Reprogramming of Three-dimensional Microenvironments for in Vitro Hair Follicle Induction

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2022 Oct 21

PMID 36269827

Authors

Tatsuto Kageyama

Akihiro Shimizu

Riki Anakama

Rikuma Nakajima

Kohei Suzuki

Yusuke Okubo

Junji Fukuda

Affiliations

Soon will be listed here.

Abstract

During embryonic development, reciprocal interactions between epidermal and mesenchymal layers trigger hair follicle morphogenesis. This study revealed that microenvironmental reprogramming via control over these interactions enabled hair follicle induction in vitro. A key approach is to modulate spatial distributions of epithelial and mesenchymal cells in their spontaneous organization. The de novo hair follicles with typical morphological features emerged in aggregates of the two cell types, termed hair follicloids, and hair shafts sprouted with near 100% efficiency in vitro. The hair shaft length reached ~3 mm in culture. Typical trichogenic signaling pathways were up-regulated in hair follicloids. Owing to replication of hair follicle morphogenesis in vitro, melanosome production and transportation were also monitored in the hair bulb region. This in vitro hair follicle model might be valuable for better understanding hair follicle induction, evaluating hair growth and inhibition of hair growth by drugs, and modeling gray hairs in a well-defined environment.

Citing Articles

Functional regeneration strategies of hair follicles: advances and challenges.

Chu X, Zhou Z, Qian X, Shen H, Cheng H, Zhang J Stem Cell Res Ther. 2025; 16(1):77.

PMID: 39985119 PMC: 11846195. DOI: 10.1186/s13287-025-04210-y.

The role of lipids in promoting hair growth through HIF-1 signaling pathway.

Seo J, Matsumoto K, Nanmo A, Tu S, Do-Won Jeong , Chun Y Sci Rep. 2025; 15(1):4621.

PMID: 39920332 PMC: 11805989. DOI: 10.1038/s41598-025-88697-8.

Biomaterial-assisted organoid technology for disease modeling and drug screening.

Shao Y, Wang J, Jin A, Jiang S, Lei L, Liu L Mater Today Bio. 2025; 30:101438.

PMID: 39866785 PMC: 11757232. DOI: 10.1016/j.mtbio.2024.101438.

Bioengineering strategies for regeneration of skin integrity: A literature review.

Shiraishi M, Sowa Y, Sunaga A, Yamamoto K, Okazaki M Regen Ther. 2025; 28():153-160.

PMID: 39790492 PMC: 11713503. DOI: 10.1016/j.reth.2024.12.006.

Materials-based hair follicle engineering: Basic components and recent advances.

Lv Y, Yang W, Kannan P, Zhang H, Zhang R, Zhao R Mater Today Bio. 2024; 29:101303.

PMID: 39498149 PMC: 11532916. DOI: 10.1016/j.mtbio.2024.101303.

References

Pleniceanu O, Harari-Steinberg O, Dekel B . Concise review: Kidney stem/progenitor cells: differentiate, sort out, or reprogram?. Stem Cells. 2010; 28(9):1649-60. PMC: 2996087. DOI: 10.1002/stem.486. View

Qiao J, Turetsky A, Kemp P, Teumer J . Hair morphogenesis in vitro: formation of hair structures suitable for implantation. Regen Med. 2008; 3(5):683-92. DOI: 10.2217/17460751.3.5.683. View

De Luca M, Siegrist W, Bondanza S, Mathor M, Cancedda R, Eberle A . Alpha melanocyte stimulating hormone (alpha MSH) stimulates normal human melanocyte growth by binding to high-affinity receptors. J Cell Sci. 1993; 105 ( Pt 4):1079-84. DOI: 10.1242/jcs.105.4.1079. View

Chen Y, Fan Z, Wang X, Mo M, Zeng S, Xu R . PI3K/Akt signaling pathway is essential for de novo hair follicle regeneration. Stem Cell Res Ther. 2020; 11(1):144. PMC: 7118821. DOI: 10.1186/s13287-020-01650-6. View

Chen R, Miao Y, Hu Z . Dynamic Nestin expression during hair follicle maturation and the normal hair cycle. Mol Med Rep. 2018; 19(1):549-554. DOI: 10.3892/mmr.2018.9691. View

de Groot S, Ulrich M, Gho C, Huisman M . Back to the Future: From Appendage Development Toward Future Human Hair Follicle Neogenesis. Front Cell Dev Biol. 2021; 9:661787. PMC: 8075059. DOI: 10.3389/fcell.2021.661787. View

Nikolov A, Popovski N . Role of Gelatinases MMP-2 and MMP-9 in Healthy and Complicated Pregnancy and Their Future Potential as Preeclampsia Biomarkers. Diagnostics (Basel). 2021; 11(3). PMC: 8001076. DOI: 10.3390/diagnostics11030480. View

Qiu W, Chuong C, Lei M . Regulation of melanocyte stem cells in the pigmentation of skin and its appendages: Biological patterning and therapeutic potentials. Exp Dermatol. 2018; 28(4):395-405. PMC: 6488374. DOI: 10.1111/exd.13856. View

Kageyama T, Yoshimura C, Myasnikova D, Kataoka K, Nittami T, Maruo S . Spontaneous hair follicle germ (HFG) formation in vitro, enabling the large-scale production of HFGs for regenerative medicine. Biomaterials. 2017; 154:291-300. DOI: 10.1016/j.biomaterials.2017.10.056. View

10.

Sikkink S, Mine S, Freis O, Danoux L, Tobin D . Stress-sensing in the human greying hair follicle: Ataxia Telangiectasia Mutated (ATM) depletion in hair bulb melanocytes in canities-prone scalp. Sci Rep. 2020; 10(1):18711. PMC: 7603349. DOI: 10.1038/s41598-020-75334-9. View

11.

Kadaja M, Keyes B, Lin M, Pasolli H, Genander M, Polak L . SOX9: a stem cell transcriptional regulator of secreted niche signaling factors. Genes Dev. 2014; 28(4):328-41. PMC: 3937512. DOI: 10.1101/gad.233247.113. View

12.

Kishimoto J, Ehama R, Wu L, Jiang S, Jiang N, Burgeson R . Selective activation of the versican promoter by epithelial- mesenchymal interactions during hair follicle development. Proc Natl Acad Sci U S A. 1999; 96(13):7336-41. PMC: 22086. DOI: 10.1073/pnas.96.13.7336. View

13.

Yao Y, Zhang Y . The lacrimal gland: development, wound repair and regeneration. Biotechnol Lett. 2017; 39(7):939-949. DOI: 10.1007/s10529-017-2326-1. View

14.

Liu D, Mai K, Zhang Y, Xu W, Ai Q . Wnt/β-catenin signaling participates in the regulation of lipogenesis in the liver of juvenile turbot (Scophthalmus maximus L.). Comp Biochem Physiol B Biochem Mol Biol. 2015; 191:155-62. DOI: 10.1016/j.cbpb.2015.11.002. View

15.

Toyoshima K, Asakawa K, Ishibashi N, Toki H, Ogawa M, Hasegawa T . Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nat Commun. 2012; 3:784. PMC: 3337983. DOI: 10.1038/ncomms1784. View

16.

Koehler K, Mikosz A, Molosh A, Patel D, Hashino E . Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature. 2013; 500(7461):217-21. PMC: 3739998. DOI: 10.1038/nature12298. View

17.

Liu S, Zhang H, Duan E . Epidermal development in mammals: key regulators, signals from beneath, and stem cells. Int J Mol Sci. 2013; 14(6):10869-95. PMC: 3709707. DOI: 10.3390/ijms140610869. View

18.

Lee J, Bscke R, Tang P, Hartman B, Heller S, Koehler K . Hair Follicle Development in Mouse Pluripotent Stem Cell-Derived Skin Organoids. Cell Rep. 2018; 22(1):242-254. PMC: 5806130. DOI: 10.1016/j.celrep.2017.12.007. View

19.

MacDonald B, Tamai K, He X . Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009; 17(1):9-26. PMC: 2861485. DOI: 10.1016/j.devcel.2009.06.016. View

20.

Foty R, Steinberg M . The differential adhesion hypothesis: a direct evaluation. Dev Biol. 2005; 278(1):255-63. DOI: 10.1016/j.ydbio.2004.11.012. View