Stem Cell Communication - Bernstein Medical - Center for Hair Restoration
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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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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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In what might be another illuminating discovery on the inner-workings of hair growth, Yale University scientists have discovered that cells from the fat layer in the skin of mice contribute to the stimulation of hair follicles.

An article by ABC News quotes the lead researcher, Valerie Horsley, saying, “The fat cells are important for hair growth. If they’re not there, the hair won’t grow. We don’t know for sure if it’s a cure for baldness, but I’m hopeful that we can get human cells to do the same as the mice cells.”

Dr. Bernstein, who was interviewed for the article, called the findings, “an interesting development in understanding why millions of people go bald.”

“It’s an important step. Mice models are not necessarily applicable to humans, but this is how we start to make discoveries,” he said.

Bernstein noted that the study’s findings don’t [directly] address genetic hair loss, in which a hormone called DHT causes hair follicles to shrink.

Dr. Horsley suggested that the next round of research should focus on finding out what cells are being effected by the fat cells, and why. She said, ”It’s very exciting because we really knew nothing about the fat in the skin. I’m hoping we can extend the research.”

Read more about research into the causes and mechanisms around hair loss in posts assigned to the tag “Stem Cells.”

Read the original article at ABCNews.com

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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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