Tissue Regeneration - 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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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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Q: Like many people who are eagerly awaiting hair cloning, I read about ACell’s new technology, but what is an “extracellular matrix”? — S.B., Chicago, IL

A: An extracellular matrix, or ECM, is the substance between the cells in all animal tissues. It provides support to the cells and a number of other important functions. ECM is made up of fibrous proteins that form a web or mesh filled with a substance called glycosaminoglycans (GAG). One type of GAG, called hyaluronic acid, functions to hold water in the tissues. Another important part of the extracellular matrix is the basement membrane on which the epithelial cells of the skin and other tissues lie. Elastin in the ECM allows blood vessels, skin, and other tissues to stretch.

ECM has many functions including providing support for cells, regulating intercellular communication, and providing growth factors for wound healing and tissue regeneration.

Read more about ACell’s MatriStem ECM on our ACell for Hair Cloning 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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