Hair Follicle Morphogenesis

Hair follicle appendage formation involves a complex sequence of signals between the dermal mesenchyme and the overlying epithelium. The precise initiating stimulus is still to be defined. Morphologically, induction, organogenesis and cytodifferentiation phases can be determined, and a division of hair follicle formation events into eight distinct developmental stages in rodents and humans can be made. The development of human hair follicles first starts between the 8th and 12th weeks of gestation. Probably in response to dermal signaling elements, which are expressed in gradients over the developing fetus, thickening of the primitive epithelium forms placodes that induce the aggregation of underlying dermal cells to mesenchymal condensates – the first visible stage in hair follicle development (Fig. 1.1). The very first hair follicle placodes are seen in the eyebrow, upper lip, and chin regions. Placode formation subsequently expands in a wave caudally and ventrally over the skin of the fetus. The dermal condensates issue instructions to the cells of their associated overlying ectodermal placodes to proliferate and initiate penetration of the dermis; stage 2 of development. As the epithelial cells grow downwards into the dermis, the dermal condensate cells lead the way. The hair follicles grow into the dermis at an angle to the skin surface, with the degree of angle determined by the location of the hair follicle. The initial placode formation stage gives way to an early peg stage (stage 3) hair follicle. By 12–14 weeks’ gestation, the epithelial base of the hair pegs on the scalp invaginates to envelop the dermal cell condensates and form dermal papillae. This stage of development is described as the bulbous hair peg stage, or stage 4 in development.


In stage 5 at 13–16 weeks’ gestation, the superficial portions of the hair follicles subsequently develop two distinct, asymmetrical bulges of cells on the “posterior” side of the follicle, which is at an obtuse angle to the skin surface. The upper bulge closest to the skin surface eventually forms the sebaceous gland, while the lower bulge forms the location of the presumptive follicular stem cells and will later anchor the developing arrector pili muscle to the hair follicle. The arrector pili muscle itself develops independently of the hair follicle and is usually first seen in the dermis near the developing sebaceous gland. The arrector pili muscle grows downwards to connect with the bulge region as the follicle pushes deeper into the dermis. Notably, the arrector pili muscle does not develop in hair follicles growing perpendicular to the skin, such as eyelash hair follicles, follicles of the external auditory canal, and those of the nasal orifice. The outer cells of the bulge, destined to become the sebaceous gland, proliferate and some differentiate into lipogenic cells that progressively accumulate lipid. Maternal hormones cause sebaceous gland hypertrophy and temporarily increase the synthesis and secretion of sebum during the second and third trimesters. With release under the influence of maternal hormones at birth, the sebaceous glands become relatively quiescent until endogenous hormone production increases in puberty. In humans, some hair follicles will develop a third superficial bulge of cells above the cells destined to become the sebaceous gland. The development of this third bulge of cells indicates the formation of an apocrine gland. In humans the face and scalp are the most common locations for hair-follicle-associated apocrine gland development. While hair-follicle-associated formation of apocrine glands can be common in other mammalian species, in humans the association is relatively infrequent.

In the second trimester, the hair follicles differentiate to eventually form the seven layers of cells in concentric cylinders seen in mature hair follicles. Beginning near the bulb at the end of stage 4 or at the beginning of stage 5, a core of epithelial cells separates from the peripheral epithelial cells which later become the outer root sheath, continuous with the non-follicular epithelium. The epithelial cell core, resting on the top of the dermal papilla, further differentiates into the inner root sheath Henle, Huxley, and cuticle layers, and the central core of matrix cells that proliferate and give rise to the hair fiber cuticle, cortex and, later in terminal hairs, the medulla. Stage 6 is defined by the visible development and growth of the hair fiber. As the hair fiber and its inner root sheath elongate, the peripheral epithelial cells move aside to allow the cone of the central core of cells to move upwards away from the bulb. By 19–21 weeks’ gestation, the developing hair follicles reach stage 7, in which the hair canals form. In stage 8 the hair follicles are fully formed and the first hair fibers erupt from the skin. The initial lanugo hair of the first anagen hair growth phase grows until 24–28 weeks of gestation.