Spontaneous hair follicle germ (HFG) formation in vitro, enabling the large-scale production of HFGs for regenerative medicine
Abstract
Hair follicle morphogenesis is triggered by reciprocal interactions between hair follicle germ (HFG) epithelial and mesenchymal layers. Here, we developed a method for large-scale preparation of HFGs in vitro via self-organization of cells. We mixed mouse epidermal and mouse/human mesenchymal cells in suspension and seeded them in microwells of a custom-designed array plate. Over a 3-day culture period, cells initially formed a randomly distributed single cell aggregate and then spatially separated from each other, exhibiting typical HFG morphological features. These self-sorted hair follicle germs (ssHFGs) were shown to be capable of efficient hair-follicle and shaft generation upon intracutaneous transplantation into the backs of nude mice. This finding facilitated the large-scale preparation of approximately 5000 ssHFGs in a microwell-array chip made of oxygen-permeable silicone. We demonstrated that the integrity of the oxygen supply through the bottom of the silicone chip was crucial to enabling both ssHFG formation and subsequent hair shaft generation. Finally, spatially aligned ssHFGs on the chip were encapsulated into a hydrogel and simultaneously transplanted into the back skin of nude mice to preserve their intervening spaces, resulting in spatially aligned hair follicle generation. This simple ssHFG preparation approach is a promising strategy for improving current hair-regenerative medicine techniques.
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We have reported an approach for engineering HFG-like aggregates in vitro through self-organization of embryonic dorsal epithelial and mesenchymal cells in a laboratory-made microwell array plate.
“We have reported an approach for engineering HFG-like aggregates in vitro through the self-organization of embryonic dorsal epithelial and mesenchymal cells in a laboratory-made microwell array plate (14).”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [14]
In this approach, two types of rodent cells initially formed a single aggregate where the two cell types were distributed randomly and subsequently spatially separated and formed HFG-like structures during 3 days of culture.
“In this approach, the two types of rodent cells initially formed a single aggregate where the two cell types were distributed randomly and subsequently spatially separated and formed HFG-like structures during 3 days of culture.”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [14]
HFGs generated hair follicles and shafts in vitro in long-term culture, but the appearance of hair follicles was quite rare.
“Furthermore, HFGs generated hair follicles and shafts in vitro in a long-term culture, but the appearance of hair follicles was quite rare.”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [14]
When transplanted into the skin of nude mice, HFGs efficiently generated de novo hair follicles in a few weeks and represented normal hair cycles.
“When transplanted into the skin of nude mice, the HFGs efficiently generated de novo hair follicles in a few weeks and represented normal hair cycles.”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [14]
A microdevice with an array of 1.0-mm-diameter round-bottom wells made of oxygen-permeable silicone rubber could produce hundreds to thousands of dumbbell-shaped HFGs under improved oxygen concentration conditions.
“In our previous study, we showed that a microdevice with an array of 1.0-mm-diameter round-bottom wells made of oxygen-permeable silicone rubber could produce hundreds to thousands of dumbbell-shaped HFGs under improved oxygen concentration conditions (14).”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [14]
Cites
Molecular Mechanisms Regulating Hair Follicle Development
Millar, S. E. (2002) · Journal of Investigative Dermatology · doi:10.1046/j.0022-202x.2001.01670.x · Cited by 967 · see citing works
The differential adhesion hypothesis: a direct evaluation
Foty, R. A., & Steinberg, M. S. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2004.11.012 · Cited by 908 · cited 1× · see citing works
“N- and E-cadherin mediate cell-cell adhesion in mes enchymal and epithelial cells, respectively [28, 29].”
BackgroundFully functional hair follicle regeneration through the rearrangement of stem cells and their niches
Toyoshima, K.-E., Asakawa, K., Ishibashi, N., Toki, H., Ogawa, M., Hasegawa, T., Irié, T., Tachikawa, T., Sato, A., Takeda, A., et al. (2012) · Nature Communications · doi:10.1038/ncomms1784 · Cited by 250 · see citing works
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Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction
Kageyama, T., Shimizu, A., Anakama, R., Nakajima, R., Suzuki, K., Okubo, Y., & Fukuda, J. (2022) · Science Advances · doi:10.1126/sciadv.add4603 · Cited by 73 · see citing works
Self-citationKageyama, T., Nanmo, A., Yan, L., Nittami, T., & Fukuda, J. (2020) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2020.08.005 · Cited by 20 · see citing works
Self-citationKageyama, T., Anakama, R., Hamano, S., Tu, S., Migita, Y., Asaba, T., Nanmo, A., Ishikawa, K., Yan, L., Seo, J., et al. (2026) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c01780 · Cited by 6 · see citing works
Self-citation
- Authors
- Kageyama, T., Yoshimura, C., Myasnikova, D., Kataoka, K., Nittami, T., Maruo, S., & Fukuda, J.
- Affiliations
- Yokohama National University (JP)
- Okayama University of Science (JP)
- Corresponding author
- Fukuda, Junji
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 154
- Pages
- 291-300
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2767226147
- Cited by
- 80
- References
- 3
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 5 · 2023: 10 · 2022: 12 · 2021: 9 · 2020: 7 · 2019: 6 · 2018: 3
- FWCI
- 6.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MEXT (16K14489)
- Japanese Society for Alternatives to Animal Experiments
- Asahi Glass Foundation
- Cross-ministerial Strategic Innovation Promotion Program
- Topics
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- hair follicle morphogenesis, self-organization, microwell arrays, hydrogel encapsulation, hair regrowth
- MeSH terms
- Animals, Mice, Inbred C57BL, Mice, Nude, Hair Follicle, Regenerative Medicine, Microtechnology
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