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.
(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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