Hair Follicle Neogenesis - Bernstein Medical - Center for Hair Restoration
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New research published in the journal PLoS One found that embryonic stem cells can be used to form a type of cell that induces new hair follicle growth, and that these cells promote robust hair growth when implanted into mice.

Background

Dermal Papilla (DP) cells play a role in new hair follicle formation and in the growth of new hair. Because of this role, it was hoped that DP cells grown in the laboratory (i.e., grown in culture) could form the basis of a treatment for genetic hair loss. However, it turned out that these cultured DP cells lost their hair follicle-inducing potential too quickly to be useful in treating hair loss.

New Research

Now, however, new research has found that human embryonic stem cells (hESCs) can generate cells that are functionally equivalent to DP cells. ((Gnedeva K, Vorotelyak E, Cimadamore F, Cattarossi G, Giusto E, Terskikh V.V, Terskikh A.V. Derivation of hair-inducing cell from human pluripotent stem cells. PLoS One. 2015 Jan 21;10(1)) Like DP cells, these functionally equivalent cells can induce hair follicle formation just as readily as DP cells. But more significantly, unlike cultured DP cells, they do not lose their potential to induce hair follicle formation when grown in the laboratory. This discovery represents an important advance in developing a hair cloning technique to cure pattern baldness.

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Dr. Claire Higgins and her colleague Dr. Colin Jahoda have published an overview of hair cloning and the challenges scientists face in attempting to develop hair regeneration therapies for androgenetic alopecia or common balding. The article, published in Hair Transplant Forum International, points to two central problems in developing a hair loss therapy. The first is the difficulty in getting dermal papilla cells in humans to self-aggregate and form hair follicles and the second is the inability, thus far, of scientists to generate normal hairs and follicles.

Higgins and Jahoda describe how it has been known for decades, through the work of Lille and Wang and others, that rat dermal papillae self-organize into new hair-producing follicles when they are injected or grafted into the skin. Human dermal papilla cells, on the other hand, have never exhibited what they call the “aggregation phenomena,” and instead they disperse in the skin in what appears to be a wound healing mechanism. In fact, human papillae, when grown in a laboratory culture, can act as “mesenchymal stem cells” and differentiate into a variety of cell types.

While multiple efforts to induce dermal papillae to form new hair follicles have failed, the research that Higgins and Jahoda have published on hair follicle neogenesis has resulted in a new technique to do just that. The success of the 3-D culturing of dermal papillae to induce hair follicle neogenesis was a breakthrough in that the scientists have found a way to improve the intercellular communication that is essential to inducing follicle growth.

Having made significant progress in improving this vital communication link between dermal papillae cells, scientists still have to contend with a series of obstacles that stand in the way of a hair cloning therapy for human hair loss. One such problem is the quality of hairs that they have been able to grow using the hair follicle neogenesis technique. The hairs they have successfully produced have been small and have grown in non-uniform direction. Another unanswered issue is how long the hair follicles will grow and whether or not they exhibit the cyclical hair follicle growth patterns of a typical human hair follicle. The ability to reproduce significant quantities of normal hair will continue to be the central focus of research going forward.

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Progress towards hair cloning may have just have shifted up another gear thanks to scientists at the University of Pennsylvania and the New Jersey Institute of Technology. The breakthrough study published January 28th, 2014 is the first to show the successful transformation of adult human skin cells into quantities of epithelial stem cells necessary for hair regeneration.

The researchers, led by Dr. Xiaowei “George” Xu, started with human skin cells called dermal fibroblasts, then transformed those into a type of stem cell called induced pluripotent stem cells (iPSCs). These were then transformed into epithelial stem cells (EpSCs). This important step had never been achieved before in either humans or mice. The epithelial stem cells were combined with mouse dermal cells, that can be induced to form hair follicles, and then grafted on a mouse host. The epithelial cells and dermal cells then grew to form a functional human epidermis and follicles structurally similar to human hair follicles. The exhibits that accompany the study include photographic evidence of human hairs.

Figure 5 - Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cellsHair shafts (arrowheads) formed by induced pluripotent stem cell-derived epithelial stem cells compared to mouse hair (arrows). — Credit: Ruifeng Yang, Perelman School of Medicine, University of Pennsylvania

The main breakthrough in the study came when the research team carefully timed the addition of growth factors to the iPSCs. Previous research showed the ability for iPSCs to be transformed into a common type of cell found in the skin called keratinocytes. By timing the addition of the growth factors, they were able to turn over 25% of the iPSCs into epithelial stem cells in a little more than two weeks. This “mass production” of epithelial stem cells holds tremendous promise for the development of a hair regeneration treatment. On this development, Dr. Xu said, “This is the first time anyone has made scalable amounts of epithelial stem cells that are capable of generating the epithelial component of hair follicles.”

As noted in a University of Pennsylvania press release on the news, there are two types of stem cell that are critical in hair follicles: epithelial stem cells and dermal papillae. While this study only achieved success in the creation of epithelial stem cells, we have extensively covered Dr. Angela Christiano’s ground-breaking research into the induction of dermal papillae into hair follicles (a process she calls hair follicle neogenesis).

“When a person loses hair, they lose both types of cells. We have solved one major problem, the epithelial component of the hair follicle. We need to figure out a way to also make new dermal papillae cells, and no one has figured that part out yet,” said Dr. Xu.

Once that it is done, we must also find a way to have the epithelial and dermal components of the follicle interact before one will be able to produce cosmetically useful hair. But with each successive breakthrough, the time when a scientist can use hair cloning techniques to regenerate human hair, and the surgeon can implant them into a person’s scalp, draws ever closer.

Reference
Yang R, Zheng Y, Xu X. Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells. Nature Communications. 2014.

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For four decades, scientists have known about the possibility of using cells derived from the base of hair follicles (dermal papilla cells) to stimulate the growth of new hair. More recently, researchers have been able to harvest dermal papillae, multiply them, and induce the creation of new hair follicles – but only in rats. Now, for the first time, scientists at Columbia University have shown in a new study that they can induce new human hair growth from cloned human papillae. This procedure, called “hair follicle neogenesis,” has the potential to solve one of the primary limitations in today’s surgical hair restoration techniques; namely, the patient’s finite donor hair supply that is available for transplantation.

A significant number of hair loss patients do not have enough donor hair to be candidates for a hair transplant procedure with the percentage of women lacking stable donor hair greater than in men. This technique would enable both men and women with limited donor reserves to benefit from hair transplant procedures and enable current candidates to achieve even better results.

According to co-study leader Angela M. Christiano, Ph.D., of Columbia University in New York, the ground-breaking publication is a “substantial step forward” in hair follicle neogenesis. While the technology still needs further development to be clinically useful, the implications of successfully inducing new hair follicles to grow from cloned hair cells could be a game-changer in the arena of hair restoration. Instead of moving hair follicles from the donor area to the recipient area, as in a hair transplant, follicular neogenesis involves the creation of new follicles, literally adding more follicles to the scalp rather than merely transplanting them from one part of the scalp to another. Regarding the new technique’s possible use as a hair restoration treatment, Dr. Christiano said:

“This method offers the possibility of inducing large numbers of hair follicles or rejuvenating existing hair follicles, starting with cells grown from just a few hundred donor hairs. It could make hair transplantation available to individuals with a limited number of follicles, including those with female-pattern hair loss, scarring alopecia, and hair loss due to burns.”

In hair follicle neogenesis, the physician would harvest a sample of healthy, hair-producing scalp tissue from a patient. The dermal papilla cells in the samples would be isolated and allowed to multiply in a laboratory culture, and then the lab-grown papillae would be injected back into balding areas of the person’s scalp where they would induce skin cells to form into hair follicles that would grow normal adult hairs.

The main hurdle that researchers had to overcome was getting human papillae to aggregate — or clump together — so that it could then develop into a follicle. Cells that are cultured on a flat surface seem to lose their ability to produce hair. Prior studies have shown that rat papillae, unlike human papillae, tend to aggregate spontaneously; a process that makes the next, critical step of forming the hair follicle possible. The research team reasoned that if they could create an extracellular environment in which human cells could aggregate, they could induce the growth of human hair follicles.

The breakthrough came as a result of encouraging human dermal papillae cells to grow in a three-dimensional culture — a spherical mass of cells — rather than in a conventional two-dimensional tissue culture. The 3-D configuration allows the cells to signal one another and direct the formation of a new hair. Normally, a culture is grown in a one-cell layer in a petri dish, however, in order to coax the papillae to aggregate, the researchers used a technique called a “hanging drop culture.” Here, droplets of culture, each containing the requisite number of papilla cells (about 3,000 cells) to form a hair follicle, are placed on the lid of a petri dish. When the lid is flipped upside-down, the force of gravity pulls the papillae into the bottom of the suspended droplet, causing the cells to ‘clump.’ This is similar to what the rat papillae do naturally.

In the study, Christiano and colleagues took dermal papillae from seven donors and cloned the cells in tissue culture. After a few days, the cells were transplanted into human skin that had been grafted onto the backs of mice. In implanting these cultured ‘clumps’ of dermal papillae, the research team induced hair follicle production in five out of seven test samples. Using a technique called gene expression analysis, the researchers were able to determine that the three-dimensional cultures restored 22% of the gene expression found in normal hair follicles, enough to induce the formation of new hairs that genetically matched the human donor’s DNA (rather than the mouse).

While hair cloning and multiplication techniques have been discussed and studied for years, the progress made by Dr. Christiano and her colleagues Colin Jahoda, Ph.D., and Claire Higgins, Ph.D. (the first author on the study), is unprecedented. In identifying the key benefit their procedure might have over current hair restoration practices, Dr. Christiano said:

“Current hair-loss medications tend to slow the loss of hair follicles or potentially stimulate the growth of existing hairs, but they do not create new hair follicles. Neither do conventional hair transplants, which relocate a set number of hairs from the back of the scalp to the front. Our method, in contrast, has the potential to actually grow new follicles using a patient’s own cells.”

In addition to combating male and female pattern genetic hair loss (androgenetic alopecia), the technique has the potential for use as a treatment for patients with severe skin injuries, such as burn victims, or sufferers of chronic conditions like scarring alopecias. In these cases, the absence of hair follicles had limited the usefulness of transplanted skin. With the ability to clone follicles, this problem can potentially be overcome.

Dr. Christiano, a colleague of Dr. Bernstein’s at Columbia University, is a world-renowned hair geneticist and a sufferer of alopecia areata, an autoimmune disease that creates bald spots on the scalp. In investigating the causes of her own balding, Dr. Christiano embarked on a career that led to she and her team identifying multiple genes associated with the disease. Her co-study leader, Dr. Jahoda, is a professor of stem cell sciences at Durham University and co-director of the North East England Stem Cell Institute. The lead author of the study, Dr. Higgins, is an associate research scientist in the dermatology department at Columbia University.

The study called, “Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth,” and published in the Proceedings of the National Academy of Sciences (PNAS). The human hair follicles in this study were donated by volunteer hair transplant patients at Bernstein Medical – Center for Hair Restoration in New York City. We are appreciative of our patients who participated in this research.

Reference
Higgins, C.A., Chen, J.C., Cerise, J.E., Jahoda, C.A., Christiano, A.M.: Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth. PNAS, 2013; doi: 10.1073/pnas.1309970110.

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Scientists from Durham University in the UK have shown for the first time that a lab technique, called a three-dimensional cell culture, can produce spherical structures that are similar to naturally occurring structures in hair follicle formation (called dermal papilla or DP). This breakthrough study by Claire Higgins and Colin Jahoda, published in the June 2010 issue of the journal Experimental Dermatology, ((Higgins C, Jahoda C, et al. Modelling the hair follicle dermal papilla using spheroid cell cultures. Experimental Dermatology 2010; 19: 546–548.)) has the potential to unlock the ability of researchers to develop functional DP cells which can be used in hair restoration techniques such as hair cloning or hair multiplication.

Background

Hair cloning techniques have been theorized for decades. The basic idea is:

  1. a physician takes a sample of skin cells from a patient
  2. dermal papilla cells are extracted
  3. the DP cells are cloned (multiplied) in a laboratory culture (i.e., a petri dish)
  4. the cell formation is then injected back into the patient’s balding scalp where it produces permanent hair that continues to grow

The first three steps are a piece of cake. But that is when the strategy breaks down. When DP cells are grown in a petri dish they exhibit some of the qualities of DP cells in the human body but not all, so injecting this aggregate into the skin fails to lead to hair follicle growth. Something was missing.

In 1991, Wobus, et al published a study in the journal Differentiation ((Wobus AM, Wallukat G, Hescheler J. Differentiation 1991: 48: 173–182.)) that described a new technique for researching cells that in nature exist as clumps or masses of cells. The idea was to suspend a group of cells under a flat surface so that gravity would pull the cells into a droplet. This “hanging drop” method yielded a three-dimensional culture that enabled the study of embryonic stem cells as well as the proteins they produce that allow for intercellular communication.

Having hit the wall with two-dimensional DP cultures, Higgins and Jahoda set out to try Wobus’ concept of using 3-D cultures to study DP cells.

The Study

Higgins and Jahoda harvested eight cell strains of human DP cells taken from scalp hair follicles. These eight strains were cultured in either 35-mm dishes or hanging drop cultures consisting of 3,000 cells each. The cultures were maintained between 30 and 72 hours, then collected and analyzed using immunofluorescence or transcriptional techniques.

Results

The DP cells grown in hanging drop, 3-D cultures exhibited behavior significantly akin to DP in human hair follicles. The 2-D cultures grown in the 35-mm dishes did not.

Conclusion

Without the ability to form functional dermal papilla aggregations, hair cloning was essentially at a dead end. In the 3-D configuration, the aggregated cells were able to communicate with one another and to continue to differentiate as hair follicles. By using Wobus’ 3-D hanging drop technique, Higgins and Jahoda may have unlocked the secret to forming these powerful, but elusive, structures that are critical to the hair growth cycle.

Following this study, more research needs to be performed to induce the spherical cells to initiate the growth of new hair follicles and to develop ways to ensure that the induced hair follicles are immune from the factors that cause genetic hair loss. Should those two riddles be solved, hair loss will have been effectively cured.

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