The study of stem cells has been an emerging field in biology and healthcare for a considerable amount of time now, and its potential continues to grow even further. As a unique breed of cells that can differentiate into a large variety of specialized cells, stem cells pose a potential solution for many different health conditions that plague the world today - cancers, diabetes, rheumatoid arthritis, and many more. By being able to take on the role of many different types of cells in the body given the proper requirements, stem cells can act as a healthy replacement for a plethora of different tissue varieties - something that was largely difficult to acquire without the use of more costly and difficult methods like organ transplantation. Areas like the skin, in particular, can be strongly benefitted by the application of stem cells, as transplantation or grafts of foreign skin are known to cause a large number of complications like bleeding, infection, or tissue contraction.
The use of stem cells has long been limited by the complexity of the human body, however. The body consists of countless different cell types, and even a single organ consists of a diverse array of cell types. These cell types support each other by filling out distinct roles to keep the organ in shape. In other words, they maintain an intricate, interconnected harmony in order to function properly as a part of the body. As such, differentiating stem cells to fit into this complex composition of cells is quite a daunting task.
The skin is a multilayered, complex organ.
The skin, while seemingly a simple organ, is also an area where stem cell application is difficult. As a multilayered organ with a diverse collection of cells including simple skin cells, immune cells, melanocytes (produces pigments), etc. the structure of the skin poses a significant challenge for the integration of stem cells. To properly apply stem cells in the treatment of damaged skin, one must first need to figure out how to replicate the numerous elements of the skin in a natural, non-problematic way.
However, recent findings published by researchers at Harvard, Johns Hopkins and Indiana University show that this may be possible in the near future. The researchers succeeded in constructing a hair-bearing skin organoid (a miniature version of an organ) entirely from stem cells, complete with hair follicle structure similar to the skin found on human embryos - in other words, just like real skin.
Starting off with a sample of pluripotent stem cells (stem cells capable of becoming any cell within the 3 germ layers of our body, a.k.a basically any part of the body) the researchers used a number of different growth factor signaling pathways to differentiate the stem cells into embryonic skin. More specifically, they configured the transforming growth factor β (TGFβ) and fibroblast growth factor (FGF) signaling pathways. TGFβ activation within the stem cells was inhibited in order to elicit a response that promoted the formation of outer skin cells, whereas FGF was activated in order to promote the formation of facial skin cells that are needed to generate mesenchymal cells, which in turn are needed for the formation of connective tissues within the skin.
The differentiation of pluronic stem cells using signaling pathway modification
After configuring the pathways, the researchers noticed the formation of small buds on the surface of the organoids, which developed into hair germs over the course of around 70 days. More importantly, the formation of hair follicles followed a pattern similar to the formation of follicles within mammals, further validating that skin organoids formed by stem cells are capable of replicating complex structures.
Furthermore, the researchers discovered that the cells within the organoid were similar in composition to that of cells within human embryos. RNA sequencing of the organoid cells revealed that they possessed similar groupings of cell clusters to that of surface epithelia (sheets of cells on the exterior) found within embryos, particularly those undergoing the second trimester of pregnancy. Such groupings showed that organoids were consistent with embryonic skin, and points to the potential capability of organoids in being compatible with natural skin.
Comparison of RNA sequencing within an organoid(left) and epithelial mesenchyme (right) shows consistency between the two
To verify compatibility, the researchers tried grafting grown organoids onto nude mice. Astoundingly, some of the organoids were able to integrate themselves into the mice skin to an extent as time passed. One sign was that a network of neurons not previously present developed into the organoids, wrapping around the hair follicles in a fashion that resembled embryonic follicles. Another was that the grafted organoids, while initially taking on the look of a cyst on the mouse skin, later became planar/flat. Of course, the extent of integrations was limited, with complications like ingrown hairs or cancerous growths occurring in some of the organoids and increasing over time, but nevertheless the level of integration showed demonstrate that the organoids can mature after implantation.
Grafting of organoids onto mice skin show integration over time
The research showed the potential viability of stem cell-derived skin organoids for a number of different purposes; some explicitly stated included the use of organoid samples for drug testing and skincare products. But even more exciting is that such organoids could be used to treat patients with severe skin damage. These organoids could be implanted in damaged areas to become new and healthy skin, solving countless cases of skin burns, cuts, and perhaps even cancer. There remain many hurdles that need to be overcome before such treatment would become reliable and safe, but organoids remain as one of the most powerful and promising advancements in skin health to date.
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