BARCELONA — A study in the Journal of Cell Biology reports collagen exists inside living cells as liquid-like droplets, contrasting with the belief it is rigid. Researchers at the Centre for Genomic Regulation in Barcelona led the work.

Collagen is a structural protein forming skin, bones, tendons, and organs, accounting for one-third of the human body's total protein mass. Outside cells, it assembles into rigid fibers. The team examined procollagen 1, precursor to type 1 collagen, comprising 90 percent of human body collagen.

ICREA Research Professor Vivek Malhotra said, "Inside a cell, collagens are not rigid molecules as one had assumed. They are in fact very pliable, taking a liquid condensate form much like oil in a drop of water." He added, "This is another way by which cells ensure that collagens probably never become fibrous inside the cell. Because if it were to become fibrous, it would kill the cell."

The study proposes a liquid extrusion hypothesis where collagens move via capillary action rather than vesicles. Purified collagen molecules measure up to 400 nanometers, while typical vesicles range from 60 to 90 nanometers. Researchers used imaging to observe collagen within human hepatic stellate cells, contributing to liver fibrosis.

Imaging by Postdoctoral Researcher Soumya Bhattacharyya in May 2024 revealed intracellular collagen gathers into droplets that merge, separate, and exchange material. Bhattacharyya said, "I had no idea what it would lead to. But when we took the samples, what struck me were these bright spherical structures you can't miss." She added, "We're just beginning to understand condensates inside the endoplasmic reticulum."

Assessment measured chaperone protein BiP levels; droplets contained helper proteins recognizing properly folded collagen, indicating they were not misfolded. Depleting TANGO1 prevented droplets from positioning at exit sites and reduced secretion. Findings indicate TANGO1 acts as a structural anchor at export sites rather than a cargo receptor.

Authors hypothesize collagen exits via wetting, where the liquid droplet adheres to and flows through the exit site. Malhotra asked, "Imagine you have a rubber ball with a nozzle, filled with liquid. You squeeze it, you force the liquid to come out of this little orifice. Is that the mechanism?"

The team plans to visualize the export mechanism and develop a mouse model. Degrading TANGO1 or dissolving the condensate could inform treatments. Malhotra said, "One of the major problems in cancer is that the cells secrete so many collagens and other proteins out into the extra cellular matrix that they hide in a shell made of these components and become chemo- and immuno-refractory, meaning they are not seen by the chemical therapeutics or by the immune system." He added, "People are trying to find ways to break this tissue cement and our study could help inform those strategies."