All we want is to recreate the regenerative development process correctly. Dr. Tsuji paid attention to two different types of cells. The first is the hair follicle playmaker dermal papilla cells. The second type are cells in the bulge area. They are a type of epithelial stem cell.They can differentiate into lots of different types of cells. These two cells are separated into two different groups after fertilization. Let’s take a look at the section of the scalp two months after fertilization. Red dots represent stem cells in the bulge area. They are epithelial stem cells which are going to be skin. They are lined systematically.
Blue dots represent dermal papilla cells. They belong to mesenchymal cells and they can move between cells freely. They are called to meet together in this period, and they communicate to each other to generate a hair follicle. In this environment, they stimulate each other and grow with each other and in the end, they generate hair follicles. The most important point of this method is to make these two types of cells adhere in a high cell density environment. Tsuji and his team experimented trial and error to create the best environment for these cells.
The most difficult part of generating organs is how to configure cells. We need to pile cells up 3D but if we just use media, cells move and the method didn’t work. We mixed two types of cells randomly, and cultured them, but they didn’t generate hair follicles properly. They really needed to create the environment that can adhere two different types of cells. They decided to use collagen gel which has high velocity and close properties to the human scalp. In the collagen gel, they placed groups of epithelial cells and mesenchymal cells.
Shiseido Talks RepliCel Technology Part 2
Because the gel has high viscosity, these cells stay together. They were able to create an environment that these cells can adhere to. This simulates the time these two different cells meet under the scalp. They cultured the cells for a few days. And then, they injected cells into nude mice. Three weeks later, they observed growing hair. This is a cross section of hair follicle from the mice. Dermal papilla cells and sebaceous glands are generated. Furthermore, these hairs fall and grow repeatedly. In other words, hair cycles were created. The cycle was approximately three weeks. This is the same cycle as regular mice.
Dr. Tsuji started experiments using human cells aiming at practical use within 10 years. It’s so amazing that the hairs grew from the bald area. Nude mice are so cute. But why is putting two cells together necessary Let’s see what is going on between them. First, protein Wnt is sent from epithelial cells to mesenchymal cells to tell mesenchymal cells to grow into dermal papilla cells. Second, protein BMP4 is sent from mesenchymal cells to epithelial cells to tell epithelial cells to grow into hair matrix cells and generate hair.
Two different signals created by communication between two different types of cells induce hair follicles. So, it doesn’t work even if only one said Ok, I’m going to generate cells now. Two cells have to collaborate together. Communications between cells is the key point. Dr. Tsuji is considering to regenerate other complicated organs. One reason we are studying hair regeneration is that a hair follicle is an organ. That means we also might be able to regenerate other organs in the future. I’m hoping that I can create whole organs, such as livers, but in reality, it is very difficult.
So it’s better to start from a small organ like hair. That’s why we started studying hair regeneration. Do you mean hair regeneration can lead to other organ regenerations Other organs are made from two different types of cells like hair follicles. That’s right. Other organs are developed by communications between two different types of cells as well. For example, hair follicles, teeth, salivary glands, lacrimal glands and nails are all developed this way. The same things happen inside bodies too. Lungs and livers are developed the same way. Regenerating hair follicles could lead to other regeneration studies.
This hair follicle regeneration study is getting close to its goal, and researchers consider that they can modify the study to develop other organs. Are there any issues in this study We need to take a biopsy from a human’s body, and the amount of cells we can get from the biopsy is limited. If we can grow only one hair from one hair, that’s meaningless. We need to generate 1,000 or 10,000 hairs from one hair for practical use. Also, the method to culture epithelial cells are under development right now, so once this is established, we can use this technology for patients as Dr. Tsuji said.
But it is still very difficult at the moment. It would be so sad if a biopsy was taken and no hair grew after that. Is there is a way that we can increase the number of cells unlimitedly. Do you have any ideas iPS cells A study using iPS cells are underway right now. Dr. Ooyama from Kyorin University is studying hair follicle regeneration using human iPS cells. Keio University School of Medicine, Dr. Manabu Ooyama in Tokyo He targeted keratinocyte which is a component of skin and a kind of epithelial cell.
To induce keratinocyte from human iPS cells is to add retinoic acid and BMP4 to the media. These pictures show you the process that human iPS cells become keratinocyte. It took one month. Hair follicles are epithelial cells, so they might generate hair follicles when they meet mesenchymal cells. Dr. Ooyama came up with an idea. These are iPS cells in the middle of differentiation induction. Dr. Ooyama decided to use cells in the middle of the differentiation process between iPS cells and keratinocyte. It is a fact that younger cells have more potential to generate tissues.
It is difficult to make immature cells from adult human biopsies. So, if we say adult cells are like hair boiled eggs, it is hard to change their shape. But it is easier is we make soft boiled eggs on purpose first, and then change the shape. Only iPS cells can do this. Dr. Ooyama mixed immature epithelial cells and mesenchymal cells. And then he injected the cells under mice’s skin. After that, these structures including hair follicles, are generated. There are hair follicles inside needle shaped structures. This is a hair follicle inside the needle shaped structure. The green part is derived from human iPS cells.
They could see a bit of hair under the skin too. Hair grew under the skin! To simulate differentiation processes is really important, isn’t it When do you think we can use hair follicles made from iPS cells It will take a while. Mesenchymal cells haven’t been made from human iPS cells yet. Dr. Ooyama is using mice cells for his study, so we need to solve this issue first before we talk about practical use. Once we establish the method using mice, we can immediately apply this technology to humans, right.
Actually, it is quite difficult. In the past, there are some methods that apply to mice but not to humans. Another thing is that studies using mice are about their body hair, but we need to grow head hair. Are there any differences between body hair and head hair Hair cycles are completely different. A hair cycle of a human body hair is about 4 weeks, an eyebrow or eye ash is two months and a head hair is between two to six years long. Also, the number of dermal papilla cells per one hair follicle are different too.
The number of dermal papilla cells from a human body hair follicle is about a few hundreds, eyebrow is about one thousand, and a head hair is about three thousand. In addition, hair follicles are probably programmed by genes where to go and what kind of hair they need to grow, so when they reach their place, they can generate proper hair types. Does it work if you inject hair follicles from eyebrows into the head They will only generate short hairs. You would probably see a lot of short hairs on the floor.
Studies using iPS came this far, how about medicine We can simulate someone’s hairs inside flasks using iPS cells. So after we make iPS cells from blood cells in flasks, we can screen hair tonics using cells induced from iPS cells. We can find out which tonic is working, and that makes it possible to prescribe a special mixture of tonics to specific patients. Furthermore, we will know which tonics are good for a specific disease such as alopecia areata, and we will be able to develop effective medicines with less side effects.
Hair study is really advancing, isn’t it Actually, there aren’t that many researchers in this area. There are more than 10,000 researchers in cancer, but less than 50 in hair. Hair study really is the minority. We are hoping that many people are interested in these studies and research together, so we can use the technology sooner to the people who need it most. How did you like today’s topic At first, I thought hair loss treatment is a narrow subject. But it is really impressive that a hair follicle is a small organ.