Journal of Cell Biology: Collagen Exists Inside Cells as Liquid Droplets Rather Than Fibers

Collagen—the body's primary structural protein, which forms the skin, bones, tendons, and organs—exists inside living cells not as rigid fibers, as scientists have believed for more than 60 years, but as liquid-like droplets. This conclusion comes from researchers at the Centre for Genomic Regulation in Barcelona. The study was published in the Journal of Cell Biology.

Collagen accounts for roughly one-third of the body's total protein mass, making it the most abundant protein in humans. Until now, textbooks have described it as a long, rigid molecule that forms strong fibers within the extracellular matrix. However, the new study suggests that this description is only accurate once collagen has left the cell.

Inside the cell, researchers found, collagen behaves very differently. It forms soft, dynamic structures resembling droplets of oil suspended in water. These "liquid condensates" can fuse, divide, and exchange contents with their surroundings—hallmarks of a special class of intracellular structures known as biomolecular condensates.

According to Professor Vivek Malhotra, one of the study's authors, this liquid state may serve a protective function. After leaving the cell, collagen must transform into rigid fibers that create the structural framework of tissues. If this process occurred inside the cell, it could be catastrophic, effectively causing the cell to become internally "ossified" and die.

The research relied on high-resolution live-cell microscopy of human liver cells, which actively produce collagen and play a major role in fibrosis. Scientists tracked procollagen-1, the precursor form of collagen, within the endoplasmic reticulum, the cellular compartment where the protein is synthesized.

The team discovered that procollagen is not packaged into conventional transport vesicles, as previously thought. Such vesicles are too small, measuring only 60–90 nanometers in diameter, while collagen molecules are considerably longer. Instead, the protein assembles into liquid droplets that subsequently move toward cellular exit sites.

The researchers proposed a new hypothesis called “liquid extrusion,” suggesting that collagen leaves the cell not through standard receptor-mediated transport mechanisms but via physical processes resembling the capillary flow of liquids.

A key role in this process is played by the protein TANGO1, which has been studied for nearly two decades. Rather than transporting collagen directly, TANGO1 appears to anchor collagen droplets at specific exit sites within the endoplasmic reticulum. When TANGO1 was removed, the droplets still formed, but collagen secretion dropped dramatically.

The authors note that this new understanding of collagen transport could have important implications for research into fibrosis, wound healing, and cancer. Excessive collagen production, for example, can help tumors build a dense protective barrier that limits the penetration of drugs and immune cells.

If the proposed model is confirmed, it could open new therapeutic avenues, ranging from targeting TANGO1 to disrupting collagen condensates themselves, potentially offering new strategies for treating fibrosis, improving tissue repair, and enhancing cancer therapies.

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