor of Medicine in the Division of Pulmonary and Critical Care and of Cell and Developmental Biology, was senior author of the study.

Epithelial cells, the most abundant cells in the body, line internal organs and the outmost layer of the skin. These cells form sheet-like barriers through intercellular adhesive junctions, protein complexes that hold cells together and coordinate intercellular behaviors such as cell division and sheet-repair after tissue injury.

“These structures immobilize cells in some ways but also allow cell-to-cell contacts to be dynamic,” Gottardi said. “Adhesive junctions have to be strong enough for cells to cohere, but flexible enough to let cells round up and duplicate themselves while also attached to cells that are flattening themselves to migrate and restore the epithelial barrier. Such competing cell behaviors occurring in close proximity can lead to mistakes in cell division, leading to polyploid cells with two or more nuclei. These ‘polyploid mistakes’ are not all bad, since polyploid cells appear to have special properties that favor their role in cell migration and barrier repair.”

How these polyploid cells are generated and whether junction proteins might be involved has remained poorly understood, according to Gottardi.

In the current study, Gottardi’s team studied a single protein within these intracellular adhesive junctions, called alpha-catenin, which links cadherins – proteins that help cells stick together – and the cell’s cytoskeleton. When this protein unfolds under cellular forces, it’s able to make stronger cellular interactions and adhesions.

Using cultured mammalian cell lines (Madin Darby Canine Kidney cells), the scientists aimed to determine how these cellular processes would be impacted by mutated alpha-catenin. By inserting mutant proteins into the cells, the scientists discovered that alpha-catenins that are persistently unfolded lead to the failure of cytokinesis: the final stage of cell division in which the cell’s cytoplasm splits and creates two new daughter cells that contain a copy of the original cell’s DNA.

The scientists also identified a protein persistently recruited to unfolded alpha-catenin, which may explain why cytokinesis fails and leads to polyploid cells with two nuclei, according to Gottardi.

“This work implies that forces on cell junctions alone, which lead to persistent opening of a protein, could interfere with cell division,” Gottardi said.

Clinically, Gottardi said the findings could inform new therapeutic strategies that aim to accelerate cell repair after injury by supporting the formation of polyploid cells.

The findings also demonstrate why mutations in alpha-catenin lead to butterfly-shaped pattern dystrophy (BPD), a rare eye disease which causes the buildup of pigmented material in the retina.

“We show that alpha-catenin mutations that lead to BPD are also persistently unfolded and interfere with cell division by this common factor,” Gottardi said. “It appears that alpha-catenin is a junction protein exquisitely sensitive to tension pathways in cells. Our ongoing studies seek to match the various unfolded states of alpha-catenin with distinct cell behaviors.”

Gottardi is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Co-authors include Sun Kim, a student in the Driskill Graduate Program in Life Sciences (DGP) and Jeanne Quinn, a student in the Medical Scientists Training Program (MSTP).

This work was supported by National Institute of Health grants HL163611, GM129312 and F30EY036267.