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Introduction

The skin is our body's largest organ. It functions to protect us from injury and water loss, as well as in keeping the body's internal temperature constant at all times (homeostasis). Human survival relies on the skin to be maintained in an undamaged state, and this requires a constant renewal of damaged cells. The fact that the epidermis is continuously regenerating led to the idea that stem cells must be present within the skin's layer. The epithelium is composed of three major compartments: the epidermis, the hair follicle, and the sebaceous gland. The epidermis is made up of stratified squamous epithelium, which consists mostly of cells called keratinocytes. This structure is renewed approximately every two weeks in humans (5, 7). The development and growth of keratinocytes starts at the basal cell layer. These cells then move upstream through the basal, spinous, and granular layers to the cornified layer at the surface, termed the stratum corneum. This top layer is made up flat, dead "squamous" cells that are constantly being sloughed off (4, 5).

Figure 1. Epidermal stem cells are located in the basal layer of the epidermis. These stem cells (SC) give rise to transient amplifying (TA) cells that migrate to the surface and form a protective layer.

Epidermal Stem Cell Location

Stem cells of the epidermis have been found to exist in three sites: the bulge region of the outer root sheath of the hair follicle, the interfollicular epidermis, and the sebaceous gland. Further investigation showed that cells in the bulge region of the hair follicle are more primitive (2).

Figure 2 - Epidermal stem cells can be found in the bulge region of the hair follicle, the interfollicular epidermis and the sebaceous gland. However, the bulge region is thought to have stem cells that are more multipotent than the other two areas.

Many experiments were conducted to pinpoint the exact location of epidermal stem cells (EpSC's). The slow cycling nature of all stem cells was behind one of the methods used to identify these cells. Epidermal or any other stem cells do not undergo cell division as rapidly as other cells within the body in order to avoid any cell damage or potential mutation to be incorporated into their genetic code. This slow cycling allows the cells to conserve their proliferative potential and minimize DNA replication errors that could possibly occur. In such experiments stem cells can be labeled with a specific marker and their location identified (3).

Epidermal Stem Cell Self Renewal via Asymmetric Division

Self-renewal is the ability of a stem cell to produce two daughter cells that can either remain as the stem cell (self-renewal), or commit to a pathway leading to differentiation to form other cells within the epidermis. This type of cell division is termed asymmetrical. All stem cells divide asymmetrically generating two daughter cells, one of which is identical to the dividing cell while the other is different. Asymmetric cell division results either from unequal segregation of cell-fate determinants such as proteins or mRNA, or from a gradient of signaling molecules present in the immediate microenvironment (2).

Figure 3 - Epidermal stem cells undergo mitosis and produce two daughter cells. One daughter cell will remain as the original stem cell while the other daughter cell will differentiate into a TA-Transient Amplifying cell that will generate large quantities of specialized differentiated cells within the epidermis. The entire process is repeated maintaining the original stem cell integrity while producing epidermal cells required for skin renewal.

Transient-Amplifying Cells

Differentiation occurs when a daughter cell becomes a precursor cell, also termed transient-amplifying (TA) cell. The TA cell will proliferate prior to further differentiation and amplify to increase the number of its progeny. TA cells in the epidermis have been found to divide only three to five times before they terminally differentiate. Their prime function is to increase the number of differentiating cells produced by one cell division. Thus, TA cells are descendents of stem cells in the epidermis and are responsible for the dynamic tissue renewal under normal conditions as well as tissue repair after wounding (5).

EpSC's are defined as self-renewable and are responsible for the long-term maintenance of the skin. They are slow cycling in nature and have the ability to be activated by wounding or in culture conditions to proliferate and regenerate tissue. They can form at least three specialized structures, i.e. the epidermis, hair follicles and sebaceous glands (3).

Epidermal Stem Cell Markers

To date, there are no specific or reliable cell surface markers that have been discovered. This makes the field of identifying and isolating the EpSC difficult. Most of the uncertainties are due to unbalanced data when comparing human vs. murine keratinocytes, hairy vs. non-hairy skin (palms of the hands, soles of the feet), and the difficulty in keeping the cells in culture for isolation (6). Studies have shown that EpSC's can alter their original phenotype according to their microenvironment further causing a difficult task in identifying unique markers. Please refer to Table 1 for a list of possible EpSC's that have been identified and their prospective function within the epidermis.

Table 1 - Possible Epidermal Stem Cell Markers

Clinical Application for Epidermal Stem Cells

Cultured human skin has been used as a source of new skin to engraft onto damaged areas of burn patients, representing one of the first therapeutic uses of the EpSC. Current research focuses on the use of EpSC in tissue bioengineering and for the treatment of damaged corneal surfaces. Additionally, they are used in stimulation of wound healing in chronic leg ulcers, cosmetic epidermal regeneration, and autologous epidermal grafts in the treatment of vitiligo, a common idiopathic skin disease. The self- renewal ability of EpSC has proven beneficial in producing the therapeutic gene that could cure genetic skin defects.

Conclusion

Epidermal stem cells are of great interest in research due to their high accessibility in the body. Current research has demonstrated that epidermal stem cells have the potential to be used for therapeutic purposes, such as engraftment of skin onto burn victims and wound healing treatment of patients with skin diseases. An improved understanding of epidermal stem cells will allow the use of these cells as treatment in the future.

References

1. Alonso, L., Fuchs, E. Stem cells of the epithelium. PNAS 2003;100:11830-35.
2. Gambardella, L., Barrandon, Y. The multifaceted adult epidermal stem cell. Current Opinion in Cell Biology 2003;15:771-7.
3. Barthel, R., Aberdam, D. Epidermal stem cells. JEADV 2005;19:405-13.
4. O'Shaughnessy, R., Christano, A. Stem cells in the epidermis. Skin Pharmacol Appl Skin Physiol 2001;14:350-357.
5. Janes, S., Lowell, S., Hutter, C. Epidermal stem cells. J Pathol 2002;197:479-491.
6. Lavker, R., Tung-Tien, S. Epidermal stem cells: properties, markers, and location. PNAS 2000;97:13473-75.
7. Alonso L., Fuchs E. Stem Cells in the Skin: Waste Not, Wnt Not. Genes & Development 2003;17:1189-200.

Acknowledgements

This review was prepared by the following graduate students in the Stem Cell Biology Class, Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey:

Diane Motto, Irina Ogan, Shobana Shanmugasundaram, Justin Sweet, Tiffany Toliver

Teaching Assistant: Marianne Castillo

The review was edited by two stem cell biologists.