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Vasculature atrophy causes a stiffened microenvironment that augments epidermal stem cell differentiation in aged skin

Nature Aging volume 2, pages 592–600 (2022)Cite this article

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Abstract

Stem cell loss causes tissue deterioration associated with aging. The accumulation of genomic and oxidative stress-induced DNA damage is an intrinsic cue for stem cell loss1,2; however, whether there is an external microenvironmental cue that triggers stem cell loss remains unclear. Here we report that the involution of skin vasculature causes dermal stiffening that augments the differentiation and hemidesmosome fragility of interfollicular epidermal stem cells (IFESCs) in aged mouse skin. Aging-related IFESC dysregulation occurs in plantar and tail skin, and is correlated with prolonged calcium influx, which is contributed by the mechanoresponsive ion channel Piezo1 (ref. 3). Epidermal deletion of Piezo1 ameliorated IFESC dysregulation in aged skin, whereas Piezo1 activation augmented IFESC differentiation and hemidesmosome fragility in young mice. The dermis stiffened with age, which was accompanied by dermal vasculature atrophy. Conversely, induction of the dermal vasculature softened the dermis and ameliorated IFESC dysregulation in aged skin. Single-cell RNA sequencing of dermal fibroblasts identified an aging-associated anti-angiogenetic secretory molecule, pentraxin 3 (ref. 4), which caused dermal sclerotization and IFESC dysregulation in aged skin. Our findings show that the vasculature softens the microenvironment for stem cell maintenance and provide a potential mechanobiology-based therapeutic strategy against skin disorders in aging.

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Fig. 1: IFESCs are prone to differentiation and delamination with prolonged calcium influx in aged plantar skin.
Fig. 2: Dermal stiffening-induced Piezo1 activation causes IFESC dysregulation.
Fig. 3: Vascular atrophy induces dermal stiffening and IFESC dysregulation.
Fig. 4: Ptx3 induces vascular atrophy that leads to dermal stiffening and IFESC dysregulation.

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Data availability

The RNA-seq and scRNA-seq data were deposited in the Gene Expression Omnibus (GSE171035) and DNA Data Bank of Japan (DRA009978), respectively. Source data are provided with this study. All data needed to evaluate the conclusions in the study are present in the article and/or Supplementary Materials. All data are also available from the corresponding author upon reasonable request.

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Acknowledgements

We thank S. Kitano, H. Miyachi, Y. Iizuka, M. Yoshikawa, A. Sada and N. Hino for support and technical advice and A. Enomoto, T. Miyata and K. Kabashima for support on AFM and calcium imaging analyses. We thank staff at the Single-Cell Genome Information Analysis Core in ASHBi for RNA-seq analysis. We thank A. Mantovani and C. Garlanda at IRCCS Humanitas for the Ptx3 KO mice and Y. Kubota at Keio University for the VE-cadherin-creER mice. This work was supported by JSPS KAKENHI 16H06280 (R.I.), 19K17796 (R.I.), 21K16209 (R.I.), 17H05640 (F.T.), 20K21601 (F.T.), 16H06279 (PAGS) (F.T.), AMED under grant no. 20gm5810029 (F.T.), CREST under grant no. JPMJCR2023 (F.T., T.Y. and K.M.), the Takeda Science Foundation (F.T.), KAO Foundation for Arts and Sciences (R.I.), Fujiwara Memorial Foundation (R.I.), ASHBi, supported by the World Premier International Research Center Initiative (WPI) and MEXT Japan. We thank J. Ludovic Croxford and M. Crawford from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Tissue Homeostasis, Department of Biosystems Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan

    Ryo Ichijo & Fumiko Toyoshima

  2. Laboratory of Biomechanics, Department of Biosystems Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan

    Koichiro Maki & Taiji Adachi

  3. Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan

    Mio Kabata & Takuya Yamamoto

  4. Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Teruasa Murata

  5. Division of Anatomy, Meikai University School of Dentistry, Sakado, Japan

    Arata Nagasaka

  6. Department of Advanced Transdisciplinary Sciences, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan

    Seiichiro Ishihara & Hisashi Haga

  7. Soft Matter GI-CoRE, Hokkaido University, Sapporo, Japan

    Seiichiro Ishihara & Hisashi Haga

  8. Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Tetsuya Honda

  9. Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

    Taiji Adachi & Fumiko Toyoshima

  10. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan

    Takuya Yamamoto

  11. Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan

    Takuya Yamamoto

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  1. Ryo Ichijo
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Contributions

R.I. and F.T. conceived the project and designed the experiments. R.I. performed most experiments. K.M., A.N. and T.A. analyzed stiffness using AFM. M.K. and T.Y performed sequencing experiments and bioinformatics analyses. T.M. and T.H. contributed to live imaging experiments using two-photon microscopy. S.I. and H.H. contributed to hydrogel-related experiments for keratinocytes. R.I. and F.T. wrote the manuscript.

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Correspondence to Ryo Ichijo or Fumiko Toyoshima.

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Nature Aging thanks Salvador Benitah, Richard Cubbon and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Aging causes stem cell dysregulation.

a, Representative immunofluorescence images and fluorescence intensities of COL17 in plantar skin from young (6 months) and aged (24–27 months) mice (n = 5). Data point; 30 cell average/mouse. b, Representative immunofluorescence images and fluorescence intensities of plectin in plantar skin from young (6 months) and aged (24–27 months) mice (n = 5). Each data point is the average of 30 cells per mouse. c, Representative immunofluorescence images of survivin in IFESCs from control (6 months) and aged (24–27 months) mice. White lines: BM. White-dotted lines: cell boundary. Radial histogram quantification of division angles (n = 5, >10 cells/mouse). d, Gating strategy for flow cytometric analysis of IFESCs derived from the plantar epidermis. Error bars show the s.e.m. Two-tailed t-test (a and b). One-sided Kolmogorov–Smirnov test (c). n = number of mice.

Source data

Extended Data Fig. 2 Prolonged calcium flux through Piezo1 causes keratinocyte differentiation and hemidesmosome fragility.

a, Piezo1 fluorescence in situ hybridization (FISH) in plantar skin. Similar results were obtained from three biological independent experiments. White-dotted lines: BM. b, qPCR for Piezo1 in plantar epidermis from aged Piezo1f/f (24 months) and aged Piezo1 cKO (24 months) mice (n = 5). c, Representative immunofluorescence images and fluorescence intensities of plectin in plantar skin from young Piezo1f/f (2 months), aged Piezo1f/f (24 months) and aged Piezo1 cKO mice (24 months) (n = 5). Data point; 30 cell average/mouse. d, Stiffness values for the dermis of young (6 months) and Piezo1 cKO aged (24 months) plantar skin (n = 5, >30 points/mouse). e, Stiffness values for the dermis of young (6 months), aged (24–27 months) plantar skin (n = 5, >30 points/mouse) and soft and stiff gels (n = 70 points on gels). f, Representative immunofluorescence images and quantification of K10+ cells in primary cultured keratinocytes (n = 3 biological replicates, >130 cells/experiment). g, Representative immunofluorescence images and fluorescence intensities of COL17 in primary cultured keratinocytes (n = 3 biological replicates). Data point; 20 cell average/mouse. h, Representative immunofluorescence images and quantification of K10+ cells in primary cultured Piezo1 cKO keratinocytes (n = 3 biological replicates, >120 cells/experiment). i, Representative immunofluorescence images and fluorescence intensities of COL17 in primary cultured Piezo1 cKO keratinocytes (n = 3 biological replicates). Data point; 20 cell average/experiment. Error bars show the s.e.m. Two-tailed t-test (b,d,f,g,h,i), Tukey’s multiple comparison tests (c). n = number of mice.

Source data

Extended Data Fig. 3 Piezo1 agonist Yoda1 induces IFESC dysregulation.

a, Representative immunofluorescence images and quantification of K10+ cells (arrowhead) in the basal layer of young (3 months) plantar skin injected with DMSO or Yoda1 (n = 5, >150 cells/mouse). Aged (24–27 months) plantar skin were injected with DMSO (n = 5, >170 cells/mouse). b, Representative immunofluorescence images and fluorescence intensities of COL17 in plantar skin from young (3 months) plantar skin injected with DMSO or Yoda1 (n = 5). Aged (24–27 months) plantar skin were injected with DMSO (n = 5). Data point; 30 cell average/mouse. c, Representative immunofluorescence images and fluorescence intensities of plectin in plantar skin from young (3 months) plantar skin injected with DMSO or Yoda1 (n = 5). Aged (24–27 months) plantar skin were injected with DMSO (n = 5). Data point; 30 cell average/mouse. d, Representative immunofluorescence images of survivin in IFESCs from young (3 months) plantar skin injected with DMSO or Yoda1. Aged (24–27 months) plantar skin were injected with DMSO. White lines: BM. White-dotted lines: cell boundary. Radial histogram quantification of division angles (n = 5, >10 cells/mouse). e, Representative immunofluorescence images and quantification of K10+ cells in primary keratinocytes after treatment with DMSO or Yoda1 (n = 3 biological replicates, >120 cells/experiment). f, Representative immunofluorescence images and fluorescence intensities of COL17 in primary keratinocytes after treatment with DMSO or Yoda1 (n = 3 biological replicates). Data point; 20 cell average/experiment. Error bars show the s.e.m. Tukey’s multiple comparison tests (a,b,c), One-sided Kolmogorov–Smirnov test (d), and two-tailed t-test (e,f). n = number of mice.

Source data

Extended Data Fig. 4 Regional variability in aging-associated IFESC dysregulation.

a, Representative immunofluorescence images and fluorescence intensities of COL17 in back skin from young (6 months) and aged (24–27 months) mice (n = 5). Data point; 30 cell average/mouse. b, Representative immunofluorescence images and fluorescence intensities of COL17 in tail skin from young (6 months) and aged (24–27 months) mice (n = 5). Data point; 30 cell average/mouse c, Representative immunofluorescence images and quantification of K10+ cells (arrowhead) in the basal layer of tail skin from young (6 months) and aged (24–27 months) mice (n = 5, >150 cells/mouse). d, Representative immunofluorescence images and fluorescence intensities of COL17 in tail skin from young Piezo1f/f (6 months), aged Piezo1f/f (24–27 months) and aged Piezo1 cKO (24–27 months) mice (n = 5). Data point; 30 cell average/mouse e, Representative immunofluorescence images and quantification of K10 + cells (arrowhead) in the basal layer of tail skin from young Piezo1f/f (6 months), aged Piezo1f/f (24–27 months) and aged Piezo1 cKO (24–27 months) (n = 5, >150 cells/mouse). White-dotted lines: BM (c and e). Error bars show the s.e.m. Two-tailed t-test (a,b,c) and Tukey’s multiple comparison tests (d,e). n = number of mice.

Source data

Extended Data Fig. 5 Skin vasculatures regulate dermal ECM and epidermal hemidesmosome fragility.

a, Representative immunofluorescence images and quantification of the length of elastin fibers in plantar skin from young (6 months) and aged (24–27 months) mice (n = 5, 10 points/mouse). White-dotted lines: BM. b, qPCR for VEGFA in plantar skin from aged WT (24–27 months) and aged K14VEGF (22 months) mice (n = 5). c, Representative immunofluorescence images and fluorescence intensities of plectin in plantar skin from young WT (2 months), aged WT (22 months), and K14VEGF mice (22 months). Data point; 30 cell average/mouse. d, qPCR for VEGFR2 in the plantar dermis from VEGFR2f/f (6 months) and VEGFR2 cKO (6 months) mice (n = 5). e, Representative immunofluorescence images and fluorescence intensities of plectin in plantar skin from VEGFR2f/f (6 months) and VEGFR2 cKO (6 months) mice (n = 5). Data point; 30 cell average/mouse. Error bars show the s.e.m. Two-tailed t-test (a,b,d,e), and Tukey’s multiple comparison tests (c). n = number of mice.

Source data

Extended Data Fig. 6 scRNA-seq analysis of mouse plantar dermis from young and aged mice.

a, Whole plantar dermal cell transcriptomes (n = 9,839) from two young (6 months) and two aged (24–27 months) mice plotted on a UMAP plot. The 15 clusters identified by unsupervised clustering are separated by color. Identity and marker genes of each cluster are indicated below the plots. b, Expression of cluster-specific marker genes projected onto UMAP plots.

Extended Data Fig. 7 Cell–cell communication analysis between endothelial cells and fibroblasts during aging.

a, Ligand–receptor interactions inferred by CellPhoneDB were shown. P values calculated in CellPhoneDB were indicated by circle size (scale on top). The means of the average expression level of interacting molecules are indicated by color. b, Violin plots showing the expression of ECM-related genes (Col1a1, Col1a2, Col3a1, Eln and Sparc), angiogenic genes (Sparc and Thy1) and anti-angiogenic genes (Thbs1 and Egr1) in fibroblast clusters (CL-4 and CL-12) from young and aged mice (two mice each). Wilcox test.

Extended Data Fig. 8 Feature plots for each fibroblast cluster.

Expression of cluster-specific marker genes projected onto UMAP plots. Samples were collected from two young and two aged mice.

Extended Data Fig. 9 Aging-induced IFESC dysregulation is ameliorated in Ptx3 KO plantar skin.

a, qPCR for Ptx3 in the plantar dermis from aged WT (24–27 months) and aged Ptx3 KO (24–27 months) mice (n = 5). b, Representative immunofluorescence images and quantification of the length of elastin fibers in plantar skin from young WT (2 months), aged WT (24–27 months), and aged Ptx3 KO (24–27 months) mice (n = 5, 10 points/mouse). White-dotted lines: BM. c, Representative immunofluorescence images and fluorescence intensities of plectin in plantar skin from young WT (2 months), aged WT (24–27 months), and aged Ptx3 KO (24–27 months) mice (n = 5). Data point; 30 cell average/mouse Error bars show the s.e.m. Two-tailed t-test (a), Tukey’s multiple comparison tests (b,c). n = number of mice.

Source data

Extended Data Fig. 10 Cellular senescence is partially rescued in Piezo1 cKO, K14VEGF, and Ptx3 KO mice.

a, Representative immunofluorescence images and fluorescence intensities of 8-OHdG in tail skin from young Piezo1f/f (6 months), aged Piezo1f/f (24–27 months) and aged Piezo1 cKO (24–27 months) mice (n = 5). Data point; 30 cell average/mouse. b, Representative immunofluorescence images and fluorescence intensities of 8-OHdG in plantar skin from young WT (2 months), aged WT (22 months) and aged K14VEGF mice (22 months) (n = 5). Data point; 30 cell average/mouse c, Representative immunofluorescence images and fluorescence intensities of 8-OHdG in tail skin from young WT (6 months), aged WT (24–27 months) and aged Ptx3 KO (24–27 months) mice (n = 5). Data point; 30 cell average/mouse. d, Schematic of the mechanism of age-associated IFESC dysregulation. White-dotted lines: BM (a,b,c). Error bars show the s.e.m. Tukey’s multiple comparison tests (a,b,c). n = number of mice.

Source data

Supplementary information

Reporting Summary

Supplementary Table 1

Top 50 DEGs in each dermal cluster.

Supplementary Table 2

Top 50 DEGs in each fibroblast cluster.

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Ichijo, R., Maki, K., Kabata, M. et al. Vasculature atrophy causes a stiffened microenvironment that augments epidermal stem cell differentiation in aged skin. Nat Aging 2, 592–600 (2022). https://doi.org/10.1038/s43587-022-00244-6

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