Collagen is the main component of the extracellular matrix (ECM), giving structure to bones, tendons, ligaments, and skin.1 As people age and the skin accumulates damage from the sun, it’s the changes in collagen proteins in the dermis that show up as those pesky wrinkles.2
While collagen supplements are available, most of them don’t contain a bioactive form of the protein. Recently, plant biotechnologist Ralf Reski of the University of Freiburg teamed up with Swiss biotechnology company Mibelle Biochemistry to change that by producing a human collagen polypeptide in a unique model system: moss.3
This Physcomitrella moss plant contains hundreds of copies of the human collagen III gene sequence in its cells, and has been stained red to show collagen production.
Mibelle Biochemistry
Limitations of Animal and Recombinant Collagens
While many collagen supplements promise improvements in visible signs of aging, not all collagens are made equal. The majority of the collagen supplements on the market are either derived from animals like cows or pigs or are recombinant collagens produced in yeast or bacterial systems, and each has major disadvantages.
“If you buy non-recombinant collagen, it's often hydrolyzed just to get rid of potential contaminations with other proteins which might harm you,” Reski explained of animal-derived collagens. By breaking down the collagen into smaller peptides, it is unlikely to have any bioactive effect on the skin or body.
For human collagen produced recombinantly in yeast or bacteria, there is another problem: These systems either produce only small peptides of the human collagen protein or cannot add the necessary hydroxyproline post-translational modifications that keep the larger sections of the protein stable and biologically active. “It makes no sense to have a protein that would degrade rather fast when it’s [used] in cosmetics,” Reski said. Despite these shortcomings, “the recombinant collagen [industry] is 1.5 billion US dollar sales per year,” he added.
Moss Produces Bioactive Collagen Polypeptides
Biotechnologist Ralf Reski of the University of Freiburg has spent his career growing valuable proteins in mosses.
Jürgen Gocke, CIBSS, ReskiLab
Reski knew exactly where to turn when scientists from Mibelle told him they wanted to produce human collagen that would be active in skincare; his career has largely focused on using mosses as factories for the scalable production of valuable proteins. Unlike yeast, bacterial systems, and other plants, mosses have no problem producing the complex post-translational modifications needed for human proteins, and they can be grown in large bioreactors with just sunlight and water.
Reski and his colleagues first codon-optimized a large, hydrophilic segment of the human collagen III gene for production in moss, ensuring that it contained the four key protein domains that are responsible for ECM formation and, therefore, its bioactivity. The addition of a signal sequence instructed the moss to secrete the product into the culture media, making isolation and purification far easier than in other systems.
After inserting hundreds of copies of the gene into the genome of the moss Physcomitrium patens, the team selected the best-performing lines and transferred them to large bioreactors to pump out as much protein as possible. “[This project] showed us that we have to optimize the process for every specific product differently, so we know what we should alter, like temperature, CO2, and light,” Reski said.
Reski and his colleagues inserted a large segment of the human collagen III gene into the moss, with a signal peptide to instruct the plants to secrete the protein into the surrounding media.
ReskiLab, University of Freiburg
Constant measuring allowed them to see when protein production had peaked: “At a certain day, we had a lot of the protein in the medium, so we could isolate it very easily and in high quantities.” The result was a polypeptide of human collagen that is water-soluble, bioactive, stable, and suitable for use in skincare. According to Reski, early data from functional studies are promising, with reductions in wrinkle depth when tested on human volunteers. “At the molecular level, they have skin cells [in a petri dish], and [Mibelle scientists] put the extract on them and see two relevant genes are stimulated by this moss-produced collagen,” he added.
- Babraj JA, et al. Collagen synthesis in human musculoskeletal tissues and skin. Am J Physiol-Endocrinol Metab. 2005;289(5):E864-E869.
- Chung JH, et al. Modulation of skin collagen metabolism in aged and photoaged human skin in vivo. J Invest Dermatol. 2001;117(5):1218-1224.
- Bohlender LL, et al. Secretion-based production of prolyl-hydroxylated human type III collagen in scalable Physcomitrella photobioreactors. Plant Cell Rep. 2026;45(2):45.
