Fully mature hair follicles generated in the laboratory as cultured “follicloids”

Fully mature hair follicles generated in the laboratory as cultured “follicloids”

A team of researchers from Japan studying the processes of hair follicle growth and hair pigmentation have successfully generated hair follicles in culture by monitoring epithelial-mesenchymal interactions (EMI) and the arrangement of epithelial and mesenchymal cells in three dimensions, in vitro. The scientists, led by Tatsuto Kageyama, PhD, an assistant professor at the Yokohama National University College of Engineering, suggest that the hair follicle model will provide new insights into hair follicle development, which could point to the development of new approaches. for hair treatment. wasting disorders, and also potentially have relevance to animal testing and drug screening.

reporting your work Progress of sciencein an article titled “Reprogramming of three-dimensional microenvironments for hair follicle induction in vitro”, Kageyama and colleagues concluded: “This approach may be useful not only for understanding the basis of EMIs in hair follicle induction, but also for applications as alternatives to animal testing, hair follicle regeneration and testing. drug screening”.

As an embryo develops, interactions occur between the outer layer of skin called the epidermal layer and connective tissue called the mesenchyme. These epithelial-mesenchymal interactions function as a messenger system to trigger the development of various tissues and organs, including hair follicle morphogenesis. Morphogenesis is the process in an organism where cells organize themselves into tissues and organs.

For the past several decades, scientists have used animal models to investigate the critical mechanisms involved in hair follicle development. But fully understanding the processes involved in hair follicle development remains a challenge, and to date, hair follicle morphogenesis has not been successfully reproduced in a laboratory culture dish. “Although knockout and knockdown mouse models can be used to identify key genes and signals related to hair follicle development based on the appearance of body hair, fully elucidating the molecular mechanisms of IMDs remains challenging due to the crowded in vivo environment,” the team explained.

The use of organoid cultures in research has more recently been the focus of widespread attention. As tiny, simple versions of an organ, scientists produce and use organoids to study the development and pathology of tissues and organs in a laboratory culture dish. “Organoids were a promising tool for elucidating the mechanisms of hair follicle morphogenesis in vitro,” said Kageyama.

Some progress had previously been reported with the reconstruction of hair follicle germ-like aggregates (HFGs) in culture, using dissociated embryonic epithelial and mesenchymal cells, the team continued. “When transplanted into the skin of nude mice, HFGs generated hair follicles de novo, implying that HFGs have capillary neogenesis capabilities.” However, the researchers noted, inducing the generation of mature hair follicles and hair neogenesis in culture remains a challenge.

For their reported study, the researchers fabricated hair follicle organoids by controlling the structure generated by embryonic epithelial and mesenchymal cells, using a fairly low concentration of extracellular matrices. The extracellular matrices adjusted the space between the two types of embryonic cells from a dumbbell shape to a nucleus-shell configuration. Newly formed hair follicles with typical characteristics emerged in core- and shell-shaped clusters. These core and shell shaped groups increase the contact area between two cellular regions to enhance the mechanisms that contribute to hair follicle growth.

A representative long-growing hair follicle generated from hair folicloids after an extended period of culture. [Yokohama National University]

The team’s newly developed organoid culture system generated hair follicles and hair shafts with almost 100% efficiency. Hair follicle organoids produced fully mature hair follicles with long stems (approximately 3 mm in length after 23 days of culture), “… something that had not been achieved previously,” the team stated. As this growth occurred, the researchers were able to monitor hair follicle morphogenesis and hair pigmentation in vitro and understand the signaling pathways involved in the processes.

The team further examined the feasibility of using hair follicle organoids for drug screening and regenerative medicine. They also added to the culture medium a melanocyte-stimulating drug that plays a key role in producing hair color pigmentation. With the addition of this drug, the researchers significantly improved the pigmentation of the hair-like fibers. Furthermore, by transplanting the hair follicle organoids, they achieved efficient hair follicle regeneration with repeated cycles of hair.

The scientists believe this in vitro hair follicle model could help scientists gain a better understanding of hair follicle induction, assess hair pigmentation and hair growth medications, and potentially how to regenerate hair follicles. .

The method is also scalable, they noted, opening up the potential for additional avenues of investigation. “Large-scale preparation of hair follicles can be combined with genetic engineering technology (using CRISPR-Cas9, short interfering RNA and signal inhibitor) to perform a comprehensive analysis of key genes related to hair follicle development, pigmentation hair and hair follicle growth. diseases.”

The findings could also be relevant to other organ systems and contribute to the understanding of how physiological and pathological processes develop. “Because EMIs are crucial for the morphogenesis of other tissues and organs, this may provide a versatile approach for the preparation of other organoids,” the scientists suggested.

The reported research used mouse cells, but looking ahead to future research, the team plans to optimize their organoid culture system using human cells. “Our next step is to use human-derived cells and apply for drug development and regenerative medicine,” said co-author Junji Fukuda, PhD, a professor at Yokohama National University’s faculty of engineering. In his article, the authors noted: “…we are currently investigating our approach using human tissue stem cells from hair follicle donors or cells induced from human pluripotent stem cells.”

Future research could eventually point to new therapeutic strategies for hair loss disorders such as androgenetic alopecia, which is common in both men and women. “This in vitro hair follicle model could be valuable to better understand hair follicle induction, assess hair growth and hair growth inhibition by drugs, and model gray hair in a well-defined environment,” the researchers suggested.

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