Mechanisms of stretch-mediated skin expansion at single-cell resolution

• Published in: Nature (London) Vol. 584; no. 7820; pp. 268 - 273
• Main Authors: Aragona, Mariaceleste, Sifrim, Alejandro, Malfait, Milan, Song, Yura, Van Herck, Jens, Dekoninck, Sophie, Gargouri, Souhir, Lapouge, Gaëlle, Swedlund, Benjamin, Dubois, Christine, Baatsen, Pieter, Vints, Katlijn, Han, Seungmin, Tissir, Fadel, Voet, Thierry, Simons, Benjamin D., Blanpain, Cédric
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.08.2020; Nature Publishing Group
• Subjects: 13; 13/100; 14; 14/19; 38; 38/39; 631/532/2438; 631/532/2441; 64; 64/60; 96; 96/95; Adaptor Proteins, Signal Transducing - metabolism; Adherens Junctions - metabolism; Animals; Base Sequence; Bias; Cell adhesion & migration; Cell cycle; Cell Cycle Proteins - metabolism; Cell Differentiation - drug effects; Cell Self Renewal - drug effects; Chromatin; Chromatin - drug effects; Chromatin - genetics; Chromatin Assembly and Disassembly - drug effects; Clone Cells - cytology; Clone Cells - drug effects; Clone Cells - metabolism; Cloning; Disease Models, Animal; Divisions; Epidermis; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Gene regulation; Gene Regulatory Networks - drug effects; Gene sequencing; Humanities and Social Sciences; Hydrogels; Hydrogels - administration & dosage; Hydrogels - pharmacology; Inflammation; Keratin; Mechanical properties; Mechanotransduction, Cellular - drug effects; Mechanotransduction, Cellular - genetics; Mechanotransduction, Cellular - physiology; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; multidisciplinary; Mutation; Physiological aspects; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; Skin; Skin - cytology; Skin - drug effects; Skin - growth & development; Stem cell transplantation; Stem cells; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Stretching; Trans-Activators - antagonists & inhibitors; Trans-Activators - metabolism; Transcription; Transcription Factor AP-1 - metabolism; Transcription, Genetic - drug effects; YAP-Signaling Proteins; Belgium
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-020-2555-7

The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery 1 . Although the response of epidermal cells to stretching has been studied in vitro 2 , 3 , it remains unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a multidisciplinary approach that combines clonal analysis with quantitative modelling and single-cell RNA sequencing, we show that stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation. Transcriptional and chromatin profiling identifies how cell states and gene-regulatory networks are modulated by stretching. Using pharmacological inhibitors and mouse mutants, we define the step-by-step mechanisms that control stretch-mediated tissue expansion at single-cell resolution in vivo. Single-cell analysis in a mouse model of skin stretching shows that stretching causes a transient expansion bias in a population of epidermal stem cells, which is associated with chromatin remodelling and changes in transcriptional profiles.