Types of stem cells in hair follicles

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Hair follicle stem cells

A multilayered epithelium, complete with the inter-follicular epidermis, with associated hair follicles, sebaceous glands and sweat glands, make up the mammalian epidermis. It is the stem cells that regulate the self-renewing characteristic of the skin and its appendages. The reservoirs of epithelial stem cells are located in the hair follicle bulge area and the inter-follicular epidermis. Most hair follicle stem cells reside at the base of the follicle bulge region, at or near the site of insertion of the arrector pili muscle. The bulge region is a contiguous part of the outer root sheath. This sheath marks the lower end of the permanent portion of hair follicles. On histological sections of human hair follicles, it can be readily identified as a unilateral thickening of the outer root sheath.

Hair follicle bulge stem cells are characterized by a distinct biochemical makeup within their well-protected niche. Normally, these stem cells depict a slow cycling, quiescent nature. The inactive nature of bulge cells was demonstrated by labelling experiments in mouse models and on human skin grafted to immunodeficient mice, where uptake of the labelling substances 3H-TdR and BrDU was only observed at the onset of the anagen phase. Studies using colony-forming experiments as well as cell clone analyses confirmed a high proliferative potential.

The cells persist throughout the lifetime of the organism. They normally proliferate only transiently at the onset of the hair growth cycle. These multi-potent bulge stem cells lead to the formation of daughter cells that serve as progenitors for generating epithelial cells that migrate downward to convert into hair-matrix transit amplifying cells which subsequently give rise to the hair shaft. Evidence supports the idea that stem cells in the inter-follicular epidermis are less potent than hair follicle bulge stem cells, leading to speculation that they are progeny, perhaps uni-potent progeny, of multi-potent bulge cells. Contrastingly, inter-follicular stem cells do not have a clearly defined niche.

Studies on the microenvironment in the bulge are gaining importance. Because it is needed to be cleared why stem cells are preferentially located in a specific niche such as the bulge region. Balanced c-myc expression seems to be crucial as its over-expression in transgenic mice causes follicle stem cells to proliferate and to terminally differentiate. Microarray profiling has identified over 150 genes, which are preferentially expressed in the bulge region relative to interfollicular epidermis. Purification and enrichment of bulge stem cells, however, is still not easy, especially since critical differences in the gene expression have been found between human and murine bulge cells. Bulge cells are more susceptible to the accumulation of genetic damage and retention of carcinogens over prolonged periods of time Due to their relative quiescence and as such they are prone to form tumors. For example, there is molecular evidence for their involvement in the formation of basal cell carcinomas and trichoepitheliomas.

The dermis derived progenitor cells gives rise to the dermal papilla and dermal sheath; their location has not been conclusively identified. Circumstantial evidence however suggests that the connective tissue is the most probable source. Differentiated dermal sheath tissues can be surgically implanted in various combinations in association with epidermal hair follicle cells that permits the redevelopment of dermal papillae and formation of hair follicle-like structures. More recently, it was shown by using green fluorescent protein expressing cells that cultured dermal sheath cells could reconstitute the dermal papilla and dermal sheath and induce new hair follicle formation. The cells could also incorporate into resident hair follicles and alter the size and growth cycle of the chimeric hair follicle. Cells from the hair follicle mesenchyme have also shown pluripotent properties under experimental conditions with dermal papilla cells being successfully manipulated to produce haematopoietic colonies of multiple blood lineages, osteoblasts, adipocytes, and chondrocytes. These and many other studies proved that mesenchymal cells from the lower one third of the anagen stage hair follicle retain regenerative and hair growth inducing capacities and have a degree of pluripotency.

Melanocyte stem cells are retained in hair follicles. During embryogenesis, melanoblasts emerge in the neural crest and migrate through the epidermis towards newly developing hair follicles. These cells localize in the outer root sheath of the hair follicles in and close to the bulge region. This repository of melanocyte stem cells leads to the repopulation of the mature melanocyte system in hair cycles. The melanocyte stem cell population produces differentiated melanocytes, which are localized to the hair matrix region with the development of each new hair growth phase. Failure in appropriate maintenance of the hair follicle melanocyte stem cells may lead to the loss of differentiated melanocytes and the process of hair graying (canities) sets in.

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