• Policy
  • Alopecia
  • Aderans Research & Development
  • Research Partners
  • Endowment Department・Joint Research
  • Research Partner Companies

Aderans Research & Development

The roles of collagen XVII that maintains hair-producing stem cells have been elucidated

Professor Emi Nishimura discovered the presence of melanocyte stem cells next to hair follicle stem cells and elucidated the system of hair turning gray. The research has been further developed and focused on collagen XVII expressed in hair follicle stem cells. When collagen XVII is missing, the conditions of gray hair as well as thinning hair are found to progress and cause hair loss. We asked Professor Nishimura about the meaning of “hair restoration” in humans and the ways to prevent hair loss.

Research to elucidate the mechanisms of age-related thinning hair/hair loss

Why does hair loss occur?
In humans, hair grows back every 2 to 6 years while repeating the hair growth cycle consisting of the anagen, catagen, and telogen phases. For example, most cases of premature balding on the front hairline and forehead and on top of the head in males are called androgenetic alopecia, which is known to be affected by the male hormone. Based on its mechanisms, some therapeutic drugs such as finasteride have been developed.
In contrast, when people get older, hair over the whole head gets thinner as one of the signs of senility and the scalp hair-whorl or scalp line become mainly visible. These conditions are called age-related thinning hair/hair loss. But are we give up fighting to prevent hair loss because “we are old now and have nothing to do about it.”
Professor Emi Nishimura is the person who have clarified the mechanisms of age-related thinning hair/hair loss, together with gray hair related to aging, through her research on “stem cells, and who continuously devotes herself into the task of elucidating the conditions of age-related diseases and developing/performing research on new treatment.
“When I was little, I had atopic dermatitis, causing itchy skin and rashes. I was very curious about those conditions and started to have a strong interest in the skin. That is why I became a dermatologist,” said Professor Nishimura, who became engaged in the research on the mechanisms of development of melanocytes (and obtained a doctor's degree) at the Kyoto University Graduate School of Medicine.

The mechanisms of gray hair were elucidated based on the discovery of melanocyte stem cells

Could you explain in details about the research on melanocyte restoration that you started to perform next?

Among pigment disorders, there is a disease called vitiligo vulgaris, known to be white patches. In the process of disappearance and healing of vitiligo with ultraviolet therapy, small dots of pigmentation form exactly at the pores and become bigger until the disease is cured. Because this phenomenon was so mysterious that I recreated the very similar phenomenon in mice. This research was started to find out whether the cells of the original source of the pigment would exist in the hair follicles housed in the pores or the cells that could become the original source of melanocytes, the cells to produce a pigment, would exist in the hair follicles.
As a result, hair follicle stem cells were found in the bulge region at the middle portion of the hair follicle, where, in fact, the cells of the original source of melanocytes were also found. When the skin receives the ultraviolet light, those cells are activated and move towards the surface of the skin, where pigmentation develops again and is continuously increased. Those cells, the original source of melanocytes, are actually melanocyte stem cells, which we found in 2002.

What roles do melanocyte stem cells play?

Melanocyte stem cells usually act as the suppliers of melanocytes that become black hair. Around the bulge region, melanocyte stem cells are located next to hair follicle stem cells that produce the cells that grow hair. Whenever hair grows back, melanocyte stem cells and hair follicle stem cells produce hair with pigments.

So, are melanocyte stem cells the ones that play a role in producing black hair?

Yes, they are. But, hair follicle stem cells, which are located next to melanocyte stem cells, are niche cells that are responsible for providing a microenvironment necessary to maintain melanocyte stem cells. In other words, hair follicle stem cells play roles not only in producing the cells that grow hair, but also in maintaining melanocyte stem cells. So, if hair follicle stem cells disappear, melanocyte stem cells also disappear.

Some people never lost hair but they get gray hair. Why is that?

Mice also have hair follicle stem cells, and they get gray hair when melanocyte stem cells tend to become weaker. For example, if the MITF gene mutations occur, mutant mice's fur turns white every time when it grows back, so we investigated the hair follicles in mice to find out how their melanocyte stem cells work. The results showed that melanocyte stem cells gradually disappeared and even melanocytes that are supposed to exist in the area where the hair matrix is produced disappeared.
In humans, the hair follicle produced by hair follicle stem cells grows and shrinks during the hair growth cycle, and as the hair follicle grows down, melanocytes produced by melanocyte stem cells are usually passed down. However, when melanocyte stem cells become weaker, melanocytes remain in the place where stem cells exist (niche), so they cannot reach the hair matrix in which hair is made. That is why no black hair can grow. This happens when our genetic information or DNA is damaged, so melanocyte stem cells cannot be maintained, meaning that there is no production of melanocytes and hair turns gray.
In 2010, we presented the further detailed mechanisms of gray hair, and through the research we came up with other questions, such as why hair gradually narrows and thins with aging and what is happening deep in the skin, so we seriously started to perform the research on hair.


Collagen XVII is indispensable for maintenance of hair follicle stem cells

As mice usually have a life expectancy of 24 to 34 months, the hair follicles of wild-type mice that can live longer were examined for a long time, such as for 12, 24, and 28 months. In the course of the study, the hair follicles themselves got dramatically smaller and became miniaturized. Even in humans, the miniaturization of hair follicles occurs when androgenetic alopecia progresses, so we found out that the miniaturization of hair follicles could also occur with aging in a similar manner.
Hair follicle stem cells and melanocyte stem cells exist in the bulge region of the hair follicle, and we found out that collagen XVII played an important role in maintaining those stem cells. The hair follicles in which collagen XVII was also decreased with aging were increasing.

The research group led by Professor Nishimura published an article stating that “collagen XVII can reduce gray hair and hair loss” in the international scientific journal Cell Stem Cell in 2011. What types of roles can collagen XVII play?

If collagen XVII (COL17A1/BP180) is congenitally missing, people develop the disease called junctional epidermolysis bullosa, and particularly, when skin friction occurs, patients with this disease are known to get blisters easily and develop alopecia in which hair is lost at a young age.
First, as the main role of collagen XVII, it plays an important role in mooring and attaching hair follicle stem cells themselves to the basal lamina. In the absence of collagen XVII, hair follicle stem cells cannot be attached, so they are released in an immature condition from the bulge region, not functioning as the stem cells, and become the matured cells and then keratinocytes in the epidermis. As I said earlier that hair follicle stem cells play a role in maintaining melanocyte stem cells. However, when hair follicle stem cells cannot sufficiently maintain melanocyte stem cells, hair follicle stem cells can provide the hair follicles with the cells from which hair can grow but not with melanocytes, the offspring cells of melanocyte stem cells, meaning that hair turns grey.
What we found out in the research using aged mice was that the hair follicles without collagen XVII were increased on the back of mice. Even in humans, the hair follicles with collagen XVII were decreased. In fact, we analyzed the excess skin in the temporal area that was resected during surgery for several years after obtaining consent from patients. Compared to the hair follicles in a patient aged 40 years old, those in a patient aged 59 years old were found to be small and the region where collagen XVII existed in the hair follicles was extremely small. Accordingly, the hair follicles themselves that were regenerated got small, so it was found that hair gradually narrowed and the number of hairs also decreased.

What is the difference between collagen XVII and other general collagens?

Generally, there are about 20 types of collagens. Collagen XVII is the transmembrane collagen shaped like an anchor to connect stem cells and the basal lamina. For example, collagen I is distributed in the dermis as the extracellular matrix, gives elasticity to the skin, and also acts as a protective cushion, while collagen XVII, in which stem cells are expressed at higher levels, plays a role in attaching the cells to the place where stem cells exist. Collagen XVII is indispensable for hair follicle stem cells to function as niche cells for melanocyte stem cells and its role in attaching the cells was found to reduce gray hair and hair loss.
Specifically, hair follicle stem cells, when attached to the basal lamina, are maintained in an immature condition as if they are staying in a cradle. However, when collagen XVII is degraded due to a stress reaction to DNA damage with aging, hair follicle stem cells are released in that condition and end up becoming the matured cells, not the cells that can produce hair but keratinocytes in the epidermis. Incidentally, those keratinocytes do not remain in the epidermis permanently, but are shed off the surface of the skin and released outside the skin as dandruff and scurf.

What is exactly the decrease of collagen XVII due to DNA damage?

DNA damage can happen to anyone while humans are alive and breathing and their cells are divided. Everyone has an ability to repair damage to their DNA, however, if aged persons or patients with progeria have lower abilities to repair, damage to their DNA occurs. When it happens, the DNA repair signaling is sent to stem cells, which cannot continue sleeping, so they are differentiated and matured to keratinocytes.

Can collagen XVII be metabolized by other collagens?

The transmembrane collagen that connects those cells and the basal lamina cannot be injected like other collagens, so the important key to prevention and treatment of thinning hair and hair loss is to prevent collagen XVII from being decreased.
One of the causes of degradation of collagen XVII is DNA damage, and to repair damage to DNA, the enzyme called neutrophil elastase is produced in hair follicle stem cells by mistake, which is most likely to cause degradation of collagen XVII. Neutrophil elastase is an important catabolic enzyme to fight against bacterial infections, and when neutrophil elastase is activated inside stem cells, it decomposes collagen XVII that is connected to stem cells and cuts its connection.
Accordingly, we are examining the possibility of reducing hair loss through the inhibition of degradation of collagen XVII by inhibiting neutrophil elastase. We are also conducting research for a drug to prevent collagen XVII from being decreased or to increase it.

Please provide us with the methods to prevent thinning hair or hair loss, or to slow it down.

The miniaturization of the hair follicle progresses with aging. If it does too much, hair cannot be easily treated, so I would recommend you to take measures when you are relatively young. Stem cells are gradually decreased with aging, but they do not completely disappear suddenly. We try to develop a technology to keep the remaining stem cells alive somehow and completely maintain the stem cell pools that an individual person has.

Interviewer/writer: Akiyoshi Sato Photographer: Kuninobu Akutsu, Naoyuki Tamura

History of development, products and services based on research of Aderans
Return to the Top Page