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What is regenerative medicine using stem cells including human iPS cells?

“Using human iPS cells and mouse cells, hair-producing hair follicles were regenerated.” Professor Ohyama, who has been getting attention as the researcher in the state-of-the-art science of hair restoration, strives to elucidate the conditions of autoimmune alopecia and develop its treatments, saying “I want to apply the results of my research to clinical settings as soon as possible,” while he is clinically involved in the treatment of many patients.

The statement “using human iPS cells and mouse cells, hair-producing hair follicles were regenerated” was publicly announced. If the hair follicles can be made by iPS cells, will hair restoration become possible in the future even in patients who have lost the function of the hair follicles to produce hair on the scalp?
?We asked Professor Ohyama who challenges himself in the state-of-the-art hair regenerative medicine using the hair stem cells and iPS cells.

Treatment while showing compassion toward patients and practical research on hair

I am conducting research out of my desire to apply the results to patients who are currently hospitalized as soon as possible. For example, alopecia areata is an autoimmune disease, in which the immune response to the hair follicles occurs in the body and inflammation develops at the hair roots, that is, in the hair bulbs, so it is the disease that causes hair loss. Some patients with alopecia areata have fulminant or accelerated disease which is more severe than that is generally considered and in those patients, alopecia areata affects the whole scalp and causes hair loss. Although it can be treated with steroid IV infusion, its efficacy varies in each patient.
Although the research on “hair production followed by hair transplant” using iPS cells is easy to understand, to be honest with you, I still have some doubts about whether it can be established as medical science. First, it takes time and cost. For that reason, it may be more meaningful to establish an experimental system by creating hair models using iPS cells, regenerating what happens in the Petri dish, and evaluating how the cells react through various studies.
To produce hair using iPS cells, it is necessary to study how well the epithelial cells that are induced to produce hair and the mesenchymal cells (stem cells) that induce to produce hair can be interacted to produce the tissues. I think this research is important to apply its results to patients in the future, but it takes more time to be applied in the clinical setting. Because of this, this research has been performed simultaneously with other clinical studies whose results can be applied in the clinical setting soon.

Discovery of the site where the hair stem cells exist
Hair restoration using the human iPS cells

Could you tell us about what triggered you to start your research on hair?

There are so many types of epithelial cells and specifically differentiated appendages such as sebaceous glands in the hair follicles that produce hair, so the structure of one hair follicle is filled with the various elements of the cells. Due to the complicated interaction of the epithelial cells with the mesenchymal cells, such a complicated structure can be regenerated, and its basic principle is same as those of other organs in humans.
I used to conduct research on autoimmune disease called bullous disease and came up with gene therapy as one of the treatment of the disease. Gene therapy is a form of therapy that involves inserting genes to produce protein which is missing and changing the characteristics of the cells. The way to maintain the effects of gene therapy permanently and for a long period is to insert genes into the stem cells that can be the original source of the tissues. In the 1990s, however, the existence of the hair stem cells that could produce hair, sebaceous glands, and the skin, was known, its location was believed to be somewhere around the hair roots or hair matrix cells. Back then, there was no technology to collect the hair stem cells yet.
As a result of the collection of the human hair follicle stem cells, the hair stem cells were found to exist not at the base of hair but in the muscle, that exists in the area higher than where the hair root exists and helps hair stand up, that is, at the bulge in the arrector pili muscle. The hair stem cells were found to protect themselves by sending out the various molecules such as the immunologic suppressor factors.
Fortunately, CD200, as one of the various molecules produced by the stem cells, was also expressed on the surface of the cells. Using that molecule, we succeeded in detaching the world's first living cells abundant with the hair stem cells. Based on that, the human hair stem cells were able to be collected and cultured, which contributed to further advances in research on regenerative medicine using the hair follicles.

Professor Ohyama has been involved in the research on restoration of the hair follicles using iPS cells.

桑名 隆一郎 医師

Recently, the therapeutic technology for androgenetic alopecia has advanced greatly. As oral therapy, finasteride and dutasteride (*See page 3) are available, as well as the various hair grow technologies are about to be established. In alopecia areata, the hair matrix cells can be damaged, while the stem cells remain alive, so hair can regrow with the proper treatment.
The disease that is really difficult to treat is cicatricial alopecia, in which the immune response to the stem cells occurs in the body and the tissues are destroyed, so hair regrowth is hopeless. This disease can be partially caused by connective tissue disease, so that it requires early diagnosis and treatment. In alopecia areata, which is also intractable, its onset mechanism and the related signaling pathways are about to be elucidated thanks to the global genetic analysis, and the future-oriented promising therapeutic methods including JAK inhibitors are soon to be developed. However, if the hair stem cells themselves are gone due to the occurrence of cicatricial alopecia, no hair can grow anymore. As the method for treating such an intractable alopecia, the restoration of the hair follicles using iPS cells are expected in hair restoration.

That must be the therapeutic method in which the hair follicles are restored after the dermal papilla and the hair stem cells are produced using the human iPS cells.

However, it is still not versatile, because the inflammatory reaction continuously remains in the body of patients with cicatricial alopecia, where the stem cells are gone. The disease may look like resolving without the targeted stem cells; however, when the hair follicles newly produced using iPS cells are transplanted, they will become the new targets and hair loss occurs. Before talking about whether hair can be produced in the restoration of the hair follicles, the disease in which hair loss occurs due to inflammation must be first elucidated. As a new way of thinking, if it is possible to produce the cells that could control inflammation or produce the hair follicle cells that could inhibit immunity using iPS cells, this will also become one of the significant solutions.

Explore new approaches in the treatment of hair loss by applying the basic medicine in the clinical setting

What are your current treatment goals with the stem cells, iPS cells, and the clinical application?

As one of my goals, there is a method in which the stem cells are extracted from the existing hair because its structure still remains in many patients with alopecia and amplified to be used for treatment in regenerative medicine through the culture and manipulation. At present, if the stem cells are cultured for a long period, their special characteristics will be lost. We are currently conducting research on the culture technology in which their special characteristics are not going to be lost.
In the future, I believe that the cells having the ability to become the components (structural elements) of hair produced using iPS cells are likely to be used for development/ research on therapeutic methods.
As the measures to be taken when the disease conditions in patients are actually examined to find out which cell structures are damaged and how they can be treated, that is, when the mechanisms behind the disease has been elucidated, the approaches using the various stem cells may be useful.

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

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