PI3K/Akt signaling pathway is essential for de novo hair follicle regeneration
Open accessAbstract
Background: Cultured epidermal stem cells (Epi-SCs) and skin-derived precursors (SKPs) were capable of reconstituting functional hair follicles after implantation, while the signaling pathways that regulate neogenic hair follicle formation are poorly investigated. In this study, we aimed to understand the interactions between Epi-SCs and SKPs during skin organoid formation and to uncover key signal pathways crucial for de novo hair follicle regeneration. Methods: To track their fate after transplantation, Epi-SCs derived from neonatal C57BL/6 mice were labeled with tdTomato, and SKPs were isolated from neonatal C57BL/6/GFP mice. A mixture of Epi-SCs-tdTomato and SKPs-EGFP in Matrigel was observed under two-photon microscope in culture and after implantation into excisional wounds in nude mice, to observe dynamic migrations of the cells during hair follicle morphogenesis. Signaling communications between the two cell populations were examined by RNA-Seq analysis. Potential signaling pathways revealed by the analysis were validated by targeting the pathways using specific inhibitors to observe a functional loss in de novo hair follicle formation. Results: Two-photon microscopy analysis indicated that when Epi-SCs and SKPs were mixed in Matrigel and cultured, they underwent dynamic migrations resulting in the formation of a bilayer skin-like structure (skin organoid), where Epi-SCs positioned themselves in the outer layer; when the mixture of Epi-SCs and SKPs was grafted into excisional wounds in nude mice, a bilayer structure resembling the epidermis and the dermis formed at the 5th day, and de novo hair follicles generated subsequently. RNA-Seq analysis of the two cell types after incubation in mixture revealed dramatic alterations in gene transcriptome, where PI3K-Akt signaling pathway in Epi-SCs was significantly upregulated; meanwhile, elevated expressions of several growth factors and cytokine potentially activating PI3K were found in SKPs, suggesting active reciprocal communications between them. In addition, inhibition of PI3K or Akt by specific inhibitors markedly suppressed the hair follicle regeneration mediated by Epi-SCs and SKPs. Conclusions: Our data indicate that the PI3K-Akt signaling pathway plays a crucial role in de novo hair follicle regeneration, and the finding may suggest potential therapeutic applications in enhancing hair regeneration.
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The up-regulation of NF-κB and PI3K-Akt pathways is consistent with previous studies reporting that these genes are crucial for early hair follicle development and de novo regeneration of hair follicles.
“which is consistent with previous studies reporting that these genes are crucial for the early development of hair follicles and de novo regeneration of hair follicles (44, 45).”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [45]
The Results and Conclusions report that PI3K/Akt signaling is essential for de novo hair follicle regeneration. This paper does not establish that NF-κB or PI3K/Akt is crucial for early hair follicle development; its Introduction instead identifies Wnt signaling as predominant in early morphogenesis. No page numbers are available in our copy. (LLM, conf=0.86)
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- Authors
- Chen, Y., Fan, Z., Wang, X., Mo, M., Zeng, S. B., Xu, R.-H., Wang, X., & Wu, Y.
- Affiliations
- Tsinghua Shenzhen International Graduate School (CN)
- Sun Yat-sen University (CN)
- Tsinghua–Berkeley Shenzhen Institute (CN)
- University of Macau (MO)
- Corresponding author
- Wang, Xusheng
- Wu, Yaojiong
- Venue
- Stem Cell Research & Therapy
- Published
- 2020-04-03
- Volume
- 11
- Issue
- 1
- Pages
- 144-144
- ISSN
- 1757-6512 (ISSN-L)
- PMC
- PMC7118821
- OpenAlex
- W3014739274
- Cited by
- 130
- References
- 55
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 30 · 2023: 16 · 2022: 24 · 2021: 12 · 2020: 3
- FWCI
- 19.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Stem Cell Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Science Foundation of China (No. 31571429, 31961160702)
- National Key R&D Program of China (2017YFC1103304)
- Shenzhen Science and Technology Innovation Committee (JCYJ20170818093935581, JCYJ20180307123901314)
- State Key Laboratory of Chemical Oncogenomics fund
- Topics
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Keywords
- PI3K/Akt signaling, epidermal stem cells, skin-derived precursors, hair follicle morphogenesis, cell migration, wound healing
- MeSH terms
- Animals, Cells, Cultured, Mice, Inbred C57BL, Mice, Nude, Signal Transduction, Hair Follicle, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Mice
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