To Multiply or Not to Multiply, That is the Question…

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To Multiply or Not to Multiply, That is the Question…

Coen G. Gho, MD

Scientific background

Stem cells in general are protected against apoptosis. Bcl-2 is known to protect cells against apoptosis, while Bax promotes cell death. Reports in the literature have indicated that stem cell populations are cytokeratin (CK) 19 positive. The presence of CK19 and Bcl-2 and absence of Bax expression, may therefore be used as an indicator of stem cell populations in hair follicle cultures.

A considerable portion of the hair follicle remains attached to a plucked hair and this can be used for follicular cell culture. We found co-expression of CK19 and Bcl-2, but not Bax in two areas of the mid-portion of the outer root sheath of the hair follicle from skin biopsies, as well as of the plucked hair, while proliferation markers were negative in these areas. This marker combination, indicative of stem cells, could not be found in the dermal papilla (partly Ki-67 positive) or the proximal part of the plucked hair. CK19 and Bcl-2 were also present in a fraction of the follicular cell culture.

We conclude that CK19-, Bcl-2-positive and Bax-negative cells can be obtained from plucked hair and remain present in follicular cell cultures. If this phenotype indeed represents follicular stem cells, our finding endorses the assumption that stem cells are located in the bulge area of the hair follicle; they were not found in or near the dermal papilla.

Follicle transplantation
We have shown that follicular stem cells are present in two areas of the mid-portion of the outer root sheath of the hair follicles obtained from skin biopsies. The question therefore arises whether or not both areas are necessary to induce hair growth. Kim et al. found that the proximal part of the hair follicles cannot regenerate into a differentiated hair follicle, but the distal part of the follicle can (Kim et al, 1995), eventually resulting in a fully developed hair follicle (Kim et al, 1996). However, Reynolds et al. found that, although the dermal papillae of human hair cannot induce new hair growth, the sheath of the lower part of the follicles can (Reynolds et al, 1999). These apparently contradictory studies indicate that both proximal as well as distal areas of the hair follicle have the potential to induce hair growth, which corresponds with our finding that there are two stem cell locations in the mid-portion of the outer root sheath.

This knowledge is used in the technique of follicle transplantation. While a part of the follicle which can induce hair growth remains in the dermis, the extracted distal part of the hair follicle can also induce hair growth. Because the exact location of the two areas of stem cell varies between patients, the potential for multiplication of the transplanted hair follicle also varies between patients.

Hair multiplication
We have shown in several studies that follicular stem cells derived from plucked hair can be cultured. Hair multiplication is a technique whereby cultured follicular stem cells derived from plucked hair from the occipital side of the head are used to regenerate new hairs in bald areas. Because the role of the connective tissue or extracellular matrix surrounding the epithelial portion of the hair follicle is very important for the survival of the implanted cells, we implant the cultured cells into hair follicles which remain in the recipient area.

The future of hair restoration

Hair multiplication may be the next step in hair restoration. The main advantage is the preservation of hair growth in the donor area. Although this advantage is very important, one has to bear in mind that there are also disadvantages. For example, the patient has to come to the clinic several times to donate the hairs, and laboratory facilities are necessary to culture the cells. Also, as in other tissue engineering projects, the consistency of the result cannot be guaranteed. Although we have improved the consistency since commencing our study program, the results are still not satisfactory enough to offer hair multiplication as a regular commercial treatment.

References:
Kim JC, Choi YC: Regrowth of grafted human scalp hair after removal of the bulb. Dematol Surg 21:312-313, 1995

Kim JC, Kim MK, Choi YC: Regeneration of the human scalp hair follicle after horizontal sectioning: implications for pluripotent stem cells and melanocyte reservoir. In: Van Neste DJJ, Randall VA (eds): Hair restoration for the next millennium: Elsevier Science B.V. 135-139, 1996

Reynolds AJ, Lawrence C, Cserhalmi Friedman PB, Christiano AM, Jahoda CA: Trans- gender induction of hair follicles. Nature 402:33-34, 1999