Their monumental discovery opened up a promising new area of medical research with wide-reaching healing and rejuvenating properties for both exhausted and damaged tissues and organs. Given their unique regenerative abilities, stem cells offer new potential for treating diseases and serving as an internal repair and rejuvenation system in the body. For over 50 years the research continued and stem cells are finally coming to clinical applications. Bone marrow transplants, which transfer healthy adult stem cells from the donor to the recipient, have been used successfully for many years. Successful clinical trials are underway to address blindness, diabetes, heart failure, and cancer. The initially unsuccessful trials to repair spinal cord injury have just achieved a positive efficacy outcome.

A variety of factors still must be addressed for a stem cell therapy to be effective. Finding the appropriate "on-off switch," which turns a specific type of stem cell into the specific specialized tissue type desired, continues to be the focus of research today.

Skin serves as the body's first line of defense against assaults from the environment, as well as plays a key role in the creation of confidence in a person's social appearance. Topical skin care remains the simplest, most widely-used, and cost-efficient way to address signs of skin aging. It is not surprising that the skin care market – which is constantly searching for the next breakthrough to follow the revolutionary ingredient, retinol – is attracted to stem cell technology.

FIRST-GENERATION PRODUCTS
In the earliest or first generation of stem cell skin care products, there was very little known about the specific type of stem cells in the skin and what was required to switch them on. Early products focused on a mixture of apple and plant stem cells and a variety of activators to switch them on. This produced a slew of plant stem cells and numerous peptides that activated "everything." In reality, the first generation products had low efficacy due to the shotgun approach that causes skin cells – which are aged, tired, and suffering from environmental and ultraviolet damage – to work even harder than before.1

SECOND-GENERATION PRODUCTS
Research continued with more focus on growth factors isolated from – or secreted by – human cells. Usually, the ingredient is a conditioned media collected from human cells growing in a laboratory. Conditioned media is a liquid media in which cells have been cultured for a period of time and used to feed laboratory cells. Cells "condition" the media through their normal process of secreting proteins, cytokines, and chemicals – one of the ways in which cells communicate with each other. This soup of secreted factors is extremely potent and offers strong
regenerative potential.

Over a decade ago, when this second generation of products came to market, the use of conditioned medium was a revolutionary approach. But, while it was a step forward and growth factors from conditioned media and cell lysates performed much more efficiently than plant stem cell-derived ingredients, the second-generation products still utilized a mixture of growth factors and activators that had the same shotgun effect, turning on "everything" and forcing old and exhausted skin cells to work harder. Furthermore, a safety concern had been raised; some of the molecules released by the cultured stem cells were well-known in biology as triggers of cancer-related pathways. The potential to transfer infections from the donor cell to the user of the skin care product remained as a risk, as well.

THIRD-GENERATION PRODUCTS
As researchers developed the third generation of stem cell skin care products, they began to define and focus on the composition of the growth media. Skin care products of the third generation were supplemented only with a very-well defined composition of specific growth factors, not a soup of whatever stem cells had been released into the conditioned medium. In other words, formulators put only those growth factors into the product that were known to be relatively safe and potent. Furthermore, the concern of product contamination with pathogens was also addressed; growth factors in third-generation products were produced synthetically or by using recombinant methods that do not utilize any human tissues or cells that may potentially be infected. This move was a step forward, but the third generation still used the shotgun approach to activate "everything" and these products continued to force existing, tired skin cells to work harder, rather than initiate the creation of new and undamaged cells in the skin.

FOURTH-GENERATION PRODUCTS
The fourth generation of stem cell skin care represents a quantum leap forward because the shotgun approach is no longer necessary. This generation of technology is based on recently published, top-notch research and requires a deep understanding of scientific basis.

Researchers have identified the target in the skin to work with – the skin's master stem cells, which scientists call LGR6-positive stem cells. This stem cell is the most basic skin stem cell from which all other types of skin cells arise during development.2 Right after birth, these stem cells "fall asleep," thus keeping a reserve in the body for future skin repair. More importantly, these cells have the ability to create basal stem cells, which produce fresh, new keratinocytes throughout a person's lifetime. During the course of a person's life, the reserve of skin's master stem cells are seldom called upon. Only during wound healing do these cells "wake up" and build new epidermal and basal stem cells that produce keratinocytes in the area of the wound.3

Researchers also needed an activator to stimulate the target: the switch that wakes up LGR6-positive stem cells, causing them to differentiate, heal, and rejuvenate damaged skin in wound healing. The switch is initiated by a specific type of peptide called defensins, which are released by the immune system.3 These peptides stimulate the LGR6-positive stem cells to begin the healing process.

The fourth generation of stem cell skin care utilizes target-specific technology and a defined activator. There is no longer an activation of "everything" – the good along with the bad; the use of an undefined soup of growth factors that may include cancer-trigging molecules is no longer required. This generation of products does not need to use low-level potency ingredients, push old and exhausted skin cells to work harder, or utilize human or animal-derived ingredients. Now, for the first time, products can be formulated using well-defined activation peptides – defensins, which turn on a very well-defined target – the body's specific skin's master stem cells, resulting in the activation of the healing and rejuvenation process through the creation of fresh and new skin cells.

So far, fourth generation stem cell skin care products, with its use of target-specific synthetically-produced peptides, is demonstrating significant results. Double-blinded, placebo-controlled studies have shown that the topically applied fourth-generation products, when applied to intact, but aged skin, dramatically improve the visible signs of aging and comprehensively improve the overall quality of the epidermis; deep wrinkles were softened, dark spots were less pronounced, and skin texture was improved. After six weeks of testing, the study participants experienced improvement in up to 16 signs of skin aging.4 Both skin care professionals and clients are waiting for more products to come to the market that utilize the unique and revolutionary fourth-generation approach.

References
1 Hilton, L. (2016, September). "Behind the hype in stem cell therapy." Dermatology Times, 37(9), 21-22.
2 Snippert, H.J., Haegebarth, A. Kasper, M. Jaks, V., van Es, J.H., Barker, N. ... Clevers, H. (2010, March 12). "Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin." Science, 327(5971), 13885-9.
3 Lough, D., Dai, H., Yang, M., Reichensperger, J., Cox, L., Harrison, C., & Neumeister, M.W. (2013, November). "Stimulation of the follicular bulge LGR5+ and LGR6+ stem cells with the gut-derived human alpha defensin 5 results in decreased bacterial presence, enhanced wound healing, and hair growth from tissues devoid of adnexal structures." Plastic Reconstructive Surgery,132(5), 1159-71.
4 Keller, G. S. (n.d.). "Use of Defensins in a New Cosmeceutical for Skin Rejuvenation." Defenage White Paper. Pilot Studies. GSK.