Abstract
The skin exhibits extraordinary plasticity, enabling it to adapt to mechanical changes in the environment. While transient deformations are accommodated without lasting structural effects, sustained mechanical stress induces durable tissue changes. To investigate if these responses are mediated by shifts in epidermal stem cell fate, we employed two-photon intravital imaging to visualize epidermal cells in live skin subjected to acute mechanical forces. Mechanical force triggered the formation of intracellular “stress” vesicles within epidermal stem cells that filled with extracellular fluid and progressively enlarged, deforming the nucleus. Lineage tracing analyses revealed that the extent of nuclear deformation can predict cell fate outcomes. Moreover, mechanical stress caused sustained elevation of intracellular calcium in basal epidermal stem cells, and conditional deletion of the mechanosensitive ion channel Piezo1 disrupted calcium dynamics and increased stress vesicle formation. Using human skin xenografts, we demonstrated that stress vesicles are conserved in mammalian skin. Together, these findings identify stress vesicles as key mediators linking mechanical stress, calcium signaling, and epidermal stem cell fate.
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Data availability
Reagents presented in this study are available from the corresponding author upon reasonable request. RNA sequencing data can be accessed through the Gene Expression Omnibus under accession number GSE217491. Source data are provided with this paper.
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Acknowledgments
We thank George Cotsarelis, John Stanley and John Seykora for their invaluable advice that guided this study. We also thank Sara Wickström, Dennis E. Discher and Jean-Leon Maitre for insightful discussions. We are grateful to the University of Pennsylvania Skin Biology and Disease Research-based Center (SBDRC) for analysis of tissue sections (CPAT Core) and support with the establishment of human-engineered skin xenograft (STaR Core). We also acknowledge the support of the Institute for Regenerative Medicine and the entire stem cell community at Penn. S.H. was supported by an IRM postdoctoral fellowship. G.R. was supported by a training grant (T32GM007229) from NIH/NIGMS. P.K. was supported by the American Association for Cancer Research-John and Elizabeth Leonard Family Foundation Basic Cancer Research Fellowship. P.R. was supported by grants from NIH (R01EY036440) and from the American Cancer Society (RSG1803101DCC). Penn SBDRC was supported by a center core NIH/NIAMS grant (P30AR069589) and a shared instrumentation grant from the NIH Office of the Director (S10OD038384).
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S.H. and P.R. conceptualized the study, designed the experiments, and wrote the manuscript. S.H., P.K., A.B., M.M., G.R., and P.R. performed the experiments. J.Z. and B.C.C. assisted with the RNA sequencing and performed the bioinformatic analysis. P.K., M.D., and T.W.R. assisted with the establishment of human-engineered skin xenograft. T.Z. and S.P. assisted with the histological assays. J.D.B. assisted with the mechanobiology assays. All authors discussed results and participated in the manuscript preparation and editing. P.R. supervised the study.
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Huang, S., Kuri, P., Zou, J. et al. Stress vesicles link epidermal mechanotransduction to stem cell differentiation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68294-7
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DOI: https://doi.org/10.1038/s41467-026-68294-7
