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In the very early development of the human embryo, there is no indication of anything resembling a hair follicle. Neither is there an indication of anything resembling bone, nerves, internal organs or skin. The only cells in the early human embryo are precursor cells—stem cells—that are nudged into becoming specialized bone, nerve, internal organ or skin cells by the action of genes and the growth-and-development molecules produced by genes. It may be surprising to learn that hair follicles have a developmental relationship with many others tissues, such as breast and prostate gland, but this shows the built-in potential of stem cells to grow into a variety of specialized forms.

Hair follicles do not just spring into existence from embryo stem cells. The path of hair follicle development begins in a group of stem cells that are nudged into different directions to become specialized cells of many different tissues and organs, including hair follicles. It may be surprising to learn that hair follicles have a developmental relationship with many other tissues, but it is not surprising to see another example of the built-in potential of stem cells to grow into a variety of specialized forms.

It has long been known that hair follicle development begins in the very early embryo, before the embryo begins to mature into the recognizably human form of a fetus. There is an exchange of molecular “signals” between the outer (epidermal) and underlying (mesenchymal) layers of cells that causes the formation of a “bud” in the epidermal layer. The exact nature of these molecular signals has not been well understood, but has long been sought. Recent research in mice has revealed more about the nature of the molecular signals, telling investigators more about the process of “budding”, and laying down a new line of research into cellular development from stem cells [Jamora C et al. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 2003; 422:317-322.]. The research is important for continuing to advance the research that is the basis for “cell therapy” and cloning technology. As researchers discover more about the workings of the hair follicle at the molecular level, there are increased possibilities for development of successful therapies for hair loss such as more powerful hair growth stimulators and even gene therapy and cloning.


The Formation of Hair Follicles

The formation of the epithelial bud on the outer surface of an embryo is the first visible indication that a collection of stem cells is being instructed to start the process of specializing. As the stem cells begin to specialize they release themselves from their dependence on underlying tissue and begin to communicate with surrounding cells by means of newly produced “messenger” molecules. This communication is central to the process of organizing surrounding cells into the specialized form of a hair follicle.

The first identifiable hair follicles appear at about 9 weeks of age, after the embryo has begun to mature into a fetus. The first follicles develop in the areas that will eventually become the eyebrows, upper lip and chin. Hair follicle development on body, face and scalp then occurs in successive waves beginning at fetal age of 4 to 5 months. The fully mature 9-month fetus usually has all of the hair follicles that will ever develop in that person. It is believed that, under normal circumstances, new hair follicles do not develop in an adult.

Molecular signals tell the specializing cells in the epithelial bud to elongate into the cellular structure that eventually becomes the fully developed hair follicle. At a later stage of development, the cells responsible for hair pigmentation (melanocytes) are instructed to intersperse among the other cells of the developing follicle. The developing follicle also incorporates a sebaceous (oil) gland that will subsequently supply lubrication for the hair that will grow from the follicle.

The developing follicle is instructed by molecular signals to develop at an angle relative to the skin surface; thus, the hair growing out of the follicle will grow out at an angle relative to the skin, not straight up like the bristles of a brush. However, tiny muscles that develop in skin next to the follicle can pull the hair straight up. This happens in response to cold external temperature when hair is pulled straight up to form a thermal layer and give the skin better protection against cold air. When this happens we also feel a prickling sensation that we call “having goose bumps”.


What Researchers Have Discovered

The research reported by the investigators at Howard Hughes Medical Institute, Rockefeller University, New York, is beginning to clarify the picture of hair follicle development at the stem cell level. The investigators have identified the signaling molecules that act under genetic instruction to up-regulate and down-regulate the genes directly involved in epithelial budding and follicle cell specialization. In research with mice, the investigators found that up- or down-regulation of the genes can produce hairy mice or bald mice—that is, force the development of extra hair follicles or impair the development of hair follicles and other organs.

The findings may, over time, contribute to better understanding of the processes by which other tissues such as teeth, bone, internal organs and limbs develop from epithelial buds. “Our findings,” the investigators stated in their paper, “shed new light on the molecular mechanism underlying the early steps of epithelial development, a process that is anticipated to have implications that extend beyond the hair follicle.” Those implications include better understanding of organ development, and of the development of cancers from epithelial tissue, they said. The investigators are currently using the development of hair follicles as a model system to learn more about epithelial budding and its implications for specialized cell formation.

Other recent research along the same lines has also contributed to better understanding of hair follicle development:

Bernet KM et al. Keratin 16 expression defines a subset of epithelial cells during skin morphogenesis and the hair cycle. J Invest Dermatol 2002; 119:1137-1149.

Smith FJ et al. Cloning of human, murine and marsupial keratin 7 and a survey of K7 expression in the mouse. Biochem Biophys Res Commun 2002; 297:818-827.

Laurikkala J et al. Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor EDAR. Development 2002; 129:2541-2553.

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