Forming sensory organs requires complicated interactions between numerous cell types. Building these tissues in a dish from human stem cells helps researchers understand how they develop over time and the cells and pathways involved in health and disease states. Growing these organs in the laboratory could also lead to novel cell therapeutics that facilitate regeneration and repair in vivo.
Karl Koehler’s team develops human skin organoids that grow tentacle-like hair follicles from pluripotent stem cells.
Karl Koehler, a neuroscientist and stem cell biologist at Boston Children’s Hospital and Harvard Medical School, spoke to The Scientist about how his research team uses stem-cell derived organoids to study development and regeneration.
What is the scope of your research involving organoids?
My research team uses an organoid approach to model sensory systems. Initially, I was focused on developing ways to guide pluripotent stem cells to become inner ear cells and use them to reconstruct the auditory nerve or the inner ear’s sensory hair cells in patients who lost their hearing or had balance issues.
Over the years, we have also worked to recapitulate developmental disorders of the inner ear and skin in a dish. Our work on the skin was naturally born out of the inner ear research because the inner ear and the skin are related organs—they arise in the same tissue layer in early development. We found ways to guide our inner ear organoids to become purely skin tissue.1 Our skin organoids have both the epidermis and dermis, and together those layers form hair follicles, sebaceous glands, and nerves, creating a complete skin system within a dish. This system is something we could use in the future for regenerative therapy.
Which disorders do you study?
We primarily use our inner ear and skin organoids to model congenital disorders. One is Usher syndrome, which causes deafness and blindness. The damage happens really early in development, particularly in the inner ear. We are trying to observe the congenital gene mutations damaging the hair cells of the inner ear organoids in real time. And then, if we apply a treatment, we want to see it working, causing structural changes within the hair cells. We are also looking at epidermolysis bullosa, which is a rare skin blistering disorder typically affecting structural proteins such as collagen. Again, we want to see the structural damage within our organoids as it happens.
Can your organoids facilitate tissue regeneration?
We have grafted skin organoids into a well-characterized nude mouse model, where these mice have hair but the hair follicles are miniaturized.2 The animals are also immunodeficient, so they do not reject the cells that we implant into small wounds on the mice’s backs. A couple of weeks after grafting, the skin organoids grew as a cyst, with the inside representing the top skin layer and the outside representing the bottom layer. The cysts opened up and integrated into the mouse skin, forming outward-growing hair follicles in this island of human skin. If we look histologically at the tissue, the follicles are clearly beginning to mature once they are in this in vivo environment. It is really amazing; I still cannot believe it works. This is a great proof of principle for using these organoids in a regenerative capacity.
What are your thoughts on the future of organoids in regenerative medicine?
We have in mind to use organoids directly in patients as cell therapeutics. The skin is a great target for cell therapy because we can easily get to it—it is right there on the surface of the body. However, a challenge is the immune system’s involvement. To rebuild somebody's skin, it probably cannot be an off-the-shelf cell therapeutic where we are generating the skin tissue from a single stem cell line. We have to generate skin tissue from the patient's cells, reprogram them, and then form skin organoids, which adds some complexity.
Additionally, we are working to determine whether the skin tissue that we make has only the cells that we would want to put into a patient. We can generate skin tissue that is fairly pure, but that still involves 40 to 50 different cell types making the different skin layers and the hair follicles. It might be a while before we can get a cell product that has that many cell types. We need to control that complicated process to make a cell therapeutic that can be safely put into a patient.
This interview has been condensed and edited for clarity.
- Lee J, et al. Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells. Nat Protoc. 2022;17(5):1266-1305.
- Lee J, et al. Hair-bearing human skin generated entirely from pluripotent stem cells. Nature. 2020;582(7812):399-404.
