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Our dreams “hair multiplication followed by hair transplant” are about to come true thanks to the rapid advancement in regenerative medicine

The 21st Annual Meeting of Japan Society of Clinical Hair Restoration will be held on Saturday, November 26, 2016.We asked Kazuo Kishi, professor of Keio University School of Medicine, who will host this scientific meeting as a chair, and Sotaro Kurata, hospital director, who is a famous hair expert, to talk about “how much hair medicine has advanced.”

How much has hair regenerative medicine advanced?

I believe that the theme of the 21st Annual Meeting of Japan Society of Clinical Hair Restoration that will be held at the end of November this year is “Dream Comes True.”

桑名 隆一郎 医師

Kazuo Kishi:Although research on hair has been performed for many years, our dreams about hair, including basic research and oral therapy, are about to come true finally. As basic research, regenerative medicine has specifically begun, so that our dreams about growing hair using regenerative medicine are almost coming true. As oral therapy for androgenetic alopecia (AGA), Propecia (finasteride) used to be the only drug available; however, dutasteride was newly launched and thought to have played an important role in our dreams.
In addition, the skin requiring hair transplant can be now collected using a robot for hair transplant surgery and it will be exhibited at the meeting this time. Our dreams about growing hair are coming true from various aspects. It seems to me that a lot has changed in one year.

Specifically, how much has regenerative medicine advanced?

Sotaro Kurata:Regenerative medicine has dramatically advanced and there are many notable research studies.

Kishi:For example, there is one research study that has been performed by Prof. Ryoji Tsuboi of the Tokyo Medical University and Dr. Jiro Kishimoto of Shiseido. When I saw Dr. Kishimoto the other day, he said that the information from his research would be applied in the clinical setting in 5 years. The goal of their research is to activate the dermal papilla by transplanting the stem cells located at the connective tissue sheath surrounding the follicle dermal papilla cells, that is, to activate and then reinforce the hair that became small. Its goal is not to grow hair?because gradual thinning of hair does not mean the loss of hair roots, but the miniaturization and shrinkage of hair roots?but to return the hair to its original thickness.

Kurata:This was the idea originally conceived by a company in Canada.

Kishi: It is clinically to rejuvenate originally existing hair, that is, to rejuvenate the hair by transplanting the original cells into which the hair grows, not to increase hair dramatically. This method is quite easy to understand. Another research, which has steadily been performed for a long time by the group led by Dr. Takashi Tsuji of the Riken Center, is about the transplantation of epidermal stem cells together with dermal stem cells. It has also been reported in Nature Communications.

Kurata: It is the technique called the organ germ method. Our hair grows induced by the mesenchymal follicle dermal papilla cells and follicular epithelial stem cells. In this method, both types of stem cells that originally provide hair are increased and combined. Since the group led by Dr. Tsuji has been successful in tooth regeneration, I got the impression that the results of their research would be soon applied in the clinical setting.

Kishi:That is the regenerative method originally using the interaction between the epithelium and the mesenchymal system.

Kurata:Most organs of the human body are constructed with those two types being interacted. In that aspect, this method makes sense.

Kishi:When Dr. Tsuji mentioned the actual progress in their research through the special lecture given at the Research Council Meeting of Japan Society of Plastic and Reconstructive Surgery, he also said that most organs could be developed by stem cells in the body, but the more perfect skin could probably be made using embryonic stem cells, that is, iPS cells. However, he said that among all parts of the skin only the hair could be made by stem cells in the body.

Kurata:In other words, stem cells are very primitive and naive cells, so that the most basic stem cells can be used for anything. If stem cells at the next stage or tissue stem cells (hair follicle stem cells) that are set to differentiate into certain directions are used, they will differentiate into those directions. This technology in which cells can go back to their original state seems very advanced and incredible.

Regeneration of the normal skin containing hair, sebaceous glands, and sweat glands

桑名 隆一郎 医師

Kurata:Of course, there is a high possibility that hair can be regenerated using iPS cells. Since hair is part of the skin, the regeneration of the whole skin will be further studied. The skin contains not only the epidermis and the dermis, but also various appendages. If the whole skin containing the hair apparatus called hair follicles to which sebaceous and sweat glands are connected can be regenerated, it will become a significant element for the clinical application in plastic surgery. The era of regeneration of the whole skin will possibly come.

Kishi:But in reality, cultured epidermal sheets are only used for that purpose at present and they have not yet included any body hair or sweat glands that Dr. Kurata mentioned. When the sheets can be really created in a three-dimensional manner, there will be a good chance that the high-quality skin that can smooth scars such as burn scars can be regenerated. The principle of hair restoration seems the same.

Kurata:When hair is regenerated using regenerative medicine, the same stem cells are called as hair follicle sebaceous glands, by which sebaceous glands will be also regenerated. If, just like these, sweat glands can be regenerated under some conditions or the skin on any different areas of the body can be regenerated depending on the conditions, which would be great.

Are those conditions different depending on the skin on each part of the body?

Kurata:They are totally different. Depending on the areas of the body, the skin has different thickness and number of appendages. Of course, the thickness of hair is different in each area. In plastic surgery, skin grafts are performed for each burn scar by transplanting the skin whose characteristics are close to those of each scarred site, but that method has its limits.

Kishi:Even though plastic surgeons seek to restore the normal skin, a scar can remain on the skin after injury. When scars are looked closely, some have no hair and others have no sweat glands. And the texture on the surface of some scars have no fine pores that can be seen on the skin at magnification. Conversely, if each of those conditions can be fixed almost completely, the normal skin condition can be restored eventually. Hair plays a significant role in the process of restoration. If hair restoration is possible, the regeneration of sebaceous glands and sweat glands can be possible simultaneously.

So, the skin is an integrated organ, consisting of hair, sebaceous glands, and sweat glands.

Kishi:Hair grows through the skin where its grooves crisscross each other. In addition, the sweat pores open from the center of the skin ridges separated by grooves. Therefore, when hair restoration can be performed, skin regeneration itself can also be performed in near future due to its integration. The skin varies depending on the area of the body. No hair grows on the epidermis layer of the skin of the palm.

Kurata:There are, however, some exceptions. In mice, hair can grow on the palm when hair follicle dermal papilla cells are transplanted there. Any types of epithelial cells can be used because the control censor for hair restoration is located on the side of mesenchymal cells of dermal papillae. This fact has been known for a long time. The article published in the 1960s described the rat whisker dermal papilla cells transplanted into the ear and changed into thick whisker. Its discovery was originated from the research on the feathers of birds performed in the 1940s. The dermal papilla cells also exist at the base of the feathers of birds and control the color and characteristics of the feathers of birds. The cultured feathers of birds led to the cultured hairs of animals. So, the control for hair restoration had been said to be on the side of mesenchymal cells from the beginning.

When would hair restoration by regenerative medicine using stem cells be possible?

Kurata:I don’t think it will be completed in 3 years, but the research has been performed in the hope that the results would be clinically used up to a certain level.

Various methods of extracting the cytokines that induce hair restoration

Much attention has been focused on the use of iPS cells in hair restoration. How much research has been done on that?

Kishi:Even though iPS cells are more advantageous in terms of producing cells that are in favorable conditions for restoration, it is extremely difficult to perform hair restoration using iPS cells. Currently, the preceding research on the retina has been performed while its safety has been investigated. We still don’t know, not to mention financial issues, whether it is possible to generate iPS cells for a patient and transplant those into the patient. As I have long been conducting research involving fetuses, it is surely difficult to generate cells that are close to those of fetuses without the process of generating iPS cells once. Similar to the case of retinal restoration itself, we face a huge challenge of eventually creating organs using iPS cells.
However, its safety must be confirmed beforehand. If the cells in the retina become tumorigenic (cancerous), laser treatment can be actually applied to cure conditions. So as the skin, from the viewpoint of safety, it can be removed if needed. In that sense, those organs such as the retina and hair may not be complicated.

Kurata:Since those organs cover the external surface of the body, they can be easily found.

Do iPS cells become tumorigenic that often?

Kishi:I don’t use iPS cells in my research, but when I asked other doctors who actually use iPS cells, they said that looking for the cells that are never going to become tumorigenic is quite difficult.

Kurata:All the iPS cells are said to be able to differentiate and have high proliferation capacity, meaning that they may go in the wrong direction. For that reason, it is very difficult to establish conditions under which those cells can stay on the rails only in the direction we prefer to go. In that sense, how about hair restoration using adipose-derived stem cells?

Kishi:Currently, adipose-derived stem cells are very popular, but they give a strong impression of their usage associated with angiogenesis. Some examples include: favorable lipotransfer fixation and favorable outcome of wounds that are unhealable due to foot lesions by applying the functions of stem cells to restore the tissues and mixing it with fat. In case of hair restoration, hair grows out of the epidermal cells in combination with the dermal cells. It seems that fat may have such stem cells from which any types of cells can be generated. For example, there are bone marrow stem cells that can be generated into any types of cells, just like adipose-derived stem cells. In the bone marrow, there are stem cells that produce angiogenic factors, which have the substantial potential to improve blood circulation. However, I don’t think different stem cells from other organs can do the same just because bone marrow stem cells can do.

Kurata:There are different types of stem cells, such as adipose-derived stem cells, bone marrow stem cells,and umbilical cord blood stem cells. After all questions?what those stem cells can produce, which types of cytokines they can produce, or how much cytokines stem cells themselves can produce?are clear, the method to use which types of stem cells for what purpose will be important. The important thing is to extract cytokines from a conditioned medium (the culture supernatant collected from a cell culture prepared for certain periods of time) and bring it to the level where the cytokines necessary for hair or angiogenesis can be surely selected. If not, this may not work well. Recently, stem cells are too often used for beauty care because the term “stem cells” has a great deal of influence over people or people came to recognize stem cells as being versatile. It seems slightly different from what I think.

Kishi:Stem cell transplantation gives the impression that stem cells can produce something good to the body, such as cell regeneration or cell-based regeneration of an organ. This is not said so often, however, that stem cells can possibly produce something bad. Accordingly, we should have a doubt about the idea “it is good because they are stem cells.”

Kurata:Hair grows according to the hair growth cycle. So, it is good when stem cells produce the cytokines that induce the anagen phase or thicken hair. However, stem cells can also produce the cytokines that induce the catagen phase. When all those stem cells in different conditions are transplanted into the body, they get confused and don’t know what they are supposed to do. Actually, I think the best way to establish therapeutic techniques for hair is to find out those things and then analyze them scientifically. However, we are still in the level where we don’t know what types of cytokines are extracted from stem cells, so researchers should keep it in their minds that something controversial can possibly happen.

What will be other remarkable aspects of this upcoming scientific meeting?

Kishi:During the scientific lectures on the second day, we will have Dr. Kenji Kusumoto of the Kansai Medical University talk about platelet rich plasma (PRP: the component of collected blood that has been enriched with platelets) which is also effective on hair. An injection of PRP only can effectively improve fine wrinkles and hair growth.

Kurata:I believe that PRP can also produce cytokines. Eventually, the important thing is which types of cytokines are included and how they can have effects. Even though we still don’t know all the cytokines that include PRP and how they can restore, thicken, or strengthen hair, there is the impression that there are currently various methods of extracting and adopting the original sources of those cytokines. Similar to stem cells mentioned earlier, culture supernatant of stem cells and PRP are currently popular. So, all those may be summarized as the term “cytokines.” For example, the research on LED is about extracting cytokines from the cells in a patient. We can say it in either way?cytokines are added externally or they are extracted internally.

Kishi:There is a very important aspect to regenerative medicine. Since the Act on the Safety of Regenerative Medicine is newly established, we will have Dr. Rika Tanaka of the Juntendo University talk about the procedures required to perform regenerative medicine.

Kurata:The almost popular method for beauty care is to culture adipose-derived stem cells derived from a patient and infuse them into the patient’s veins. This is a potential medical care, but I also think that evidence must be carefully observed.

Kishi:The levels of difficulty of regenerative medicine have become dramatically lower after the Act on the Safety of Regenerative Medicine was newly established; however, if any significant issue occurs after the initiation of research or treatment, such research or treatment may be discontinued suddenly. Regenerative medicine should be carefully performed.

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

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