The epidermis is one of the most active tissues in terms of regeneration. This renewal capacity experiences a decrease with time, leading to the appearance of ageing signs, such as wrinkles and dullness. The new peptide presented below showed a potential capacity to improve the epidermal regeneration process, with a suggested reprogramming effect of epidermal cells through the modulation of epigenetic mechanisms. When applied on the skin of volunteers, it helped accelerate the renewal time and improved their skin appearance.
Incorporating epigenetics into cosmetics
Epigenetics is a concept based on the interpretation of gene expression and it represents a current trend in the cosmetics field with a strong interest placed on it. As a more clarifying way to understand such concept, genetics and epigenetics could be compared to the processes of writing and reading a book. Genes are known to be identical among the human beings, and these could be related to the written information of a book, which is the same for all of its copies. On the other hand, once this text is read by different readers, the emotions or reactions that it may cause can vary depending on their mood or previous experiences. The same thing could be extrapolated to epigenetics, being this related to the possible interpretations of the information stored in the DNA or genes which, depending on environmental and lifestyle factors, can result in different read-outs.
Epigenetic processes represent molecular mechanisms able to regulate gene expression, activating or silencing it, independently of the genetic sequence of the genes. These mechanisms can vary from DNA methylation, modifications of histones, chromatin conformation and non-coding RNAs, such as the microRNAs (miRNAs). These epigenetic modifications determine how cells behave, playing an important role in certain physiological functions, such as the control of the fate of progenitor cells located in the basal layer of the epidermis.
The role of basal cells in epidermal regeneration
In the basal layer of the epidermis reside the stem and progenitor cells, which have a significant regenerative capacity. Stem cells are unspecialized cells capable of undergoing divisions for long periods of time. They divide to generate progenitor cells, known to have a limited proliferative potential and to eventually undergo differentiation into keratinocytes.
The self-renewal abilities of basal cells are maintained by the transcription factors OCT4, SOX2, and KLF4, which are stem cell markers whose activity is repressed by microRNA-145 (miR-145). Levels of this non-coding RNA are low in basal cells but increase during differentiation, with a concomitant decrease of the stem cell transcription factors. This switch is associated with changes in the characteristic markers present in the cells: basal cells express keratin 14 (K14) and p63 (required for their high regenerative potential), whereas suprabasal keratinocytes produce keratin 10 (K10).
With age, progenitor cells decrease their division rate, reducing the generation of functional keratinocytes. This consequently decreases the efficiency of epidermal renewal and results in a more aged complexion.
The latest launch of REPROAGE peptide, inspired by epigenetics, showed to modulate microRNA-145, aiming to support cellular reprogramming to reactivate the progenitor's pool and help epidermal self-renewal last longer. When tested on volunteers it helped accelerate epidermal regeneration, associated with an improved skin complexion.
Modulation of miR-145 and induction of stem cell factors
Human keratinocytes from adult (HEKa) were used to evaluate the ability of the peptide to modulate the epigenetic factor miR-145 and to boost the stem cell transcription factors.
HEKa were incubated with 0.01 mg/mL REPROAGE peptide for 24 hours, while non-treated cells were used as a control. miR-145 levels were then detected and quantified by means of a hybridization-based assay. Another test was performed by incubating HEKa with 1 or 5 µg/mL REPROAGE peptide or by leaving the cells untreated as a control. Following incubation, the quantification of the stem cell markers SOX2, OCT4 and KLF4 was assessed by RT-PCR.
After the treatment, results showed a 25.4 percent decrease (p<0.001) in the quantity of microRNA-145 and an induction of the three transcription factor, suggesting a cellular reprogramming effect and an improved self-renewal capacity.
Favouring progenitor cells of the epidermis
Reconstructed human epidermis (RHE) were used to verify changes in specific cell markers after the treatment with 0.01 mg/mL REPROAGE peptide or with the medium alone (control). Keratins K14 and K10 and the transcription factor p63 were separately detected in different epidermal models by means of immunohistochemistry. Levels of each protein were quantified through fluorescence microscopy images.
After the active treatment, K10 decreased by 71.3 percent and K14 increased by 325.8 percent in a statistically significant manner (p<0.001), suggesting a stimulation of the basal layer, formed by the progenitor and stem cells.
The second treatment with the peptide resulted in an enhancement of p63 by 110.9 percent (p<0.0001), associated with an activation of the pool of epidermal progenitors for a better regenerative potential.
Renewal and smoothing of the skin surface
The epidermal renewal capacity and the changes in skin roughness were evaluated on two groups of female volunteers of different ages: 20 subjects aged 35-40 years old and 20 aged 50-55 years old. The subjects applied, twice a day, a cream containing 2 percent REPROAGE peptide solution and a placebo cream.
Renewal of the stratum corneum was assessed on the forearm skin of the subjects by means of dihydroxyacetone staining. The stratum corneum turnover time (SCTT) was evaluated under different conditions for the two groups of volunteers, but also for a third younger group (18-25 years old), which was used to obtain a correlation between SCTT and age from the 3 groups and hence, interpolate the years of rejuvenation after each treatment.
A significant decrease in the SCTT was obtained in the skin where the cream containing REPROAGE peptide solution was applied on, reducing differences between age groups. These results show an accelerated cell renewal and point to a revitalization of the skin.
With respect to placebo, the SCTT in 35-40 years old subjects treated with the active cream corresponded to that of 13 years younger skin. In 50-55 years old volunteers, the skin renovation was equivalent to that of 17 years younger.
Skin roughness was measured on the area underneath the eyes by means of a microtopography imaging system and the average surface roughness (Sa) was obtained. Following the treatment with the active cream, skin roughness decreased in a statistically significant way after 28 days, being the results even better after 56 days: in the 35-40 years old group Sa decreased by 10.2 percent on average (**p<0.01) and up to 44.4 percent; in 50-55 years old volunteers, Sa improved by 13.7 percent (***p<0.001) and up to 41.6 percent, suggesting a smoothing effect by the active ingredient.
Radiant and better-looking skin
To determine the improvement of the skin complexion, a clinical test was performed on 20 female volunteers (35-55 years old), who applied a cream containing 2 percent REPROAGE peptide solution to the face, twice a day.
After 56 days of treatment, skin luminance was measured from high-resolution photographs, resulting in an increase of 1.5 percent (*p<0.05). The enhancement in radiance, together with a general improvement in the skin appearance were further supported by the digital images of the volunteers.
Conclusion
By means of epigenetics through the modulation of miR-145 levels, which is involved in the regulation of epidermal differentiation, REPROAGE peptide suggests a reactivation of the pool of epidermal progenitors for a longer-lasting epidermal self-renewal ability.
When evaluated on the skin of volunteers, it showed to accelerate the stratum corneum renewal process, and it helped obtain a smoother and more radiant skin appearance. Hence, the peptide is intended to be introduced into cosmetic formulations aiming to counteract the slowdown of the skin regeneration process and to revitalise the dull complexion experienced with age.
REPROAGE™ is owned by The Lubrizol Corporation or its affiliates.
Authors: Julia Comas, Cristina Davi, Elena Canadas, Sandra Mendez and Raquel Delgado are from Lipotec SAU (Lubrizol Corporation company) in Gava, Spain.
© Chemical Today Magazine
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