Fully mature hair follicles generated in the lab as cultured "follicloids"

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

A team of Japanese researchers studying the growth and pigmentation processes of hair follicles succeeded in generating hair follicles in cultures, by controlling epithelial-mesenchymal interactions (EMI) and the arrangement of epithelial and mesenchymal cells in three dimensions, in vitro. The scientists, led by Tatsuto Kageyama, PhD, assistant professor at the Yokohama National University School of Engineering, suggest that the hair follicle model will provide new insights into hair follicle development, which could indicate the development new approaches to hair treatment. shedding disorders, and also potentially have relevance for animal testing and drug screening.

report on their work in Scientists progressin a paper titled “Reprogramming 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 NDEs in hair follicle induction, but also for applications as alternatives to animal testing, hair follicle regeneration and drug testing.

As an embryo develops, interactions occur between the outer layer of skin called the epidermal layer and the connective tissue called the mesenchyme. These epithelial-mesenchymal interactions function much like 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 are organized into tissues and organs.

Over the past few decades, scientists have used animal models to study the critical mechanisms involved in hair follicle development. But fully understanding the processes involved in hair follicle development remains difficult, and to date, hair follicle morphogenesis has not been successfully replicated in a culture dish in the laboratory. “Although both 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, full elucidation of the molecular mechanisms of NDEs remains. difficult due to the crowded in vivo environment,” the team explained.

The use of organoid cultures in research has recently received wide 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 to elucidate the mechanisms of hair follicle morphogenesis in vitro,” Kageyama said.

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

For their reported study, the researchers made 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 spacing between the two embryonic cell types from a dumbbell shape to a nucleus-shell configuration. Newly formed hair follicles with typical features emerged in core-shell shaped clusters. These core-shell clusters increase the area of ​​contact between two cellular regions to enhance the mechanisms that contribute to hair follicle growth.

A representative long hair follicle generated from hair follicles after a long period of culture. [Yokohama National University]

The team’s newly developed organoid culture system generated hair follicles and hair shafts with almost 100% efficiency. The hair follicle organoids produced fully mature hair follicles with long hairs (approximately 3 mm long after 23 days in culture), “…which has not been achieved before,” the team said. As this growth occurred, researchers could monitor hair follicle morphogenesis and hair pigmentation in vitro and understand the signaling pathways involved in the processes.

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

Scientists believe this in vitro hair follicle model could help scientists better understand hair follicle induction, evaluate hair pigmentation and hair growth drugs, and potentially regenerate hair follicles.

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

The findings may also prove 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 in the National University’s Faculty of Engineering. from Yokohama. In their paper, the authors noted, “…we are currently investigating our approach using cells derived from human tissue stem cells from hair follicle donors or cells induced from human pluripotent stem cells.

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

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