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Scientific research is often the quintessential example of taking something apart to learn how it works. A team of researchers has used that age-old technique to unwind the complex process by which embryonic cells organize into functional skin that includes “organoids” like hair follicles. By untangling this biological mystery, they were able to develop a model that could potentially lead to hair regeneration treatments and other advances in regenerative medicine. The study — “Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells” — was published in the August 22nd, 2017 issue of the journal PNAS. ((Lei M, Schumacher LJ, et al. Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells. Proceedings of the National Academy of Sciences. 114. 201700475. 10.1073/pnas.1700475114.))

Background

Scientists have long known that embryonic cells organize and form bodily organs like the heart, liver, and skin, but understanding the details behind this spontaneous process of “self-organization” was a challenge. It has been understood that the DNA code produces chemicals that enable “cross-talk” between cells as they go through several stages in forming 3-dimensional, functional organs. But what these stages represented, and which specific molecules were involved in this communication, needed to be understood.

The Study

The researchers set out with two goals in mind: 1) to describe the conditions that enable a group of cells to self-organize into skin organs and 2) to describe transplant techniques that allow these skin organs to grow normal, functional hairs.

To achieve their first goal, the researchers started with populations of individual “dissociated” epidermal and dermal cells from newborn mice. They then combined these cells in a 3-D cell drop and observed the cells’ interactions. At every stage, they measured how the cells behaved and which proteins and molecules were present to promote or inhibit certain processes. The dissociated cells self-organized into functional skin through a complex 5-stage process:

  • Stage 1: Cells form aggregations
  • Stage 2: Aggregates form cysts
  • Stage 3: Cysts fuse to form epidermal “planes”
  • Stage 4: Small epidermal planes merge to form a larger, multi-layered plane of embryonic skin
  • Stage 5: Embryonic skin forms “placode” structures that can develop into hair follicles

When the Stage 5 cultured skin was transplanted to the back of a hairless mouse, it grew robust hair follicles.

Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells
(A) The experiment design. (B) Images showing the self-organization process. (C) Diagram of the stages of new skin formation. (D) Robust hair regeneration seen with cells from newborn mice but not adults. (E) Adult cells form only small aggregates. (F) Aggregate size with cells from newborn mice vs. adults. (G) Schematic showing how self-organization in adult cells stops before growth is complete. Image c/o PNAS

With a better understanding of these processes using embryonic cells, they went about attempting to induce this same process in adult mouse skin cells. Adult cells on their own formed only a few small aggregates which did not grow. To confirm the significance of newborn dermal cells and the chemicals that cause them to self-organize, the researchers experimented by first combining newborn dermal cells and adult epidermal cells and then combining newborn epidermal cells and adult dermal cells. The population that contained newborn dermal cells formed numerous hairs, while the population with newborn epidermal cells formed very few hairs.

Findings

  • Researchers identified several different classes of molecules that are required to induce the transitions between the various stages of skin development
  • The transition periods were not discrete events, but instead occurred over time and were dependent on the presence of the “communication” molecules
  • Inhibiting or promoting the key communication molecules can suppress or accelerate the phase transition process
  • Adding the communication molecules to adult cell cultures at the appropriate times can induce the adult cells to form functional skin complete with a robust number of hair follicles
  • It is both the progression of the phases and the presence of the molecular signals that, together, form the key to self-organization

Conclusion

The researchers behind this study sought to achieve two complicated tasks: to explain how cells self-organize and to induce self-organization in cells which had lost that capability. Only through painstaking experimentation were they able to untangle some of the mystery behind how these embryonic cells transform from a group of individual cells into fully-formed skin complete with hair follicles. This effort paid off, as they were able to apply the newfound knowledge to populations of adult cells. The capability to induce robust hair follicle growth in adult skin is a significant achievement.

For now, we must be content that the adult skin that was cultured in the lab needed to be grafted onto a healthy host. Next steps would be to determine how to use the same or similar process to induce hair follicle growth directly in the skin. Much more research must be done in that regard. However, the implications of this technique for the field of regenerative medicine may be substantial, as scientists explore the ability to regenerate not only skin organs but other body organs in the future.

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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.

Bookmark our Hair Cloning Research page to stay on top of developments in this field

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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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We have previously discussed Dr. Angela Christiano‘s work on hair loss genetics with her team at Columbia University in New York. A review of the 16th annual meeting of the European Hair Research Society; held recently in Barcelona, Spain; brings to our attention new research being conducted by a very astute scientist, Dr. Claire Higgins, who works at Dr. Christiano’s laboratory.

With tissue supplied by Bernstein Medical, Dr. Higgins is studying the inductive properties of the dermal papilla (DP), a group of cells that forms the structure directly below each hair follicle. As outlined in our Hair Cloning Methods page, the dermal papilla is of great interest to hair restoration physicians. Ideally, research of this kind will lead to a breakthrough in hair cloning or hair multiplication which will allow physicians to effectively “cure” hair loss by developing a limitless supply of donor hair that can be used in hair restoration procedures.

A description of Dr. Higgins’ work is provided by the Hair Transplant Forum International:

“After isolating [dermal papilla] from human hair follicles, they grow the human DP cells in spheroid cultures in order to retain their inductive potential. Then they place the dermal papilla spheres between the epidermis and dermis of neonatal foreskin and graft it onto the back of mice. Human [hair follicle] neogenesis can be observed after 6 weeks.”

In essence, the scientists were able to capitalize on the potential of dermal papilla cells to induce the growth of a hair follicle by enclosing the DP cells in a small sphere. When implanted, the DP cells maintained their properties of inducing the development of follicles, and, indeed, follicles did grow.

It is another example of how far our understanding of the biology of hair has come in the last 10 years. And it is another example of scientists closing in on the elusive “hair loss cure.”

Read up on the latest Hair Cloning Research

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Japanese Researchers Bioengineer Hair Follicles from Stem Cells, Dermal PapillaeCredit: Tokyo University of Science

Japanese researchers have demonstrated that scientists can bioengineer viable, hair-producing follicles from epithelial stem cells and dermal papilla cells. Using these components, the team produced follicles that exhibit both the normal hair cycle and piloerection (the reflex contraction of a tiny muscle in the hair follicles which creates what is commonly referred to as “goose bumps”). The bioengineered follicles also developed the normal structures found within follicles and formed natural connections with skin tissues, muscle cells, and nerve cells.

The scientists used a breakthrough type of hair multiplication to achieve a functional bioengineered hair follicle. In hair multiplication, germinative cells are harvested non-surgically and then multiplied outside the body in a laboratory. These cells are then injected into the skin where they, ideally, grow into hair follicles. The Japanese research team takes this concept one step further by first combining the stem cells and dermal papillae in the laboratory to create a germ of the hair follicle. This germ is then implanted into the scalp where it grows into a viable hair follicle.

The study opens the door to treat common baldness (androgenetic alopecia) and a host of other medical conditions that can cause hair loss.

View the Hair Cloning section to read more on hair multiplication and hair cloning methods.

Reference:

Koh-ei Toyoshima, Kyosuke Asakawa, Naoko Ishibashi, Hiroshi Toki, Miho Ogawa, Tomoko Hasegawa, Tarou Irié, Tetsuhiko Tachikawa, Akio Sato, Akira Takeda, Takashi Tsuji. Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nature Communications, 2012; 3: 784 DOI: 10.1038/ncomms1784

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RepliCel Life Sciences; a company out of Vancouver, Canada; is studying the use of hair cloning techniques to treat male pattern baldness and hair loss in women.

The study is in progress, but analysis of the 6-month interim results of the first phases has been published. The preliminary results at 6 months show that almost two-thirds of subjects (10 out of 16, or 63%) received a greater than 5% increase in hair density at the injection site. Of that group of 10 subjects, seven of them saw hair density improve by more than 10%. In one subject vellus hair density increased 24.9%, terminal hair density increased 14.5%, overall hair density increased by 19.2%, and cumulative thickness per area increased by 15.4%. There were no significant adverse safety events reported in the first 6 months of the trial.

Phase I/IIa of the RepliCel study involved injecting male and female subjects with their own (autologous) dermal sheath cup cells (DSCC), which were replicated or cloned using RepliCel’s laboratory technology. A preliminary analysis of the safety of the injections, as well as a preliminary analysis of the efficacy of the treatment in growing hair, was announced in May 2012 and presented to the European Hair Research Society in June 2012. Subjects in this part of the study will continue to be monitored for any adverse physical reactions and to assess hair growth at 12 months and 24 months after treatment.

Phase IIb of the study is designed to help the RepliCel researchers formulate the optimal treatment for hair growth. Some of the treatment regimens that will be tested include the use of different concentrations of cells and different treatment schedules, plus the effects of single injections versus repeat injections. The final protocols for Phase IIb are currently being worked out, with the clinical trial expected to begin in late 2012.

Reference:

Lortkipanidze, N. Safety and Efficacy Study of Human Autologous Hair Follicle Cells to Treat Androgenetic Alopecia. In Clinicaltrials.gov. Retrieved July 26, 2012, from http://clinicaltrials.gov/ct2/show/NCT01286649.

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RepliCel Life Sciences; a company based in Vancouver, Canada; is investigating hair cloning techniques in order to develop a treatment for androgenetic alopecia, or common genetic hair loss.

Research conducted by the company’s scientific founders and lead scientists, Drs. Kevin McElwee and Rolf Hoffmann, has shown that a certain type of cell, called a dermal sheath cup cell, is integral in initiating the growth of mature hair follicles. ((McElwee KJ, Kissling S, Wenzel E, Huth A, Hoffmann R (2003) Cultured peribulbar dermal sheath cells can induce hair follicle development and contribute to the dermal sheath and dermal papilla. J Invest Dermatol 121: 1267–1275.)) This mechanism of follicle growth, when coupled with previous research on dermal papillae cells, is key to our understanding of hair loss and is a potential avenue for developing a treatment that could reverse hair loss.

In their 2003 study, “Cultured Peribulbar Dermal Sheath Cells Can Induce Hair Follicle Development and Contribute to the Dermal Sheath and Dermal Papilla,” the scientists found that the dermal sheath cup cells are the “reservoir” of stem cells that control both the hair growth cycle of a follicle and formation of new hair follicles.

These breakthrough findings led to RepliCel’s seeking patents for their proprietary process of isolating and preparing dermal sheath cup cells for the treatment of hair loss. Patents have been issued in Europe and Australia, and are currently pending in the US, Canada, and Japan.

In 2012, RepliCel is studying the safety and efficacy of hair regeneration from autologous dermal sheath cup cells. In the study, cells will be harvested from patients, replicated in a laboratory, and then injected into a balding area to determine if the treatment will stimulate the growth of new hair follicles in what was a bald area.

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Following some new research on stem cells, and their relationship with androgenetic alopecia (genetic hair loss), an article on stem cells and the way they organize hair growth was published in the April 29th issue of the journal Science.

At issue is not the conversion of hair follicle stem cells into the progenitor cells that stimulate hair growth, as with the prior research, but the ways in which large numbers of stem cells coordinate the cycle of hair growth over thousands of hair follicles. How do all of those hair follicle stem cells know when to grow hair, and how do they know what their “neighbor” hair follicles are doing?

The researchers studied hair growth patterns in rabbits and mice and discovered that certain types of molecules, which were previously known to act as a signaling mechanism for stem cells in maintaining an individual hair follicle’s growth cycle, were also important in enabling large groups of stem cells to coordinate their activity.

The scientists found that hair stem cells coordinate their regeneration with each other with the aid of a pair of molecular activator WNT and inhibitor BMP. When WNT and BMP signals are used repetitively among a population of thousands of hair follicles across the entire skin surface, complex regenerative hair growth behavior emerges via the process of self-organization.

Perhaps more importantly, they found that the stem cell communication pathway present in rabbits and mice is far more robust than in men and women.

“When each human hair follicle wants to regenerate, it can only count on itself; it’s not getting help from other follicles,” Chuong said. “But when a rabbit hair follicle regenerates, it can count on two inputs: its own activation, and the activation signal from its neighbors. Rabbits have a very active hair growth, and that is essential for their survival in the wild.”

The article suggests that if there was a way to manage that process in humans, or “turn back on” the stem cell communication process in human hair follicles, then a treatment could be developed which would substantially increase the number of hair follicles that produce healthy hair.

Read a summary of this new research at ScienceDaily.com.

For more discussion on recent research, visit the Hair Cloning topic.

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We recently discussed ground-breaking research that pointed to the important differences between stem cells and progenitor cells in the development of common baldness, or androgenetic alopecia (AGA).

In the March/April 2011 issue of Hair Transplant Forum International, we see a review of that research and another indication of the importance of this research in achieving the goal of being able to clone human hair.

It is now well established that, in each hair cycle, stem cells divide and generate progenitor cells, and that these progenitor cells stimulate the growth of the hair follicle. In conducting the experiment, the scientists’ original hypothesis was that the number of stem cells would be lower in scalp samples from bald areas than areas of scalp with hair. Surprisingly, they found that the stem cells were present in both samples. However, they found that the number of progenitor cells in the samples with hair was significantly higher in comparison to the bald samples. These findings suggest that it is not a reduced number of stem cells that leads to AGA, but the decreased conversion of stem cells into progenitor cells.

The research also suggests that the conversion of stem cells to progenitor cells may be the crucial mechanism that, when disrupted, leads to miniaturization of hair follicles, and common baldness. If there was a way to prevent the breakdown of stem cell conversion to progenitor cells, that could, in theory, stop the process of miniaturization and prevent androgenetic alopecia from occurring.

The study’s results and the review in the hair restoration journal indicate that, while a great deal of research must still be conducted, the scientific community is zeroing in on the cause of, and a potential cure for, genetic hair loss which has affected men and women for millennia.

For further reading on this exciting topic, here are some links:

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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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ACell, Inc. - Regenerative Medicine TechnologyHair cloning is one of the most hotly discussed topics in the field of hair transplantation today. “When will hair cloning become available?” and “How will it work?” are among the most frequently asked questions about treating hair loss that we receive at Bernstein Medical – Center for Hair Restoration.

New developments in regenerative medicine technology, presented at the 18th Annual Scientific Meeting of the International Society for Hair Restoration (ISHRS), may have opened the door to commercialization and medical use of new techniques which could provide an answer to both questions.

ACell, Inc., a company based in Columbia, Maryland, has developed and refined what they consider, “the next generation of regenerative medicine.”

For more information on this exciting development, view our page on ACell technology and hair cloning

Follow news and updates on our Hair Cloning News page.

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She turned me into a newt! I got better…

~ John Cleese, Monty Python and the Holy Grail

Have you ever thought that you want to be more like a newt? You might not have thought about it in those terms, but these tiny amphibians have a physical capability that human beings have dreamed about for eons: the capability of regenerating tissue. If we could tap into this capability, the possibilities for medical treatment are limitless. We could regrow an arm, a leg, a hand, repair a heart after a heart attack, or even regrow hair. Two new avenues of scientific research, discussed in an article in the New York Times, might just help us enable human beings regenerate tissue.

The Stanford Approach

For ages, it has been well known that humans do not possess the regenerative powers of lower vertebrates, such as newts and fish, but the reason has been a mystery. The researchers at Stanford University in California, working with mouse muscle cells, have begun to understand the mechanism behind the capability for certain animals to regenerate tissue.

It seems that lower vertebrates have a genetic makeup that allows their cells to multiply when tissue regeneration is needed. Since unchecked cell multiplication can also lead to tumor (cancer) formation, they also have a tumor suppressor gene known as Rb. This gene is naturally inactivated in newts and fish when they start regenerating tissue.

Mammals possess both the Rb gene and a backup, called the Arf gene, which will close down a cancer-prone cell if Rb fails to do so. […]

The Stanford team shut off both Rb and Arf with a chemical called silencing-RNA and found that the mouse muscle cells started dividing. When injected into a mouse’s leg, the cells fused into the existing muscle fibers, just as they are meant to.

It would appear then, that mammals, including humans, have regenerative capabilities normally programmed into their DNA, but over hundreds of millions of years these capabilities have been suppressed so that the more important function -– that of cancer prevention -– could operate. To clone human tissue, one would theoretically just need to deactivate the suppressor genes, but in a way that would not put the person at an increased risk of developing cancer. Of course, these genes have not yet been identified in man, nor is it known if they even exist.

The UCSF Approach

A second, but very different, approach to tissue regeneration has been taken up by Dr. Deepak Srivastava and his team at the University of California, San Francisco. Based on work by Japanese scientist Shinya Yamanaka, Dr. Srivastava successfully converted ordinary tissue cells (fibroblasts) of the mouse heart into heart muscle cells:

[Dr. Yamanaka] showed three years ago that skin cells could be converted to embryonic stem cells simply by adding four proteins known to regulate genes. Inspired by Dr. Yamanaka’s method, Dr. Srivastava and his colleagues selected 14 such proteins and eventually found that with only three of them they could convert heart fibroblast cells into heart muscle cells.

To make clinical use of the discovery, Dr. Srivastava said he would need first to duplicate the process with human cells, and then develop three drugs that could substitute for the three proteins used in the conversion process.

The drugs could then be injected into damaged areas of the heart to repair the cardiac muscle cells following a heart attack. By using heart fibroblasts to produce cardiac muscle cells, rather than using embryonic stem cells, it is possible that risk of unwanted tumor formation, often noted with stem cell therapies, can be avoided.

It is not a stretch to assume that if scientists can undo the inability of animals to grow heart muscle or limbs, we might someday be able to genetically reverse the inability of a bald person to grow hair.

View more information on hair cloning and hair cloning methods. Also view our hair cloning news and hair cloning glossary pages.

View Nicholas Wade’s NYT article, “Two New Paths to the Dream: Regeneration.” Also take a look at the diagram that accompanies the article.

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Alopecia areata is an auto-immune disease that causes hair loss that ranges from small circular areas on the scalp to extensive or even total baldness. When extensive, it can be a socially debilitating disease, and it can be particularly difficult when those suffering are children.

When alopecia areata is localized, i.e. there are a limited number of bald patches, the condition often responds well to cortisone injected directly direct into the scalp. When the condition is more extensive, current treatments do not have a high rate of success. A new study, using hair cloning therapy to regrow hair, shows promise for all individuals suffering from the disease.

The study — conducted by Marwa Fawzi, a dermatologist at the University of Cairo Faculty of Medicine, and reported on Bloomberg.com — used stem cells from the scalps of eight children with alopecia areata to regenerate their own hair:

The Cairo researcher took small amounts of skin from the scalps of the children, isolated the hair follicle stem cells that stimulate hair production, and grew them in the lab, increasing the number of cells. After one month, she put the cells back into the scalps of the children, with numerous injections across the bald areas of their heads. ((Kids Shunned for Hair Loss Get Help From Their Own Stem Cells by Rob Waters. Posted on Bloomberg.com, July 10, 2009))

To read more on how various cloning processes work, view the Hair Cloning Methods page.

Six months after the hair cloning treatment, an evaluation showed a 50% increase in hair in more than half of the subjects. One of them, an 8-year-old boy, grew nearly a full head of hair after being almost completely bald before treatment. The article reports that the boy is grateful that he is now able to lead a more normal life, free from social isolation over his balding scalp.

Dr. Fawzi took new skin samples and examined the hair follicles themselves and could see that the injected stem cells had migrated into the follicles. There, the stem cells stimulated the follicles to transition from a dormant phase to a hair-generating phase.

Further testing is needed and a double-blind study using a larger number of patients in planned, but the study’s success could prove to be a turning point in stem cell cloning for hair restoration. Unlike alopecia areata, where the body’s immune system attacks one’s own hair follicles, in common baldness the culprit is the hormone DHT. In spite of the differences between these two conditions, we appear to be inching closer to the use of stem cell cloning therapy in the treatment of male pattern baldness.

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Jing Gao, Mindy C. DeRouen, Chih-Hsin Chen, Michael Nguyen, et. al.
Genes & Development 22:2111-2124, 2008

The growth of a hair follicle from its developmental cell stage to a hair bearing follicle is through an interactive process between epidermal cells and those of the dermal papilla. It was found that Laminin-511 is instrumental in facilitating this process.

It has been felt that the extra-cellular protein Laminin is critical to both adhesion and the signaling process in hair development; however, the mechanism is not fully understood.

Through this study, it was shown that the signaling pathways introduced by the administration of noggin and sonic hedgehog alone were insufficient to develop a hair follicle. When Laminin-511 protein was introduced to the tissue culture, the dermal papilla developed. When the protein was inhibited, hair follicle growth again ceased. This information supports prior studies suggesting that Laminin is critical in the early stages of follicle cell development and is required for continued follicle development and growth.

This study reaffirms in vitro and in vivo studies in mice, the importance of Laminin-511 in the formation of dermal papilla to promote the development of more organized dermal papilla cells and the hair follicle development. It also suggests that there is a reciprocal mechanism between the signaling pathways of noggin and sonic hedgehog with Laminin-511.

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by Jeff Teumer, PhD
Hair Transplant International Forum, Volume 18, Number 3, May/June 2008

Follicular cell implantation (FCI) is based on the ability of the dermal papilla (DP) cells, found at the bottom of hair follicles, to stimulate new hairs to form. DP cells can be grown and multiplied in a culture so that a very small number of cells can produce enough follicles to cover an entire bald scalp.

In order to produce new follicles, two types of cells must be present. The first is Keratinocytes, the major cell type in the hair follicle, and the second are dermal papillae cells (DP) which lie in the upper part of the dermis, just below the hair follicle. It appears that the DP cells can induce the overlying keratinocytes to form hair follicles. There are a number of proposed techniques for hair regeneration that use combinations of cells that are implanted in the skin. The two major techniques involve either transplanting dermal papillae cells by themselves into the skin or implanting them with keratinocytes. These techniques can be used with or without an associated matrix used to help orient the newly forming follicles.

Implanting Dermal Papillae Cells Alone

  1. Implanting DP cells by themselves into the dermis, with the hope that they will cause the overlying skin cells (keratinocytes) to be transformed from normal skin cells into hair follicles. This method is called “follicular neo-genesis” since new hair is formed where none previously existed.
  2. Cells of the dermal papillae are placed alongside miniaturized follicles. The transplanted cells would induce the keratinocytes of the miniaturized follicles to grow into a terminal hair. A potential advantage of this technique is that the existing miniaturized follicles already have the proper structure and orientation to produce a natural look growth.

Implanting Dermal Papillae with Keratinocytes

  1. A mixed suspension of cultured keratinocytes and DP cells are implanted into the skin.
  2. Keratinocytes and DP cells are cultured together such that full or partial hair formation takes place in a culture dish. These culture-grown hairs, or “proto-hairs,” are then implanted into the patient. The advantage of using a proto-hair is that there would be better control over the direction of hair growth because of the structural orientation of the proto-hair.

Cell Implantation using a Matrix

  1. A variation of the above techniques is to use a matrix to help orient the implanted cells. This could be either an artificial matrix composed of materials such Dacron or it could be a biological matrix composed of collagen or other tissue components. The matrix would act like a scaffold to help cells organize to form a follicle. If the matrix were filamentous (like a hair) it could help direct the growth of the growing follicle. A matrix could be used with dermal papillae cells alone or in combination with cultured keratinocytes.

With all of the varied approaches for FCI, the aim is to combine keratinocytes and DP cells to efficiently and reproducibly generate thousands of follicles for hair restoration. In some cases, cells are combined in vivo and all of the hair formation must take place in the body after implantation, while in others, some hair formation takes place in culture before implantation.

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Dr. Bernstein summarizes a New York Times article on stem cell research:

A major advance in regenerative medicine has recently been announced. A new technique, which can convert adult skin cells into embryonic form, has been successfully performed on interbred mice by Dr. Shinya Yamanaka of Kyoto University. The technique, if adaptable to human cells could allow new heart, liver, or kidney cells to be regenerated from simple skin cells. This tissue could potentially replace organ tissue that has been damaged due to disease. As this tissue would be formed from the patient’s own skin cells, it would not be subject to rejection by the patient’s immune system.

Prior to this discovery, the conversion of adult cells into embryonic cells was done only through nuclear transfer; the implantation of the nucleus of an adult cell into an egg. The egg then reprogrammed the adult genetic material into an embryonic form.

This new technique involves the insertion of four genes into a skin cell. These genes would then complete the reprogramming of the nucleus of the skin cell into embryonic form, just as the egg had in nuclear transfer.

If adaptable to human cells, this could provide a simple, inexpensive and politically uncontroversial technique for regenerating stem cells. It should eliminate the ethical debates regarding stem cell research.

But this discovery does not mean that cloning will be available anytime soon. There are many obstacles which must be overcome prior to its implementation. The most immediate problem is discovering if this technique, which has been performed only in mice, can be used successfully with human cells. Another problem is that the mice that were used in the experiment were interbred, something obviously not acceptable for humans. In addition, the cells must be infected with a gene-carrying virus, a process that may not be safe for humans. Finally, two of the four genes which are needed to begin this regenerative process are carcinogenic (potentially cancer forming). In fact, 20% of Dr. Yamanaka’s mice died of cancer.

Although scientists cannot begin to predict when these considerable problems might be overcome, they are still confident in this advancing breakthrough and that these obstacles will someday be overcome.

Reference: Biologists Make Skin Cells Work Like Stem Cells by Nicholas Wade, NYT, June 7, 2007

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The advantage of using embryonic stem cells in cloning research, organ transplantation, and in finding cures for disease, is that these cells are basically “unprogrammed.” This means that the stem cell has not yet determined what it will grow to become so, in theory at least, scientists can manipulate them into becoming anything that they are programmed to be.

Two teams of scientists working independently (Kazutoshi Takahashi and Shinya Yamanaka at Kyoto University, Japan and James Thompson’s team at the University of Wisconsin) announced that they had successfully replicated the biological abilities of the embryonic stem cell using only skin cells. Called “induced pluripotent stem cells” these former skin cells were programmed to become other types of cells, acting in the same way as the embryonic stem cells.

This transformation was accomplished by introducing four basic genes into skin cells, via a viral carrier. These genes cause the adult skin cells to revert and become the equivalent of embryonic stem cells. The breakthrough is in the ability to “unprogram” skin cells so that they revert to cells that have the same response and abilities as embryonic stem cells.

The debate regarding embryonic stem cells has been focused on the harvesting of the cells. A fertilized embryonic egg is allowed to mature until it formed blastocysts. These blastocysts contain the newly formed stem cells. When these stem cells are removed, the embryo is destroyed. If skin cells can be successfully converted to stem cells, this could negate the ethical questions of the use of embryonic stem cells and produce a large amount of readily available stem cells for research.

Caution must be taken with this new technology. For example, one of the genes used to unprogram the skin cells is carcinogenic (cancer-causing).

Research must also be done to verify that these reprogrammed cells don’t have subtle differences between themselves and true embryonic stem cells.

Although the ability to “unprogram” skin cells to form pluripotent stem cells is a significant breakthrough, it is important to stress that this is still a research tool and it will take quite some time before it is known if these cells can truly substitute for stem cells in the treatment of disease.

References:

Kazutoshi T, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S: Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors: Cell (2007), 131, 1-12.

Kolata G, Scientists Bypass Need for Embryo to Get Stem Cells, New York Times, 2007; A-21:23.

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Dr. Bernstein summarizes an article on stem cells that was published in the journal Nature:

This study demonstrates that after wounding the skin of an adult mouse, an embryonic-like change in the epidermal cells outside of the hair follicle stem cells can be induced to form new hair follicle stem cells. In other words, these cells originate from epidermal skin cells in the wound, but then are able take on the characteristics of hair follicle stem cells and actually produce hair. These regenerated hair follicles establish a stem cell population that can produce a hair shaft and continue through all stages of the follicular cycle. The research suggests that these regenerated hair follicles grow new hair through the introduction of Wnt proteins.

The technology, developed at the University of Pennsylvania School of Medicine, has been licensed by Follica Inc. a privately held medical device company.

Reference: “Hair Follicle Regeneration in Adult Mouse Skin After Wounding,” Ito, M., et al. Nature 447, 316-320, May 17, 2007

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The British government has awarded Intercytex a grant to automate the production of their new hair regeneration therapy. Intercytex is a cell therapy company that develops products to restore and regenerate skin and hair. Intercytex has partnered with a private company, The Automation Partnership (TAP), to develop an automated manufacturing process for their novel hair multiplication treatment.

The hair multiplication product, ICX-TRC, has been submitted as a hair regeneration therapy that uses cells cloned from one’s own scalp. It is intended for the treatment of male pattern baldness (androgenetic alopecia) and female pattern hair loss. The key researcher, biochemist Dr. Paul Kemp, founder of Intercytex, is developing the hair multiplication treatment at their Manchester facility. This investment in hair cloning research is spearheaded by UK Science Minister, Lord Sainsbury.

The government grant will be used mainly to develop a robotic system specifically designed to support the commercial-scale production of their hair cloning product ICX-TRC, at a scale that can handle a large number of people. The company is currently in Phase II clinical testing.

How Intercytex’s Hair Cloning Product Works

Intercytex’s method of hair regeneration involves removing a slice of the scalp, complete with hairs and follicles, from the back of the head. Hair follicles from this area are most resistant to typical hereditary baldness. The sample is taken to a laboratory where the hair producing dermal papilla (DP) cells are extracted and multiplied in flasks. After eight weeks, the DP cells should have cloned into millions of hair cells.

To complete the hair cloning process, the new cells are injected back into the patient’s scalp under a local anesthetic. These cultured cells should then develop into brand new hair follicles.

Intercytex

Intercytex is a 6-year-old company with its main office is in Cambridge, UK and has a clinical production facility and research and development laboratories in Manchester, UK. Additional laboratories are located in Boston, Massachusetts. TAP, founded in 1988, is a private company with headquarters near Cambridge, UK. Intercytex is publicly traded on the London Stock exchange (LSE: ICX).

Additional information about this hair cloning product can be found at www.intercytex.com.

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Dr. Bernstein summarizes an article on hair cloning in The Plain Dealer:

An English based company called Intercytex has claimed some success in its research on hair cloning with its first testing in humans. This technique is similar to the one initially proposed by Dr. Colin Jahoda and published in 1999. (Download the article )

The idea is that certain cells (called fibroblasts) found at the bottom of hair follicles can be separated from the follicles after they have been removed from the scalp, and then be used to form new follicles.

The way this works is as follows: a few hair follicles at the permanent area from the back of the scalp (the area that does not bald) are removed. In a lab, the germinative cells at the base of the follicle are dissected off and placed in a Petri dish. They are then incubated in a special medium and allowed to multiply thousands of times.

These cultured cells are then injected into the balding area of the scalp where they induce complete hair follicles to form. In contrast to traditional hair transplants, where the doctor is limited by the patient’s finite donor supply and hair is literally just moved around (from the back to the front), in hair cloning, there will be an actual increase in the total number of hairs on a person’s head.

Initial testing involved seven male volunteers that were suffering from androgenetic alopecia (common baldness). After the process, five of them showed an increased amount of hair. Fortunately, there were no complications, such as skin inflammation or tissue rejection. However, the test area was small and volunteers only grew a little hair.

Towards the middle of next year, additional patients will be tested using a greater number of cloned cells, so that a larger area of the scalp could be covered. The researchers speculate that this new cloning technology may be on the market in as soon as five years.

The researchers speculate that in the distant future, traditional hair transplants may not be needed at all. Instead, as patients start to thin, they could come to the clinic on a regular basis for injections of their own cells to stimulate the growth of new follicles and stop the impending balding – a sort of hair maintenance.

Reference: The Plain Dealer, Tuesday, November 15, 2005. “Hope grows for bald baby boomers,” Malcolm Ritter, Associated Press.

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Dr. Bernstein summarizes an article in the Journal of the National Cancer Institute:

Curis, Inc., a drug development company, has published data showing the effectiveness of a proprietary Hedgehog pathway activator to stimulate hair growth in adult mice. The study shows that a topically applied small molecule agonist of the Hedgehog signaling pathway can stimulate hair follicles to pass from the resting stage to the growth stage of the hair cycle. The Hedgehog agonist produces no other noticeable short or long-term changes in the skin of the mice.

This study also demonstrated that the Hedgehog agonist is active in human scalp in vitro as measured by Hedgehog pathway gene expression. The results suggest that topical application of a Hedgehog agonist could be effective in treating hair loss conditions, including male and female pattern genetic hair loss.

Preliminary results were presented at the American Academy of Dermatology (AAD) in February 2005. This work was based on a study in 2001 by Sato et. Al. who showed that the Sonic hedgehog gene is involved in the initiation of hair growth in mice.

Reference: Sato N., Leopold PL, Crystal, RG. Effect of Adenovirus-Mediated Expression of Sonic Hedgehog Gene on Hair Regrowth in Mice With Chemotherapy-Induced Alopecia. Journal of the National Cancer Institute, 2001, Vol. 93, No. 24.

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