Hair-bearing skin organoids offer valuable insights into human skin development and pathology

By Yeji Hong

A new approach to curing baldness may be on the horizon, as researchers have successfully produced hair-bearing skin organoids. Skin organoids are 3D cell culture models composed of layers of epithelial cells, called epidermal and dermal layers, and these organoids are made with the intent to mimic the function and structure of skin. They are usually generated from stem cells or progenitor cells and can be generated from adult or embryonic cells. 

Human skin is one of the most challenging organs to mimic; hence the lack of accurate in vitro models that have been created. This makes studying skin pathologies exceptionally difficult. Substantial improvements have been made in 3D organoid cultures in the past decades, and different methods of forming skin organoids are constantly being designed in the hopes of creating an accurate skin organoid well-suited for clinical applications. 

An eye-opening study conducted by Kim E. Boonekamp and colleagues (2017) focuses on the self-organisation process that occurs during the formation of a skin organoid from dissociated adult murine cells. The study aims to identify the changes that occur to the epithelial cells during this critical organisation process to elucidate the exact biological mechanisms and crosstalk that drive the process.  Initially the key molecular changes that occur during the process were identified and six distinct stages were highlighted showing how the aggregate transitions through to form a recognisable skin organoid. Furthermore, through RNA-sequencing, immunostaining and in-situ hybridisation, changes in spatiotemporal gene expression were investigated, ultimately allowing them to identify certain factors, such as growth factors, adhesion molecules, Wnt proteins and metalloproteinases, as key players that are involved in self-organisation. These factors were found to trigger the interactions amongst cells, as well as between the cells and the microenvironment, to encourage skin organoid morphogenesis.

The latter part of the study was particularly interesting and insightful, where they attempted to rescue the hair regeneration ability of adult murine skin cells. By treating dissociated murine adult skin cells with the identified key players involved self-organisation, they were able to successfully ‘reprogramme’ the cells to form hair-bearing skin. This was achieved by treating isolated adult murine cells with growth factors in a stepwise manner, enlarging the organoid size and coalescing the cells. Upon reaching an appropriate size, the skin organoids were transplanted onto immunocompromised nude mice, where the reprogramming was deemed successful upon observing up to a 40% increase in hair follicle regeneration. 

A more recent study conducted by Lee J. and colleagues (2020) at Harvard Medical School also focused on generating hair-bearing skin organoids, but utilised human pluripotent stem cells. The researchers successfully generated human skin organoids displaying hair follicles with sebaceous glands and sensory neurons. They accomplished this by plating human embryonic stem cells to form aggregates and culturing them for several months with key factors until the organoids reached a hair-bearing stage. Observations indicated that the hair follicles of the skin organoids underwent a morphogenesis consistent to mammalian hair follicles, and the patterning of the follicles seen were also similar to that of seen in human skin. They also identified the presence of neuroglial cells with axons that interwove between the hair follicles, innervating the organoid. Intriguingly, the researchers determined that the external appearance of the skin organoids after approximately 14 weeks in culture resembled an 18-week old human fetal skin, and after 18 weeks in culture, the neuronal processes were similar to the nerve endings found in an 18-week old fetus. Next, they assessed if these organoids could be successfully implanted into mice. 140 day old skin organoids were implanted onto immunocompromised nude mice, which led to the finding that these organoids were able to fully integrate into the mice epidermis. This demonstrated that these human skin organoids could unfold and insert themselves into wound sites of mice epidermis seamlessly. 

These achievements not only place us closer to a reality where an unlimited supply of hair follicles could be a cure for thinning or balding hair, but also provide meaningful and valuable insight into previously unknown details of cellular dynamics underlying human skin development. These novel in vitro skin models pose as critical tools for assessing skin pathologies such as genetic skin disorders and cancer, which could be valuable for drug discovery and development. Furthermore, these appendage-bearing skin organoids open up a plethora of different possibilities for regenerative medicine, where skin transplants could be considered as a possible cure for patients with skin burns or wounds.

References:

Lei, M., Schumacher, L., Lai, Y., Juan, W., Yeh, C., Wu, P., Jiang, T., Baker, R., Widelitz, R., Yang, L. and Chuong, C., 2017. 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(34), pp.E7101-E7110.

Lee, J., Rabbani, C., Gao, H., Steinhart, M., Woodruff, B., Pflum, Z., Kim, A., Heller, S., Liu, Y., Shipchandler, T. and Koehler, K., 2020. Hair-bearing human skin generated entirely from pluripotent stem cells. Nature, 582(7812), pp.399-404.

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