The transition from a single cell to a complex multicellular organism during development involves a myriad of intricate cellular processes. Among these processes, cell-generated (endogenous) forces at cell-cell contacts propagate across cells and tissues to generate tissue-scale changes. The interplay of these forces during morphogenesis sculpts tissues such as epithelia—originating as flat sheets—into complex 3D organs. Beyond development, these forces also maintain tissue homeostasis, drive tissue repair, and, when disrupted or dysregulated, can drive disease.

Among the diverse array of adhesions found at cell-cell contacts, it is the E-cadherin–mediated adhesions that are essential for transmission of endogenous forces. E-cadherin interacts on the extracellular side with other E-cadherin proteins on neighboring cells, whereas intracellularly, E-cadherin binds b-catenin, which in turn binds α-catenin, to create a link between cell contacts and the actin cytoskeleton. The resultant E-cadherin–b-catenin–α-catenin complex couples to the actin cytoskeleton directly by binding to actin or indirectly through various proteins, including vinculin. The recruitment of vinculin by α-catenin has been shown to occur through a force-dependent mechanism. However, the precise impact of vinculin on endogenous force transmission at cell-cell contacts, particularly in comparison to the role of α-catenin, remains underexplored. A more comprehensive understanding of the forces and the key contributors that govern these cell-cell interactions may help us further understand developmental processes and disease mechanisms.

In a recent study titled  “Vinculin is essential for sustaining normal levels of endogenous forces at cell-cell contracts,” Mezher et al. delve into the intricate mechanics that underly force transmission at E-cadherin adhesions. Their study focuses on elucidating the key mechanical links necessary for sustaining force transmission at E-cadherin–mediated adhesions. To do so, this study uses CRISPR technology to knock out vinculin and α-catenin in epithelial cells that are grown on soft silicon substrates. Using the traction force imbalance method enables the authors to measure endogenous intercellular force at cell-cell contacts (between cell pairs).

Mezher and colleagues first characterize wild-type (WT) and vinculin knockout (KO) cell pairs to assess the specific role of vinculin, revealing that the absence of vinculin significantly impairs cells’ ability to exert normal levels of endogenous tension at cell-cell contacts. WT cell pairs exhibited a tension of 51 ± 24 (mean ± standard deviation) nN, whereas vinculin KO cell pairs experienced a reduction of >50%, down to 23 ± 12 nN. This finding underscores the substantial contribution of vinculin to force transmission. On the other hand, characterization of cells lacking α-catenin—expected to decrease endogenous forces more severely—instead revealed a tension at cell-cell contacts of 39 ± 23 nN. Thus, this reduced tension in epithelial cells lacking α-catenin did not differ significantly from that observed in WT cell pairs.

Although this evidence underlines an important role for vinculin in endogenous force transmission through cell-cell adhesions, it does not preclude that the absence of α-catenin may simply grant vinculin greater access to b-catenin. To rule out this possibility, the authors characterized epithelial cells lacking endogenous α-catenin and expressing α-catenin devoid of the vinculin binding site. Measurements of intercellular force for these cell pairs revealed a tension at cell-cell contacts of 36 ± 20 nN, not significantly lower than for WT cell pairs. Notably, double KO cells lacking both α-catenin and vinculin exhibited cell-cell tension comparable to cells lacking only vinculin. These findings highlight that it is vinculin, and not α-catenin, that is essential in transmitting normal levels of endogenous forces at cell-cell contacts.

The authors next investigated the role of vinculin under external mechanical stress by subjecting both WT and vinculin KO cells to large external stretching. This final experiment enabled the authors to conclude that vinculin, beyond its role in generated endogenous cell-generated forces, also plays an essential role in maintaining the integrity of cell-cell contacts under external mechanical strain.

In essence, Mezher et al.’s study unveils the pivotal contribution of vinculin in transmitting cell-generated forces at cell-cell contacts and preserving contact integrity when cells are exposed to external mechanical strain. This knowledge enables us to gain further insight into cell and tissue mechanics, paving the way toward a more comprehensive understanding of the forces that orchestrate both developmental processes and disease mechanisms.