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Researchers at Okayama University have recently investigated collagen production in the ‘glass-skinned’ amphibian known as the axolotl, challenging the traditional understanding that fibroblasts are the sole producers of skin collagen. Their research has revealed that keratinocytes, which are the cells forming the outer skin layer, play a crucial role in generating collagen that later integrates into the deeper dermal structure.
The skin comprises two main layers: the epidermis, the outer layer dominated by keratinocytes, and the dermis, which lies beneath and contains blood vessels, nerves, and essential proteins like collagen that contribute to the skin’s resilience and texture. Historically, fibroblasts, the specialized cells located within the dermis, have been thought to be the primary source of collagen production.
In humans, collagen is formed both during fetal development and after birth. The prevailing belief in the scientific community has been that only fibroblasts are involved in this process, leading to a widespread acceptance of the idea that “Collagen production in human skin is exclusive to fibroblasts.”
A study published in the journal Nature Communications on February 24, 2025, from researchers at Okayama University significantly challenges this perspective. By focusing on the transparent skin of axolotls, which are frequently used in dermatological research, the scientists uncovered an alternative mechanism for collagen formation in the dermis.
Utilizing advanced fluorescence microscopy, the team tracked collagen development across various growth stages of axolotls measured at 5 cm, 8 cm, 10 cm, and 12 cm in length. They noted that at 5 cm, the axolotl’s skin consisted of an epidermis and a thin collagen layer within the dermis that was devoid of fibroblasts, which they designated the stratum coniunctum. As growth progressed, the collagen layer thickened, with fibroblasts entering the layer only later — ultimately leading to the formation of three distinct dermal layers: the stratum baladachinum, the stratum spongiosum, and the stratum compactum. Each layer exhibited a unique collagen structure that did not resemble that of the original stratum coniunctum.
Curious about the source of collagen prior to fibroblast formation, the researchers employed a novel collagen labeling technique to analyze newly synthesized collagen fibers. The results were telling: significant fluorescent signals indicated that keratinocytes were the actual source of collagen fibers, not fibroblasts. According to Ayaka Ohashi, a Ph.D. student involved in the research, “This study challenges the existing paradigm; we have established that keratinocytes are indeed the primary contributors to collagen production in the dermis.”
Further analysis revealed that keratinocytes produce collagen in a structured, grid-like pattern on their undersurface. Subsequently, fibroblasts with finger-like projections migrate into this collagen layer, refining and enhancing its structure. To validate that these findings were not exclusive to axolotls, researchers investigated other vertebrate models, such as zebrafish, chick embryos, and mouse embryos, confirming that keratinocyte-driven collagen production appears to be an evolutionarily conserved process.
Gaining insights into how collagen is synthesized before birth could prove vital for combating skin aging and formulating new therapies for collagen-related disorders. Professor Akira Satoh from Okayama University noted, “Axolotls maintain their skin’s texture and appearance remarkably well, resembling a state of prolonged youth. The prolonged collagen production by keratinocytes may be the key. Unlike humans, who cease collagen production by keratinocytes following birth, understanding the mechanisms that facilitate this in axolotls might help us achieve similar longevity in skin health.”
This revelation fundamentally alters our comprehension of skin biology and holds the potential for significant advancements in regenerative medicine, wound healing, and skin care formulations. While current skincare efforts primarily aim at regulating fibroblast activity, future strategies may shift to enhancing keratinocyte-driven collagen production.
By overturning a belief that has persisted for decades, this research marks the dawn of a new chapter in skincare science, with the promise of fostering youthful, resilient skin throughout our lives.
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