Summary and Key Features
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Regenerative medicine involves stem cells and is typically defined as a process of replacing or regenerating human cells, tissues, and organs to restore or reestablish normal function.
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Effective stem cell–based cosmetics and cosmeceuticals must be able to preserve growth factors while maintaining their effectiveness and allowing them to penetrate the stratum corneum.
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The two main stem cell types are embryonic stem cells (hESCs) and adult stem cells (or somatic stem cells).
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Stem cell–derived products do not contain stem cells, but rather a complex composition of media in which stem cells were grown, enriched with growth factors, cytokines, and proteins secreted by stem cells.
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Human embryonic stem cells maintain high telomerase activity and exhibit remarkable long-term proliferative potential, providing the possibility for unlimited expansion in culture.
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Introduction
Regenerative medicine is typically defined as a process of replacing or regenerating human cells, tissues, and organs to restore or reestablish normal function. Regeneration of damaged tissues and organs can be achieved by stimulating and nursing the body’s own repair mechanism to heal itself or by growing tissues and organs in the laboratory and safely implanting them. This technology can solve the problem of the shortage of organs available for donation and the problem of organ transplantation rejection.
Use of stem cells is one of the most rapidly expanding fields of regenerative medicine, including regenerative medicine targeting skin regeneration. Skin regeneration has become the focus of the dermatologic field as an aging population overexposed to sun, noninvasive treatment, and topical products seeks treatment for reversal of wrinkles and the appearance of photoaged skin.
Aging of the skin, and aging in general, is influenced by both intrinsic and extrinsic factors. Intrinsic factors such as physiology, endocrine agents, and genetic makeup are also better known as chronological aging. Extrinsic factors include environmental influences, such as air pollution, exposure to sun and ultraviolet (UV) rays, smoking, chemical exposure, and poor nutrition; skin aging that is a result of extrinsic factors is referred to as photoaging. Photoaging causes a decrease in epidermal thickness, degradation of collagen, and deposition of altered elastic tissue, which shows as wrinkles, and yellow skin discoloration. In addition, photoaging leads to the production of free radicals, which in turn activate matrix metalloproteinases (MMPs), whose role is to degrade the extracellular matrix (ECM).
Clinically, youthful skin is characterized by smooth, unwrinkled appearance and even pigmentation, redness, and radiance. In contrast, aged skin is thin and finely wrinkled with deep facial expression lines. Histologically, aged skin is characterized by thinned epidermis and dermis with flattening of the rete pegs at the dermo-epidermal junction, depolarization of keratinocytes, and loss of collagen production in dermis.
The goal of stem cell–based cosmeceutical products is to mitigate some of the effects of extrinsic factors while harnessing the potential of intrinsic ones.
Effective stem cell–based cosmetics and cosmeceuticals must be able to preserve these growth factors while maintaining their effectiveness and allowing them to penetrate the stratum corneum. They should also provide for visible improvement in skin appearance in a reasonably short time and without impacting the skin barrier.
Some examples of stem cells used in skin regeneration and rejuvenation include topical products that contain biologically active secretions of human adult or embryonic stem cells.
Types of Stem Cells and Their Source
Stem cells have the limitless ability to divide and proliferate to build, repair, or regenerate tissue. Stem cells are distinguished from other cell types by two important abilities. The first ability is self-renewal, or the ability to renew themselves even after long periods of inactivity. The second is potency, which is the cell’s ability to differentiate into specific cells when induced by certain physiologic or experimental conditions. Each time a stem cell divides, it has the potential to either remain a stem cell or become some specialized type of differentiated cell.
There are several types of stem cells based on their origin. The two main stem cell types are embryonic stem cells (hESCs) and adult stem cells (or somatic stem cells). Other types, such as induced pluripotent stem cells (iPSCs), are produced in the lab by reprogramming adult cells to express hESC characteristics.
Human embryonic stem cells are isolated from the inner cell mass of blastocysts of preimplantation-stage embryos. These cells have the greatest capacity of becoming any cell type under the right growing conditions. Because the cells have the potential to form so many different adult tissues, they are also called pluripotent (pluri = many, potent = potentials) stem cells.
Adult or somatic or tissue-specific stem cells are specialized cells found in tissues of adults, children, and fetuses. They are thought to exist in most of the body’s tissues and organs. These cells are typically committed to becoming a cell from their tissue of origin, but they still have the broad ability to become any one of these cells. Stem cells of the bone marrow, for example, can give rise to any of the red or white cells of the blood system. Stem cells in the brain can form all the neurons and support cells of the brain, but they cannot form nonbrain tissues. Unlike embryonic stem cells, researchers have not been able to grow adult stem cells indefinitely in the lab.
Different organs have different regeneration abilities and stem cell content. For example, colon stem cells regularly divide to repair and replace dead or damaged tissues. In other organs, however, such as the pancreas and the heart, stem cells only divide under special conditions.
Skin Stem Cells
Skin stem cells are of special interest because they are easily accessible and can be targeted with growth factors or other reagents that can stimulate their division. Skin stem cells are found in the basal layer of epidermis as well as in the dermis. The dermis is of mesodermal embryonic origin and contains adult stem cells that are mesenchymal stem cell–like cells. The stratified epidermis is of ectodermal origin and composed of keratinocytes that differentiate to a water-impermeable stratum corneum. Epidermal stem cells are better characterized than the dermal ones and typically easier to target with topical solutions. The terminally differentiated cells in the epidermis are shed from the skin, necessitating a continuous delivery of newly differentiating cells. The epidermis is completely renewed about every 4 weeks. Given that the differentiated cells cannot divide anymore, their replacement depends on epidermal stem cells. There is strong evidence that the hair bulge forms a reservoir of epidermal stem cells. From there, stem cells periodically migrate to the matrix of the hair follicle, the sebaceous gland, or the basal layer in the interfollicular epidermis to produce progenitors that differentiate into hair cells, gland cells, or cells of the upper epidermal layers, respectively.
Use of Stem Cells in Cosmetics
Stem cell cosmetic products can contain many stem cell extracts that can lead to renewal, regeneration, and repair of the skin. Stem cell–derived products do not contain stem cells, but rather a complex composition of media in which stem cells were grown, enriched with growth factors, cytokines, and proteins secreted by stem cells. The idea of using cell-derived growth factors was based on the hypothesis that the extrinsic aging process of skin is similar to that of chronic wound healing. As a topical ingredient, it is supposed to activate the skin stem cells and induce them to differentiate into new skin. Growth factors and cytokines are regulatory proteins that mediate signaling pathways between the cells and within cells.
Dermal stem cells play key roles in wound healing processes as they interact with keratinocytes, fat cells, and mast cells. They are also a source of the cytokines and other molecules that support cell-to-cell interaction, accelerate wound repair, and maintain the skin’s integrity and youthfulness. The ability of these secreted growth factors to increase fibroblast and keratinocyte proliferation within the dermis, thus inducing ECM formation, supports this idea. Aging skin has a reduced turnover rate of fibroblasts, keratinocytes, and melanocytes and decreased levels of growth factors secreted by those cells. Topical supplementation of these normal growth factors may allow for the natural repair of skin. A general overview of the growth factors and cytokines found in cosmetic products and their functions can be found in Table 14.1 .
| Growth Factor, Cytokine, Protein | Role in Skin Biology |
|---|---|
| Bone morphogenetic protein 5 | Regulates number and size of keratinocytes |
| Collagen type I | Part of skin extracellular matrix |
| Epidermal growth factor | Most potent mitogen of fibroblasts and keratinocytes |
| Fibroblast growth factor | Induces proliferation of fibroblasts and keratinocytes Induces collagen synthesis in dermis |
| Fibronectin | Part of skin extracellular matrix |
| Granulocyte-macrophage colony-stimulating factor | Secreted by keratinocytes shortly after injury to induce wound healing Cytokine for fibroblasts in skin |
| Growth differentiation factor 15 | Regulation of keratinocyte differentiation |
| Growth hormone | Induces growth of keratinocytes and fibroblasts Induces wound healing |
| Hepatocyte growth factor | Involved in tissue regeneration and wound healing |
| Heparin binding epidermal growth factor | Mitogen for fibroblasts and keratinocytes |
| Insulin-like growth factor and binding proteins 1 and 2 | Mitogen for fibroblasts and endothelial cells |
| Keratinocyte growth factor | Stimulates reepithelialization and hair growth |
| Placenta growth factor | Mitogen for fibroblasts and promotes growth of endothelial cells |
| Platelet-derived growth factor-AA and receptors | Induces fibroblast migration and matrix production |
| Transforming growth factor-β1, -β2 | Induces keratinocyte, fibroblast, and macrophage migration Regulates angiogenesis Initiates collagen and fibronectin synthesis |
| Vascular endothelial growth factor | Mediates angiogenesis |
| Interleukins IL-1α and IL-1β | Activates growth expression in macrophages, keratinocytes and fibroblasts |
| IL-6 | Regulates wound healing process |
| IL-10 | Antiinflammatory |
| Tumor necrosis factor-α | Activates growth expression in macrophages, keratinocytes, and fibroblasts |
| Interferon-γ | Antiinflammatory |
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