Embryonic Cells - 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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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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Q: What is the major obstacle to hair cloning?

A: Although many problems remain, the main one is to keep cloned cells differentiated (the ability to perform a specialized function, like producing a hair). There are certain cells in the skin, called fibroblasts, which reside around the base of the hair follicle. These cells are readily multiplied in a Petri dish. When these cells are injected into the skin, they have the ability to induce a hair to form (they are differentiated). The problem is that when these cells are multiplied in culture, they tend to lose this ability (they become undifferentiated).

A number of methods are being examined to keep these cells differentiated. Among them is the insertion of new genes into the cell’s nucleus to alter the expression of the existing genes. Another method is to change the spatial relationship of multiplying cells. The idea behind the second technique is that all embryonic cells have the same basic genetic material, but grow to have different functions (i.e., grow to form muscle, bone or nerves). One reason is that that the cells have a different physical relationship to one another and thus send different signals to each other based on this relationship. For example, the cells on the outside of a growing ball of cells may act differently than the cells on the inside, etc. If researchers can influence the way cells orient themselves as they multiply in the lab, this may enable them to become differentiated to produce hair and stay that way as the multiplication process continues.

For more on this intriguing topic, see the Hair Cloning and Hair Cloning Methods pages at the Bernstein Medical – Center for Hair Restoration website.

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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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Q: What is the difference between hair cloning, hair multiplication, and follicular neogeneis? I have read about these terms on the internet and am completely confused.

A: Cloning generally refers to the multiplication of fetal stem cells or embryonic tissues. “Hair cloning”, as the term is generally used, involves the multiplication of adult tissue cells that are used to induce the formation of new hair, so the term is not exactly accurate.

“Hair multiplication” refers to the multiplication of adult hair structures. This model is not actively being pursued since the hair follicle is too complex to be simply cultured in a tube. Instead individual cells called fibroblasts are removed from the scalp multiplied in tissue culture and then these are injected back into the scalp in the hope that they will induce intact follicles to form.

“Follicular neogeneis” is probably the best of these terms, as it describes the formation of new follicles derived from inducer cells that are cultured and then injected into the scalp. It is the preferred term of Ken Washenik at Aderans. Interctyex uses the term “follicular cell regeneration” for its technology.

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