Study Finds Collagen Forms Liquid Droplets Inside Living Cells

Collagen, the most abundant protein in the human body, does not take the form of a long, rigid rod inside living cells, as textbook depictions have suggested for decades. Instead, it exists as a liquid-like droplet, according to a new study from the Centre for Genomic Regulation (CRG) in Barcelona, published in the Journal of Cell Biology.

The finding is the first direct observation of how collagen naturally exists inside cells before it is exported to form the fibrous structures that hold tissues together. "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," explains Vivek Malhotra, senior author of the study. 

The liquid state appears to serve a protective function. Once outside the cell, collagen assembles into the rigid fibers that give tissues their strength. That same process happening inside the cell would be damaging. "This is another way by which cells ensure that collagens probably never become fibrous inside the cell," says Malhotra. "Because if it were to become fibrous, it would kill the cell."

The discovery emerged from high-resolution live-cell imaging of human hepatic stellate cells,  liver cells that produce collagen and drive scarring in liver fibrosis. Using this system, first author Soumya Bhattacharyya observed small, bright spherical structures inside the endoplasmic reticulum, the cellular compartment where collagen is built. "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," recalls Bhattacharyya.

The droplets merged, split, and exchanged material with their surroundings,  hallmarks of a condensate, in which proteins become so concentrated they separate from the surrounding cellular environment. The team confirmed the droplets contained properly folded collagen rather than misfolded protein aggregates.

The study also sheds light on TANGO1, a protein the Malhotra lab identified roughly two decades ago as required for collagen export. When TANGO1 was depleted, collagen droplets still formed but were no longer positioned at the ER exit sites, and secretion dropped. The researchers propose that TANGO1 acts as a mooring point rather than a conventional cargo receptor, and that collagen exits through a physical process called wetting, flowing through the exit site like liquid through a nozzle, or rising by capillary action.

If confirmed, the model has implications for fibrosis and cancer. "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," Malhotra says. Disrupting either TANGO1 or the condensate itself could represent new approaches worth exploring.