Stem cells for anti-aging

STEM cell research has progressed considerably in recent years, and new findings have first transformed the field of regenerative medicine and then that of cosmetic care. Declining regenerative potential at the tissue level is a major contributor to the aging process. Since regeneration depends centrally on adult stem cells to supply the new cells required for tissue repair and replacement, any decline in stem cell activity will accelerate the aging process¹.

Adult stem cells are undifferentiated cells with a capacity for self-renewal and the potential to evolve into the different cell types within the tissue in which they are found. The skin consists of two layers and each one has its own adult stem cells. In the epidermis, the stem cells reside in the basal layer (Figure 1)². Following asymmetrical division, epidermal stem cells reproduce more rapidly, dividing transient amplifying cells (daughter cells of stem cells), which after a limited number of divisions enter terminal differentiation³. As the cells differentiate, they migrate up through the epidermis, finally forming the stratum corneum (SC) serving as a physical barrier. With age, the turnover of the epidermis is reduced, making it thinner, more fragile, and more likely to suffer from impaired wound healing.

Not only cells in the epidermis can age, but also dermal cells, namely fibroblasts. The dermal papilla was identified as a niche for dermal stem cells⁴. Cells of the dermal papilla were shown to express the stem cell marker gene Sox2, to self-renew and to migrate into the inter-follicular dermis where they proliferate and differentiate to fibroblast cells, able to regenerate the extracellular matrix (Figure 2). The dermal fibroblasts interact with epidermal (stem) cells and melanocytes, regulating their survival and proliferation. Furthermore, the thickness and elasticity of the dermis is controlled by fibroblasts through synthesis of collagen and elastin. These proteins form the so-called extracellular matrix, a three-dimensional structure that grants elasticity and firmness to the skin. Aging skin is distinguished by an increasing number of senescent fibroblasts. These cells have not only stopped producing collagen and elastin, but have even started to breakdown the existing matrix⁵. The replacement of these senescent fibroblasts by new ones can only be provided by dermal stem cells. Due to the Hayflick limit, the number of divisions stem cells of adult tissues can undergo is limited; therefore, exhaustion of this pool of cells limits the lifespan of the tissue. These dermal stem cells do not grow adherent like normal fibroblast cells, but grow by forming non-adherent cell aggregates (3D spheres)⁶.

Therefore, it is clear that the need for new cells is met by stem cell proliferation and by expansion of transit amplifying cells, in the case of the epidermis³. Constant renewal and repair is essential for the maintenance of healthy and young skin.

Treatment and Rejuvenation

Treatments that strengthen the functional capacity of tissue stem cells are essential to achieve deep-seated rejuvenation.

Recent discoveries have shown that it is possible to reestablish adult stem cells or differentiated cells to a pluripotent state without altering the underlying DNA sequence. These methods typically use a defined group of small molecules to establish the required gene expression pattern through an intricate web of normal epigenetic control mechanisms that do not alter the DNA^7-9.

PhytoCellTec? is the name of a new biotechnology that researchers from Mibelle Biochemistry have successfully used to both generate and cultivate plant stem cells. The PhytoCellTec technology relies on the wound-healing mechanism of a plant. Following injury, the healing of the cut surface begins with the formation of callus cells. This healing tissue consists of dedifferentiated cells, which are stem cells, and for this purpose a small part of the respective plant (germ, leaf, fruit) is selected and injured to induce callus formation (Figure 3). The callus cells are then cultivated in an appropriate medium and large-scale production is achieved in a specially developed WAVE bioreactor system.

The PhytoCellTec technology was presented as an eco-breakthrough in natural cosmetic ingredients at the Rio+20 2012 – the “United Nations Conference on Sustainable Development” as it allows the production of active raw materials for the beauty industry without harming the environment.

Both plant cells cultured in vitro by the technique described above and human adult stem cells are in an un-differentiated state. The degree of cellular differentiation is regulated by altered gene expression. Modifications of the DNA and the histone proteins by methylation and acetylation, known as epigenetics, are used to modulate gene expression. Epigenetic regulation of gene expression depends therefore on the activities of the modifying enzymes such as methyltransferases, acetyltransferases and deacetylases. The activity of these enzymes can be regulated by small molecule modulators (activators and inhibitors). Such epigenetic factors are conserved among species^{10, 11}.

PhytoCellTec stem cell active ingredients are formulated in a vector system (liposomes) that bring the active ingredient right to the basal layer where the epidermal stem cells are located. To reach the dermal stem cells, liposomes can even penetrate to the hair papilla via the follicular pathway. Several in vitro and in vivo studies have demonstrated the positive effect of PhytoCellTec products on the vitality of human skin stem cells and their regenerative capacity. Formulated into skincare products, these ingredients could benefit the epidermis and /or dermis of consumers by improving skin regeneration abilities.

References

¹ Mimeault, M. & Batra, S. K. “Recent advances on skin-resident stem /progenitor cell functions in skin regeneration, aging and cancers and novel anti-aging and cancer therapies.” Journal of Cellular and Molecular Medicine 14, 116 –134 (2010).

² Fuchs, E. & Nowak, J. A. “Building epithelial tissues from skin stem cells.” Cold Spring Harbor Symposia on Quantitative Biology 73, 333 – 350 (2008).

³ Winter, M. C. & Bickenbach, J. R. “Aging epidermis is maintained by changes in transit-amplifying cell kinetics, not stem cell kinetics.” The Journal of Investigative Dermatology 129, 2541– 2543 (2009).

⁴ Driskell, R. R., Clavel, C., Rendl, M. & Watt, F. M. “Hair follicle dermal papilla cells at a glance.” Journal of Cell Science 124, 1179 –1182 (2011).

⁵ Campisi, J. “The role of cellular senescence in skin aging.” The Journal of Investigative Dermatology. Symposium proceedings of the Society for Investigative Dermatology, Inc. & the European Society for Dermatological Research 3, 1– 5 (1998).

⁶ Higgins, C. A., Richardson, G. D., Ferdinando, D., Westgate, G. E. & Jahoda, C. A. “Modelling the hair follicle dermal papilla using spheroid cell cultures.” Experimental Dermatology 19, 546 – 548 (2010).

⁷ Lyssiotis, C. A. et al. “Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.” Proceedings of the National Academy of Sciences 106, 8912 – 8917 (2009).

⁸ Muller, L. U., Daley, G. Q. & Williams, D. A. “Upping the ante: recent advances in direct reprogramming.” Molecular Therapy 17, 947– 953 (2009).

⁹ Page, R. L. et al. Induction of stem cell gene expression in adult human fibroblasts without transgenes. Cloning and stem cells 11, 417– 426 (2009).

¹⁰ Carmell, M. A., Xuan, Z., Zhang, M. Q. & Hannon, G. J. “The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes & Development 16, 2733 – 2742 (2002).

¹¹ Verdel, A., Vavasseur, A., Le Gorrec, M. & Touat-Todeschini, L. “Common themes in siRNA-mediated epigenetic silencing pathways.” The International Journal of Developmental Biology 53, 245-257 (2009).