Revitalizing Skin: Potential of Stem Cells in Dermatology and Anti-Aging
Since the discovery of multipotent stem cells in 1961, their functions have been recognized in developing new cells and maintaining the balance of normal cells. Stem cells have been utilized in various medical applications and play a significant role in understanding aging and age-related issues, as DNA damage and the decline of endogenous stem cells are key factors in the aging process. There are different types of stem cells, including pluripotent cells, unipotent progenitors, and various birth-associated stem cells. While these stem cell types offer potential for treating aging and age-related diseases, they also have limitations and ethical concerns.
Alternative approaches, such as modulating endogenous stem cell populations using pharmaceuticals, are being explored. Advances in regenerative medicine provide opportunities to target individual stem cells for addressing age-related dysfunctions like skin aging.
In this blog, the potential of Lgr6+ cells and defensins to reverse the signs of skin aging will be explored.
Types of Dermatological Stem Cells
The regulation of skin stem cells for the purpose of repairing aged skin have been the subject of extensive research. Studies involving wound healing and genetic manipulations have revealed various populations of stem cells in the skin with potential applications in regenerative medicine. Basal epidermal stem cells play a crucial role in maintaining the turnover and balance of the epidermis, while hair follicle stem cells are involved in transient skin wound repair. Different types of follicular-based stem cells, such as Lrig1+, Gli1+, and Lgr6+ cells, contribute to specific components of the hair follicle and the overall skin structure.
These stem cells are capable of multi-lineage contributions and exhibit resilience to aging-related damage. This resilience has sparked interest in further investigations to explore their regenerative capabilities.
1. Epidermal Stem Cells
The stratum basale of the epidermis contains basal cells that serve as stem cells for maintaining epidermal homeostasis. The precise mechanisms of their proliferation are still being studied, and two main models have been proposed. The first model, known as the epidermal proliferative unit model, suggests that a single basal cell is responsible for self-renewal and proliferation within a specific unit. According to this model, the entire epidermis is composed of multiple units, each characterized by the presence of a single basal cell. In contrast, the Committed Progenitor model proposes that basal cells divide randomly, giving rise to either two differentiated daughter cells, additional basal cells, or a combination of both. To reconcile these two models, a third model has been proposed, integrating aspects of both. This model suggests that the coexistence of these two modes of division allows for the maintenance of the epidermis under normal conditions and also facilitates wound healing when necessary. Further research is needed to fully understand the mechanisms and significance of these different modes of division in epidermal stem cells.
2. Hair Follicle Stem Cells
Hair follicles house a significant population of stem cells that play essential roles in hair cycling, sebaceous gland maintenance, and wound healing. These stem cells exhibit distinct marker expressions, such as Shh, Sox9, K15, Lhx2, Lrig1+, and Lgr6+. Bulge cells, located in the hair follicle bulge region and positive for K15 expression, are slow-cycling stem cells that can participate in anagen hair follicle cycling and temporarily contribute to interfollicular epidermis regeneration after injury. Lrig1+ cells, found in the junctional zone above the bulge, maintain the infundibulum and sebaceous gland structures. They can also contribute to wound healing by producing epidermally fated clones. Lgr6+ cells, located above the hair bulge, are unlike other populations that normally maintain one aspect of dermatologic homeostasis. They are multipotent stem cells that can replenish both the epidermis and sebaceous gland under normal conditions. During wound healing, Lgr6+ cells are involved in long-lasting repair of the epidermis. These different populations of hair follicle stem cells demonstrate specialized functions in both homeostasis and regeneration processes of the skin.
3. Sebaceous and Sweat Gland Stem Cells
The sebaceous and sweat glands are skin appendages that serve important functions in maintaining skin health. Sweat glands contribute to thermoregulation, excretion, and immune function, while sebaceous glands lubricate the skin. The sweat gland contains suprabasal progenitor cells that are capable of generating sweat-producing luminal cells. Additionally, ductal cells within the sweat gland are responsible for maintaining the openings of the ducts on the skin and can participate in the regeneration of the surrounding epidermis following tissue injury. In sebaceous glands, Blimp1+ cells are responsible for producing sebocyte progenitors, which are the cells that give rise to sebocytes, the main cells of the sebaceous glands.
Aging is characterized by the decline of physiological functions, which can be attributed to various factors such as genomic alterations, decreased telomere length, protein and cellular damage, increased inflammation, cell senescence, exhaustion of endogenous stem cells, and impaired intercellular communication. While these mechanisms can contribute to the aging process, they can also be involved in beneficial repair mechanisms that ultimately become detrimental and compromise tissue integrity.
Skin aging is influenced by factors like UV damage, environmental insults, inflammation, and oxidative stress. These lead to the deterioration of epidermal and dermal tissues, loss of collagen and elastin, decreased epidermal thickness, and reduced growth factors in the skin.
The healing of wounds and the aging process share similarities in genetic and cellular pathways, but adult skin healing is associated with scar formation and altered skin composition, unlike scarless fetal skin repair. Understanding the mechanisms involved in fetal wound healing offers insights into potential strategies to reverse or delay skin aging. Mesenchymal stem cells derived from the placenta or umbilical cord, as well as the use of growth factors to induce keratinocyte and collagen proliferation, have shown promise in skin aging therapies.
However, there is a need for further research to determine the necessary components, address safety concerns, and improve treatment specificity. Current approaches, such as using plant stem cell extracts or conditioned medium growth factors, have limitations in terms of efficacy, specificity, and potential risks, including tumorigenesis. The use of well-defined growth factors offers greater control, but nonspecificity and activation limited to aged skin cells remain challenges. Standardization of growth factor products and a better understanding of their effects are also needed for more effective skin aging treatments.
Applications of Lgr6+ Stem Cells & Defensins
Lgr6+ cells, as mentioned previously, are multipotent cells located in the hair follicle above the bulge that actively contribute to both the epidermis and sebaceous gland. Their expression begins during embryonic development and continues throughout hair development, eventually becoming restricted to the central isthmus above the hair bulge in adult skin. These cells are considered primitive epidermal stem cells due to their role in establishing the epithelial placode and their multipotency in adult skin. Transplantation studies and lineage tracing experiments have confirmed their ability to form all skin lineages and aid in long-term wound healing. Lgr6+ cells are of particular interest in the study of skin aging and regeneration, as they migrate to the wound center and participate in reepithelialization. Additionally, they have shown potential in promoting hair follicle neogenesis within wounds. Understanding the development, localization, and recruitment of Lgr6+ cells in adult hair follicles and their involvement in wound healing is important for advancing skin regeneration and addressing aging-related concerns.
Defensins are a group of antimicrobial peptides with different functions and structures from growth factors. Specifically, β-defensins, secreted by the skin epithelium, play a crucial role in Lgr6-mediated skin healing. These peptides provide innate immunity by preventing microbial colonization on the skin surface. They also enhance tight junctions and reduce the permeability of the skin, thereby preventing water loss. Moreover, β-defensins induce wound healing by recruiting Lgr6 stem cells to generate new basal stem cells and stimulate the production of keratinocytes in the wound bed. Researchers have explored the use of α-defensins, specifically intestinal α-defensins, to stimulate Lgr6 stem cells and enhance wound healing in murine skin wounds. The application of α-defensins could be particularly beneficial in large-scale wounds or burns where the local stem cell niche is compromised, and β-defensins are no longer present. Additionally, due to Lgr6's involvement in keratinocyte production and the rejuvenation of skin, α-defensins may hold potential for reversing skin aging.
Role of Lgr6+ Stem Cells & Defensins in Anti-Aging
Defensins offer a new approach to address skin aging by activating Lgr6+ stem cells specifically. This targeted approach minimizes potential side effects or tumorigenic risks associated with other treatments. Defensins have shown the ability to suppress tumor growth and are naturally involved in protective immune responses. Lgr6+ cells, residing in a UV radiation-protected area, are less likely to accumulate mutations and damage compared to basal stem cells. Activating these cells leads to the proliferation of less damaged keratinocytes.
Clinical studies have demonstrated positive outcomes with defensin-based skincare regimens, including improved wrinkle reduction, decreased skin oil production, increased epidermal thickness, and improvements in skin texture, pigmentation, and evenness. Though further research is needed, defensins provide a promising targeted therapy for skin aging.
See below the figure comparing nonspecific versus specific targeting, where the activation by growth factors is nonspecific and is based on a “switch-on of everything” mechanism, while defensins activate only 1 specific cell type in skin, Lgr61 stem cells, thus representing a target-specific activation. (From Taub, 2018)
New skin therapies are being developed to reverse signs of aging. Growth factors have been used, but they lack specificity and may activate cells not involved in rejuvenation, posing risks.
Stem cells in the hair follicle, particularly Lgr6+ cells, have shown potential in wound healing and skin regeneration. Defensins, peptides produced by the skin for immunity, can target and activate Lgr6+ cells, promoting their migration and proliferation in the wound bed. Defensins offer advantages over growth factors, as their composition is known, they specifically target Lgr6+ cells, and they activate stem cells with less genetic damage.
Pilot studies have demonstrated improved epidermal quality and comprehensive reduction of visible signs of aging with topical defensin application. This effect may be due to the repopulation of the epidermis with new and healthy basal cells, leading to enhanced dermal renewal and function.
See below the figure illustrating comprehensive improvement of signs of skin aging, with defensin-based full formula, C shows a high-resolution photograph of a participant in the full formula group at baseline, and D shows the results after 12 weeks. (From Taub, 2018)
Aging and Mesenchymal Stem Cells: Basic Concepts, Challenges and Strategies (2022)
Stem cell therapy in dermatology (2020)
Stem Cells in Dermatology and Anti-aging Care of the Skin (2018)
Stem cells in dermatology (2014)
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