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Antagonistic stem cell fates under stress govern decisions between hair greying and melanoma

Nature Cell Biology (2025)Cite this article

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Abstract

The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes, including hair greying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate tracking in mice revealed that McSCs undergo cellular senescence-coupled differentiation (seno-differentiation) in response to DNA double-strand breaks, resulting in their selective depletion and hair greying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in cells harbouring double-strand breaks, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones—expansion versus exhaustion—cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.

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Fig. 1: Age- and IR-associated McSC depletion and resultant hair greying.
Fig. 2: Carcinogenic stresses antagonize hair greying and McSC depletion.
Fig. 3: DMBA antagonizes IR-induced hair greying via AA metabolism.
Fig. 4: Carcinogenic stresses increase the expression of KITL by niche cells.
Fig. 5: Age-associated reduction of niche-derived cytokines and McSC depletion.
Fig. 6: A stem-cell-based phenotypic antagonism between hair greying and melanoma.
Fig. 7: Schematic illustration of antagonistic stem cell fates that determine pigmented tissue ageing and cancer development.

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Data availability

Microarray data were deposited in the GEO public database (accession codes GSE158611 and GSE248613). Bulk RNA-seq data were deposited in the GEO public database (accession codes GSE248614 and GSE249074). scRNA-seq data were deposited in the GEO public database (accession code GSE252031). All other data supporting the findings of the present study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

The original code is available via GitHub at https://github.com/seitalab/project_mohri_nishimura/tree/main (ref. 84).

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Acknowledgements

We are grateful to S. Morrison (HHMI Investigator at UT Southwestern Medical Center) for the Kitl flox mice and Kitl-GFP mice. We are grateful to A. Berns (University of Amsterdam), M. McMahon (U.C. San Francisco) and P. Oberdoerffer (The National Cancer Institute) for the p53 flox mice, Braf CA mice and I-PpoI mice, respectively. The aged mice were provided by the Foundation for Biomedical Research and Innovation at Kobe through the National BioResource Project of the MEXT, Japan. We also thank R. Yajima, K. Takenouchi and T. Ando for technical support, the staff of the Laboratory Animal Research Center (IMSUT) for mouse care support and all laboratory members for helpful comments on this project and DASS Manuscript for editing. E.K.N. is supported by a JSPS Grant-in Aid for Scientific Research (S) (25H00439), an AMED CREST Project (JP22gm1710003-JP25gm1710003), an AMED Project for Elucidating and Controlling Mechanisms of Ageing and Longevity (JP17gm5010002-JP21gm5010002), an AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers (JP223fa627001), a JSPS Grant-in Aid for Scientific Research (A) (20H00532) and a JSPS Grant-in Aid for Scientific Research on Innovative Areas ‘Stem Cell Aging and Disease’ (26115003). Y.M is supported by a JSPS Grant-in-Aid for Young Scientists (18K15114) and a JSPS Grant-in Aid for Scientific Research (C) (25K10315). J.S. is supported by an AMED Project for Elucidating and Controlling Mechanisms of Ageing and Longevity (JP19gm5010003 JP20gm5010003) and a JSPS Grant-in Aid for Scientific Research (C) (18K08377).

Author information

Authors and Affiliations

  1. Division of Aging and Regeneration, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yasuaki Mohri, Jialiang Nie, Daisuke Nanba, Hiroyuki Matsumura & Emi K. Nishimura

  2. Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, presently the Institute of Science Tokyo, Tokyo, Japan

    Hironobu Morinaga, Tomoki Kato, Takahiro Aoto, Sakura Kirino & Emi K. Nishimura

  3. Advanced Data Science Project, RIKEN Information R&D and Strategy Headquarters, Tokyo, Japan

    Takashi Yamanashi & Jun Seita

  4. Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan

    Takashi Yamanashi & Jun Seita

  5. Division of Vaccine Science, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Kouji Kobiyama & Ken J. Ishii

  6. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Kouji Kobiyama & Ken J. Ishii

  7. Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, Japan

    Masahiro Hayashi & Tamio Suzuki

  8. Department of Dermatology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan

    Takeshi Namiki

Authors
  1. Yasuaki Mohri
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  2. Jialiang Nie
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Contributions

Y.M. performed the majority of the experiments with support from J.N., H. Morinaga, T.A., H. Matsumura and S.K. Y.M., T.K., T.Y. and J.S. performed and analysed the single-cell RNA-seq experiments. D.N. and H. Matsumura established Dct-CreERT2 mice. K.K. and K.J.I. provided TBK1 flox mice. T.N., M.H. and T.S. collected and provided the human melanoma samples. Y.M. and E.K.N. designed the study and wrote the paper. E.K.N supervised the project.

Corresponding author

Correspondence to Emi K. Nishimura.

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Competing interests

E.K.N. is a co-founder and shareholder of EADERM Co., Ltd., which is not related to the content of this study. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 IR-induced p21 expression is coupled with hair cycle progression.

a, Appearance of young (2 months old) and of old (23 months old) C57BL/6N mice with some gray hairs. White arrowheads indicate gray hairs. b, Graph showing the percentage of gray hairs per 100 hairs (Young; n=3, Old; n=10, biological independent experiments). Data are presented as means ± SEM. Mann-Whitney’s U test. c, Immunohistological analysis of the bulge of Dct-H2B-GFP KI mice at the indicated time points with or without IR. Arrowheads indicate p21+ McSCs (GFP+ cells). Scale Bar = 50 μm. Dp; Hair depilation.

Source data

Extended Data Fig. 2 Carcinogens promote McSC self-renewal.

a, Experimental scheme for DMBA treatment (upper). Macroscopic time-course images of the dorsal skin of C57BL/6 mice treated with Vehicle or DMBA at the indicated time points. Immunohistological analysis of the dorsal skin of Dct-H2B-GFP KI mice showing the distribution of GFP+ melanocytes (arrows) at 12 weeks post-onset DMBA treatment. The two panels of acetone and DMBA, respectively, show different hair follicles. Scale Bar = 60 μm. Dp; Hair depilation. b, Coat colors in the 2nd hair cycle after treatment with or without IR and UVB. Immunohistological analysis of hair follicles of Dct-LacZ Tg mice at 5 days in the 2nd hair cycle (2nd-D5). Arrowheads indicate McSCs (LacZ+ cells). The dotted lines show the Bg/sBg (Bulge/sub-Bulge). Scale Bar = 50 μm.

Extended Data Fig. 3 Induction of DSBs in McSCs induces their depletion and hair graying.

a, Diagram illustrating the induction of melanocyte-specific DSBs with I-PpoI endonuclease by Cre-mediated recombination and TAM-dependent transfer into the nucleus. b, Experimental scheme for Tyr-Cre/I-PpoI mice (upper). Coat colors of WT and Tyr-Cre/I-PpoI mice in the 2nd hair cycle and immunohistological analysis of KIT+ cells in the bulge at 5 days in the 3rd hair cycle (3rd-D5). Scale Bar = 30 μm. The dotted lines show the Bg/sBg (Bulge/sub-Bulge). Dp; Hair depilation. c, Immunohistological analysis of γH2AX in McSCs of Dct-H2B-GFP KI mice at 24 h after treatment with different types of genotoxins. Scale Bar = 20 μm. Bg=Bulge, Hg=Hair germ, DP=Dermal papilla. Graph showing the percentage of γH2AX+ McSCs (n=3, biological independent experiments). Data are presented as means ± SEM. One-way ANOVA with Dunnett’s post-hoc tests. d, FACS sorting analysis of McSCs in Dct-H2B-GFP murine skin at telogen. The 7AAD(-)/Singlets/GFPhigh/SSClow population was used as McSCs. e, Graph showing the relative expression of melanocyte-related genes in McSCs at telogen. Data are from one of two separate experiments. f, Identification of DMBA-induced CAA → CTA mutations in codon 61 of the H-Ras gene (H-RasQ61L) in McSCs by digital droplet PCR (left). McSCs were sorted from the skin of Dct-H2B-GFP KI mice at 28 days after vehicle or DMBA treatment. One-dimensional (1D) amplitude plots are shown with the associated manual threshold gating (pink line) for HEX (WT, green) and FAM (mutant, blue) amplitudes. Genomic DNAs collected from melanocytic lesion (bulk) developed by the DMBA/TPA method and mutated plasmid (H-RasQ61L) are used as positive controls. DDW is also used as a negative control. Graph showing the percentages of H-RasQ61L within McSCs (right). Data are from one of two separate experiments.

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Extended Data Fig. 4 Activation of p53 and cytosolic DNA/RNA sensing pathways by IR.

a, Enrichment plot for KEGG pathways. b, Heatmap of expressed genes ranked by GSEA. Colors range from dark red to dark blue representing the highest and lowest expression of each gene, respectively. Circles indicate representative core enrichment genes. c, Coat colors of irradiated C57BL/6 mice with or without dmPGE2 in the 1st hair cycle after irradiation with 5 Gy IR. d, Immunohistological analysis of the bulge of irradiated Dct-H2B-GFP KI mice with or without dmPGE2 at 5 days in the 1st hair cycle. Scale Bar = 50 μm. e, Quantification of the relative mRNA expression level of p21 in NHEMs (in vitro) at 3 h after IR treatment with Vehicle or PGE2 (n=3, biological independent experiments). One-way ANOVA with Tukey’s post-hoc tests. Rpl11 is used as an internal control for the qPCR analysis.

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Extended Data Fig. 5 Kitl deficiency in the niche for McSCs causes McSC depletion and resultant hair graying.

a, FACS sorting analysis of HFSCs/Hg in K15-EGFP Tg murine skin. The singlets/7AAD−/GFPhigh/ITGA6high/ScaI− population was used as niche cells for McSCs. b, Immunohistological analysis of KITL in the bulge (KRT15+) and hair germ (P-CAD+) of Kitl-GFP KI mice at telogen. Scale Bar = 30 μm. Bg=Bulge, Hg=Hair germ. c, Immunohistological analysis of KITL in the dorsal skin of Kitl-GFP KI mice at 3 days after treatment with Vehicle or DMBA. Arrows indicate GFP+ cells in Bg/sBg (Bulge/sub-Bulge) and arrowheads indicate GFP+ cells in the IFE. Scale Bar = 200 μm. d, Experimental scheme for Kitl cKO mice. Dp; Hair depilation. e,f,g, Coat colors of WT and K15CrePR; Kitlfx/fx (Kitl cKO) mice at 3 weeks (e), at 7 weeks (f) and at 28 days in the 1st hair cycle (1st-D28) (g). h, Immunohistological analysis of McSCs in the bulge of WT and Kitl cKO mice at 5 days in the 2nd hair cycle (2nd-D5). McSCs are visualized with Dct-LacZ Tg mice. Graph showing quantification of McSCs in the bulge (WT; n=3, Kitl cKO; n=4, biological independent experiments). Scale Bar = 30 μm. Two-tailed Student’s t-test. i, Coat colors of WT and K14-Kitl Tg mice after irradiation with 0 Gy or 5 Gy IR. Immunohistological analysis of McSCs in the bulge of WT and K14-Kitl Tg mice. McSCs are visualized using Dct-LacZ Tg mice. Scale Bar = 50 μm. Graph showing the frequency of hair follicles still containing McSCs in the bulge (n=3, biological independent experiments). Two-tailed Student’s t-test. j, Coat colors of Tyr-Cre; I-PpoI (I-PpoI) and K14-Kitl; Tyr-Cre; I-PpoI (K14-Kitl/I-PpoI) mice and immunohistological analysis of KIT+ cells in the bulge. The dotted lines show the Bg/sBg. Scale Bar = 30 μm. k, Experimental scheme for microarray analysis with FACS-purified McSCs. McSCs are labeled using the Dct-H2B-GFP KI allele. l, GSEA Enrichment plot for KEGG Arachidonic acid metabolism, RIG-I like receptor signaling pathway and Cytosolic DNA sensing pathway. m, Quantification of the relative mRNA expression level of COX2 in vitro using NHEMs (n=3, biological independent experiments). One-way ANOVA with Dunnett’s post-hoc tests. Rpl11 is used as an internal control for the qPCR analysis. Data are presented as means ± SEM (h,i,m).

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Extended Data Fig. 6 KITL promotes the repair of DSBs and ROS scavenging.

a, Representative images showing DSBs caused by IR in NHEMs pre-treated with or without KITL in vitro. Scale Bar = 200 μm. Graph showing the quantification of the percentage of cells with a comet tail. Three biological independent experiments were performed (n=9 fields, total: > 70 cells). Two-way ANOVA with Tukey’s post-hoc tests. b, Quantification of the relative mRNA expression levels of the indicated genes in NHEMs following the addition of KITL (n=3, biological independent experiments). One-way ANOVA with Dunnett’s post-hoc tests compared to 0 h. c, FACS data of NHEMs showing changes in fluorescence intensity of H2DCFDA, an indicator dye of oxidative stress, caused by IR pretreated with or without KITL in vitro. Normalized Mean Fluorescence Intensities (MFI) are shown in the right graph (n=7, biological independent experiments). Two-way ANOVA with Tukey’s post-hoc tests. d, Quantification of the relative mRNA expression levels of the indicated genes in NHEMs following the addition of KITL (n=3, biological independent experiments). One-way ANOVA with Dunnett’s post-hoc tests compared to 0 h. Rpl11 is used as an internal control for the qPCR analysis (b,d). Data are presented as means ± SEM (a-d).

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Extended Data Fig. 7 Niche-derived KITL promotes melanomagenesis.

a, Immunohistological analysis of the distribution of GFP+ melanocytes in the epidermis of WT and of Kitl cHetero mice at 4 weeks post-onset DMBA treatment. GFP+ melanocytic lineages are visualized with Dct-H2B-GFP KI mice. Arrows indicate melanocytes in the IFE. Graph showing the number of GFP+ cells in the epidermis (WT; n=5, Kitl cHetero; n=4, biological independent experiments). The experimental scheme for DMBA treatment is shown in Extended Data Fig. 2a. Scale Bar = 100 μm. Two-tailed Student’s t-test. b, Macroscopic views of the dorsal skin of WT and of Kitl cHetero mice at 16 weeks post-onset DMBA treatment. Graph showing the number of melanocytic pre-cancerous lesions (indicated by arrowheads) on the dorsal skin (WT; n=8, Kitl cHetero; n=5, biological independent experiments). The experimental scheme for DMBA treatment is shown in Extended Data Fig. 2a. Two tailed Student’s t-test. c, Line graph showing the number of melanocytic precancerous lesions on the dorsal skin at the indicated time points after DMBA treatment (Ink4a/Arf−/−; K14-Kitl; n=3, Ink4a/Arf−/−; n=3, Ink4a/Arf+/−; K14-Kitl; n=12, Ink4a/Arf+/−; n=6, Ink4a/Arf+/+; K14-Kitl; n=5, Ink4a/Arf+/+; n=9, biological independent experiments). Data are presented as means ± SEM (a-c). d, Macroscopic view of dorsal skin showing melanocytic tumors (arrow) in Mc1re/e; Ink4a/Arf+/−; K14-Kitl mice at the indicated time points.

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Extended Data Fig. 8 Defining the main epidermal clusters by lineage-specific marker genes.

a, UMAP plot of all 61,787 single-cell transcriptomes visualized for individual mice. b, Expression of group-specific marker genes projected onto the UMAP plot.

Extended Data Fig. 9 Decreased expression of niche-derived cytokines and down-regulation of the p53 pathway in an aged niche for McSCs.

a, Graphs showing the expression of the indicated genes in FACS-purified HFSCs/Hg at early anagen (n=3, biological independent experiments). Two-tailed Student’s t-tests. b,c, Pathways down-regulated (b) or up-regulated (c) in FACS-purified HFSCs/Hg at early anagen analyzed by GSEA using the c2.cp.biocarta.v7.5 gene set collection (permutation test). d, Enrichment plot for Biocarta P53_pathway (Young, early anagen vs Old, early anagen). e, Heatmap showing the Biocarta P53_pathway gene set core signature. Colors range from dark red to dark blue representing the highest and lowest expression of each gene, respectively. f, Graphs showing the expression of p53, Cdkn1a (p21) and Cdkn2a (p16) in HFSCs/Hg at telogen and early anagen (n=3, biological independent experiments). Two-tailed Student’s t-tests. g, Enrichment plot for KEGG P53_signaling_pathway (Vehicle, early anagen vs DMBA, early anagen). Data are presented as means ± SEM (a,f).

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Extended Data Fig. 10 Dct-CreERT2 mice enable the specific targeting of McSCs in hair follicles, allowing the controlled induction of invasive melanoma.

a, Experimental scheme for tracing of McSC-lineage cells. b, Distribution of GFP+ cells in the dorsal skin of Dct-CreERT2; Rosa-H2B-GFPKI/+ or Tyr-CreERT2; Rosa-H2B-GFPKI/+ mice at 4 weeks post-TAM injection. GFP+ cells in the dermis of Tyr-CreERT2; Rosa-H2B-GFPKI/+ mice are indicated by a yellow arrowhead. Scale Bar = 60 μm. c, Distribution of GFP+ cells in hair follicles of Dct-H2B-GFP KI mice at telogen and anagen. GFP+ cells in the bulge represent McSCs. Scale Bars = 60 μm. d, The percentage of GFP+ cells located in the dorsal skin of Tyr-CreERT2; Rosa-H2B-GFPKI/+ mice (Tyr promoter) and of Dct-H2B-GFP KI mice (Dct promoter). A total of 388 GFP+ cells and 269 GFP+ cells were counted for the Tyr promoter (n=2) and Dct promoter (n=3), respectively (biological independent experiments). e, Distribution of tdTomato+ cells in hair follicles of Dct-CreERT2; Rosa-tdTomato mice. Arrowheads indicate tdTomato+/KIT+ cells in the hair follicle. Scale Bars = 20 μm. f, Tyr-CreERT2; BrafV600E; Ptenfx/fx mice were depilated and injected with TAM for 3 consecutive days. Macroscopic view of Tyr-CreERT2; BrafV600E; Ptenfx/fx mice at 1 month after the 1st TAM injection. Expansion of GFP+ melanocytic lineages in the dermis of the mice was visualized using the Dct-H2B-GFP transgene. g, Macroscopic views of the dorsal skin of WT and of Dct-CreERT2; BrafV600E; Ptenfx/fx (DBP) mice at the indicated time points post-onset TAM injection. One-half of the dorsal skin was depilated. Yellow arrows indicate dome-like unpigmented nodules that mimic human Nodular-type melanomas. Graphs showing the quantification of melanomas (shown by yellow arrows) on the dorsal skin at 4 weeks (WT; n=20, DBP; n=11, biological independent experiments) and at 8 weeks (WT; n=8, DBP; n=6, biological independent experiments). Data are presented as means ± SEM. Mann-Whitney’s U-tests. h, Dct-H2B-GFP mice or Rosa-tdTomato mice were used to trace the fate of McSC-lineage cells. Immunohistological analysis of the dorsal skin of Dct-H2B-GFP and of DBP mice at the indicated time points post-onset TAM injection. The two panels of DBP mice at 4 weeks post-onset TAM injection show different hair follicles of the same skin. Scale Bars = 100 μm. i, Macroscopic images of lymph nodes (LN).

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Supplementary Tables

Supplementary Table 1. Selected genes associated with melanogenesis in the HFSC/Hg (Telogen). Genes that show a significant change in expression (P < 0.05) are highlighted in yellow. Supplementary Table 2. Selected genes associated with melanogenesis in the HFSC/Hg (early anagen). Genes that show a significant change in expression (P < 0.05) are highlighted in yellow. Supplementary Table 3. Primer sequences.

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Mohri, Y., Nie, J., Morinaga, H. et al. Antagonistic stem cell fates under stress govern decisions between hair greying and melanoma. Nat Cell Biol (2025). https://doi.org/10.1038/s41556-025-01769-9

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