• Hair follicle cycling
• Why do hair follicles cycle?
• Theories of hair follicle cycling
• How and why do hair follicles cycle references

Hair follicle cycling

Whilst these alterations to hair growth provide some clues as to how the hair growth and regression mechanism works, we do not know what defines the normal clock cycle. The key question is what triggers a growing follicle to switch off and enter a telogen resting state? How does the hair follicles know that after x number of days growth it should switch off? And how does the hair follicle know that it must switch on again after x number of days in a telogen resting state? These are questions that we cannot answer with any confidence. There is much speculation that some factor gradually accumulates in the hair follicle over the duration of anagen growth and when it reaches a certain concentration it triggers the follicle to switch off. As the factor dissipates in telogen so the concentration may drop to a level that triggers the follicle to switch back on again. However, this is just one of several possible mechanisms that may be involved and right now there is no evidence in support of any hypothesis as to how hair follicles regulate their growth cycle. In short, no one knows what regulates the hair follicle clock cycle.

All mature hair follicles have a permanent portion above the point of the arrector pili muscle insertion and a transient portion below. During anagen, there is complete regrowth and regeneration of the lower portion of the follicle on receiving the proper growth signals. The earliest changes begin in the cells of the papilla and the secondary hair germ – the epithelial cells at the base of the telogen follicle. The cells of the secondary hair germ first go down as an epithelial finger. When they reach a certain depth, the cells in the central cylinder differentiate and move upwards forming the inner root sheath and the hair shaft. These cells also undergo large structural changes to produce the rigid IRS and hair shaft. It has been found that the actively dividing cells of the lower matrix express a high level of LEFI agents like telomerase, while the zinc finger protein basonuclein is expressed by ORS cells during the anagen phase.

After a period of time, follicular growth stops and catagen begins. The exact signals responsible for this change in not fully understood. It may be due to accumulation of growth inhibiting agents or because of the limited number of mitoses of the growing cells. Severe stress, trauma or chemicals can also precipitate catagen. The catagen process of cell differentiation tops cell growth and pigmentation, the papilla is released from the bulb and there is marked remodeling of the matrix cells.

By the time telogen or the time of rest begins, the hair follicle is only in the upper dermis, sitting on top of a cluster of papilla fibroblasts. There is no DNA or RNA synthesis of protein such as trichohyalin and cortical keratin. K14 synthesis, however, continues in the telogen follicle. In the epithelical sac of the telogen follicle, the club hair is embedded. This is composed of tightly packed small cells known as the hair germ. When the follicle enters the anagen stage, these germs swell and go down to enclose the papilla.

Thus, the cycle indicates an ectodermal – mesodermal interaction which leads to growth, regression and tissue remodeling. The epithelial stem cells differentiate into hair matrix, outer root sheath, inner root sheath, kerationcytes, as well as the cortex of the medulla of the fiber. Hair follicle epithelial stem cells can also regenerate sebaceous glands or epidermis after a loss. Again, at the end of anagen, these cells, which were actively needed for hair growth, are deleted by apoptosis. Along with the epithelial cells, other cells of the epidermis also undergo a cyclic change of proliferation, differentiation and apoptosis. The mesenchyme of the follicle, the extracellular matrix and the blood vessel distribution and the nerves of the follicle are also remodeled along with the different stages of the follicle cycle.

It has been clearly established that the oscillatory system that is responsible for this clock resides in the follicle itself and in the surrounding tissues and is not stimulated by any central system. Extending beyond hair research, this enigmatic oscillatory system leads to the premise that other biological tissue remodeling events are controlled by biological clock systems in the peripheral tissues itself where such changes are taking place.

Why do hair follicles cycle?

Cycling is a unique feature of the hair follicle, no other structure in an adult mammal cycles in such a way. A single answer is not possible, but a number of reasons have been cited by biologists. Foremost among them is that skin molting is an integral characteristic of all organisms. Hair being an appendage of the skin is also shed periodically. Animals shed their fur to adapt to seasonal changes and during the mating season. Fur is also shed to cleanse their body surface, protect from improper formation of follicle or to protect from malignant degeneration, which might occur due to rapid cell degeneration.

Although this explains the hair follicle cycle in animals, it does not explain the cycling of individual follicles in other mammals. Even in rodents and other animals that display synchronized cycling of follicles, the cycle becomes heterogeneous as the animals age, and there are also individual waves of hair follicle cycling traveling through the skins of these animals. An argument presented by Jahoda suggests that the hair follicle cycling is an evolutionary process and originated from the need to regenerate a single shaft of hair, when it had been lost. The cycling process has perhaps evolved only because of wear and tear due to environmental pressures.

Hair follicle cycling also allows limiting the length of the hair shaft on a particular location in the body. The eye brows, facial hairs, scalp hair etc all have a distinct length as very long hairs on these parts would cause an impediment to seeing, smelling and other functions. The anagen phase in different skin locations differ, thereby restricting hair growth. The follicle grows only as long as it is in anagen. Furthermore, the regular shedding of the shaft helps to clean the skin of parasites and other harmful toxic material that may be produced. It therefore serves as a survival mechanism for the species.

The regenerative property of the follicle also contributes to the survival mechanism. Whenever the follicle is destroyed, as in chemotherapy, the speed of cycling is accelerated – damaged anagen bulbs are rapidly destroyed, there is a premature onset of catagen, followed by a very brief telogen. A new anagen hair bulb is thus formed at a surprising speed. As the hair is such a vital organ, cycling thus helps to keep the regeneration mode alive.

During the anagen phase of the hair follicle cycling, several growth-modulating agents are produced in the follicle. Cytokines, neurotrophins and growth hormones that are usually found in the hypothalamus, pituitary or adrenal glands are expressed in anagen. These agents are generally used by the follicle for its own growth pigmentation, innervations and vasculature, but the hair follicle may also secrete these into the surrounding skin or even into circulation. Again, since these agents are expressed only during anagen or catagen, they are dependent on the cycle. The hair cycling can therefore be said to be acting as a regulator for the endocrine secretory activity of the follicle.

Studies on mice with synchronized hair follicle cycling have shown that the skin architecture of the vicinity changes dramatically with each phase of the cycle. Subsequent to anagen development, the dermis, epidermis and the subcutin become thicker and show significant angiogenesis. They get thinner once again when telogen sets in. It may therefore be concluded that cycling makes the pilosebaceous unit the chief secretory agent in skin biology.

Theories of hair follicle cycling

Though the evolutionary pressures and other reasons for hair follicle cycling are understood to some extent, where the rhythm center originates is still unknown. It is commonly believed that the signals for follicle formation come from the mesenchyme, but i is yet to be understood what stimulates the telogen hair follicles to go into anagen. To initiate anagen, the cells must have some characteristics of stem cells, a way of maintaining a unique rhythm and the ability to send a signal to the surrounding epithelium and mesenchyme. The presence of soluble growth factors suggests a paracrine mechanism, but how the signal spreads is not understood. Apart from the paracrine form, it is possible that the signal is passed through the epithelium by means of an electric pulse or ion flow through gap junctions. Much needs to be explored yet in this field.

Several theories have been proposed to explain the mechanism of hair follicle cycling. Six theories have been discussed recently.

The Epithelical Theory – It suggests that in bulb area, a cluster of slow cycling cells harbor a second cycle that triggers follicle cycling
The Papilla Morphogen Theory – Growth morphogens are released by the cells of the papilla during the Go and G1 phases of their cycle to trigger anagen. It is also related to the fluctuation in mitotic inhibitors.

The Bulge Activation Theory – The cycle is initiated by the stem cells of the papilla region. The growing cells only undergo a limited number of mitosis and thereby determine the duration of anagen and onset of catagen

The Resonance Theory – This proposes that the hair cycle clock is not located in a single cell compartment, but is a result of the diffusing and reacting morphogens interacting within a whole tissue pace.

The Oscillating Signal Theory – An oscillating mechanism exists within the telogen cells which, after a definite time moves the follicle into anagen.

The Inherent Embryonic Cycle Theory – The hair cycle clock is established during embryogenesis and continues throughout life.

The Inhibition – Disinhibition Theory – A mitotic inhibitor accumulates in the epithelial hair bulb during anagen. When a certain threshold level of this accumulation is reached cell growth stops and catagen sets in. During telogen, the accumulation drops to a level of disinhibition and anagen again sets in.

Unfortunately, none of the theories fully explains the hair cycling mechanism. It is yet to be determined how the follicle cycle is autonomous and spontaneous, independent of any seasonal or circadian rhythms, and how individual cycles differ in duration. How the activities of the mesenchymal stem cels are co-ordinated and how all the remodeling of the associated tissues takes place along with follicular cycling also need to be answered. The future of hair research must therefore attempt to answer these fundamental questions of what is the central pace maker, what are the essential molecular signals to change from one phase of growth to another and what is the hierarchy and interdependence of the signals regulating the cycle.

How and why do hair follicles cycle references

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