Collagen synthesis: should cosmetics target keratinocytes instead of fibroblasts?

The quest for firm, smooth, and age-resistant skin largely depends on maintaining optimal collagen production. This structural protein, which is abundant in the dermis, ensures skin elasticity and cohesion. Traditionally, dermal fibroblasts are considered the main players in collagen synthesis, and many cosmetic approaches aim to stimulate their activity.

However, recent research suggests that keratinocytes – the dominant cells of the epidermis – play a crucial role in regulating this process. This discovery raises a strategic question: to effectively stimulate collagen synthesis, shouldn't we target keratinocytes rather than fibroblasts themselves?

1. Collagen: An Essential Architecture

Collagen makes up about 70 to 80% of the proteins in the dermis. Its thick fibers form a network that gives skin its mechanical strength and suppleness. With age, sun exposure, pollution, or oxidative stress, collagen production decreases while its breakdown accelerates, leading to wrinkles, sagging, and loss of firmness.

The main goal of anti-aging skincare is therefore twofold: to stimulate new collagen synthesis and to slow down its enzymatic degradation (by matrix metalloproteinases, MMPs).

2. Fibroblasts: The Architects of the Dermis

Fibroblasts are found in the dermis, just beneath the epidermis. They are responsible for producing collagen, elastin, and glycosaminoglycans (including hyaluronic acid). For decades, most cosmetic research and formulations have focused on directly stimulating these cells.

For example:

  • Retinoids (Vitamin A and its derivatives) activate the expression of genes involved in collagen production and inhibit certain MMPs.

  • Biomimetic peptides mimic natural collagen fragments to "alert" fibroblasts and restart production.

  • Vitamin C acts as an essential cofactor for stabilizing collagen's triple helix and improves fibroblast activity.

However, a major challenge remains: most cosmetic ingredients struggle to penetrate deep enough into the dermis. The skin barrier limits their spread, thereby reducing their direct effectiveness on fibroblasts.

3. Keratinocytes: Just Simple Epidermal Building Blocks?

Keratinocytes make up about 90% of the cells in the epidermis. Their most well-known role is forming the protective skin barrier using the keratin and lipids they produce. But these cells are not just passive "building blocks": they constantly communicate with fibroblasts through biochemical signals (growth factors, cytokines, peptides).

Thus, keratinocytes can indirectly influence fibroblast activity and, consequently, collagen synthesis. This "epidermis → dermis" communication pathway is sometimes more accessible for cosmetic products, as ingredients applied to the skin reach keratinocytes first.

4. Epidermis-Dermis Communication Mechanisms

Several mediators released by keratinocytes play a key role in regulating collagen:

  • TGF-β (Transforming Growth Factor-β): one of the most powerful signals for activating fibroblasts and stimulating collagen synthesis. Keratinocytes can secrete TGF-β in response to certain stimuli.

  • Interleukins and cytokines: these modulate inflammation and influence the expression of MMPs, thereby affecting collagen degradation.

  • Growth factors (EGF, KGF, VEGF): these promote cell proliferation and wound healing, processes where collagen production is essential.

Therefore, targeting keratinocytes could trigger a cascade of beneficial events, indirectly but effectively stimulating fibroblasts.

5. Emerging Scientific Evidence

In vitro and ex vivo studies have shown that:

  • Plant extracts applied to keratinocytes increase TGF-β secretion, leading to higher collagen production by neighboring fibroblasts.

  • Certain antioxidant molecules, by protecting keratinocytes from oxidative stress, maintain their ability to positively regulate fibroblast activity.

  • Signal peptides, by interacting with keratinocytes, trigger the release of factors that can amplify extracellular matrix synthesis in the dermis.

These findings suggest that the epidermis is a more realistic and strategic target for anti-aging cosmetics than the deep dermis.

6. Advantages of a Keratinocyte-Focused Strategy

  1. Accessibility: Keratinocytes are directly exposed to ingredients applied to the surface, unlike fibroblasts which are located deeper within the skin.

  2. Cascade Effect: A small stimulus on keratinocytes can trigger an amplified response in the dermis through powerful mediators.

  3. Synergy: Keratinocytes also contribute to antioxidant and immune protection, two factors that indirectly influence collagen preservation.

  4. Innovation: Cosmetics could be revitalized by exploring this little-known communication pathway, opening the door to new and unique active ingredients.

7. Limitations and Precautions

Targeting keratinocytes is not without its challenges:

  • The signals sent by keratinocytes can be ambivalent: some promote collagen synthesis, while others stimulate inflammation and degradation.

  • Overstimulation can disrupt skin balance, leading to undesirable reactions (redness, sensitivities).

  • Clinical evidence is still lacking to confirm that these mechanisms observed in the laboratory translate into visible long-term benefits on human skin.

8. Emerging Cosmetic Approaches

Several avenues are currently being explored:

  • Epidermal-Dermal Peptides: designed to specifically activate keratinocytes and trigger the secretion of TGF-β.

  • Next-Generation Antioxidants: capable of protecting keratinocyte DNA and mitochondria to preserve their regulatory role.

  • Prebiotics and Postbiotics: by modulating the skin microbiome, they influence the health of keratinocytes and their communication with the dermis.

  • Keratinocyte-Derived Exosomes: natural signal carriers, they represent a promising but still experimental avenue.

9. Towards an Integrated Anti-Aging Vision

The question of whether to target fibroblasts or keratinocytes does not necessarily imply an exclusive choice. Skin physiology is complex and relies on constant interactions between its different layers. An optimal strategy could combine:

  • Direct stimulation of fibroblasts with penetrating active ingredients (retinoids, stabilized vitamin C).

  • Indirect regulation via more accessible keratinocytes, which provide biological mediation.

  • Overall protection of the skin environment (antioxidants, sunscreens, anti-pollution).

Conclusion

Long considered the sole players in collagen synthesis, fibroblasts are actually only one part of the equation. Keratinocytes, although located on the surface, have a crucial regulatory role thanks to their ability to communicate with the dermis. Targeting these epidermal cells appears not only more accessible for topical cosmetics but also potentially more effective due to the cascade effect of the mediators they secrete.

Nevertheless, caution is advised: scientific knowledge must be strengthened by robust clinical studies, and the regulation of keratinocyte signals must be finely tuned to avoid undesirable effects.

In the future, cosmetic anti-aging could thus evolve towards a more systemic approach, integrating all cellular communications rather than focusing solely on the traditional fibroblast target. Keratinocytes, long perceived as simple "building blocks" of the epidermis, could well become the true conductors of skin youth.

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