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Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding

Abstract

Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by γδ T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound-induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from γδ T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans.

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Figure 1: Fgf9 expression modulates WIHN.
Figure 2: Kinetics of γδ T cell density and Fgf9 expression in wound dermis during late healing and in unwounded skin.
Figure 3: Fgf9, secreted by wound dermal γδ T cells, is an important component of WIHN.
Figure 4: Late-stage wounds of Tcrd−/− mice showed reduced dermal Wnt activity.
Figure 5: Fgf9 secreted from γδ T cells induces a feedback loop resulting in widespread wound dermal Wnt activation.
Figure 6: Humans lack a robust population of resident dermal γδ T cells.

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Acknowledgements

We thank R.L. O'Brien for thoughtful reading of the manuscript, P. Coulombe (Johns Hopkins University) for providing K17-specific antisera and members of A. Bhandoola's laboratory and The University of Pennsylvania Flow Cytometry and Cell Sorting Resource Laboratory for assistance with cell-sorting experiments. We also thank J. Tobias and D. Baldwin of the Penn Microarray Core Facility, L. Ash of the Dermatology Department Histology Core and the Penn Human Cooperative Tissue Network. Funding was provided by US National Institutes of Health (NIH) grant R01-AR46837, NIH Skin Diseases Research Core grant P30-AR057217, the Edwin and Fannie Gray Hall Center for Human Appearance at University of Pennsylvania Medical Center and The Dermatology Foundation. This work was also supported by NIH grant 5RO1 AR055309-4 and, for D.M.O., grant R01 HL105732. P.D.H. is supported by NIH training grant 5T32AR007465-29.

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Contributions

D.G., O.K. and G.C. designed the studies and analyzed and interpreted the results with assistance from Z.Z., M.S., P.D.H., Z.Y., E.T., C.D.K., A.N., X.Z. and S.B. D.G. wrote and D.G and G.C. edited the manuscript. M.V.P., P.D.H., M.I., F.W., D.M.O. and S.E.M. provided theoretical and technical advice and assistance. F.W. and D.M.O. provided TRE-Fgf9-IRES-EGFP and Fgf9fl/fl mice, and S.E.M. provided Krt14-Wnt7a mice. D.M.O. provided pGEM-Fgf9 plasmid.

Corresponding author

Correspondence to George Cotsarelis.

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Competing interests

O.S.K. and G.C. are co-inventors on a patent application filed through the World Patent Organization by the University of Pennsylvania describing the Fgf9 pathway as a target for promoting hair growth, among other claims. It is currently being prosecuted in multiple countries.

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Gay, D., Kwon, O., Zhang, Z. et al. Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding. Nat Med 19, 916–923 (2013). https://doi.org/10.1038/nm.3181

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