Single-Cell Transcriptomics of Traced Epidermal and Hair Follicle Stem Cells Reveals Rapid Adaptations during Wound Healing.

Epithelial tissues, such as the skin, rely on cellular plasticity of stem cells (SCs) from different niches to restore tissue function after injury. How these molecularly and functionally diverse SC populations respond to injury remains elusive. Here, we genetically labeled Lgr5- or Lgr6-expressing cells from the hair follicle bulge and interfollicular epidermis (IFE), respectively, and monitored their individual transcriptional adaptations during wound healing using single-cell transcriptomics. Both Lgr5 and Lgr6 progeny rapidly induced a genetic wound signature that, for Lgr5 progeny, included the remodeling of receptors to permit interactions with the wound environment, a property that Lgr6 progeny possessed even before wounding. When contributing to re-epithelialization, Lgr5 progeny gradually replaced their bulge identity with an IFE identity, and this process started already before Lgr5 progeny left the bulge. Altogether, this study reveals how different SCs respond and adapt to a new environment, potentially explaining cellular plasticity of many epithelial tissues.

[1]  Jian Yan,et al.  Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth , 2017, eLife.

[2]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[3]  Allan R. Jones,et al.  A robust and high-throughput Cre reporting and characterization system for the whole mouse brain , 2009, Nature Neuroscience.

[4]  Gaël Varoquaux,et al.  Scikit-learn: Machine Learning in Python , 2011, J. Mach. Learn. Res..

[5]  Matthias Schäfer,et al.  Cancer as an overhealing wound: an old hypothesis revisited , 2008, Nature Reviews Molecular Cell Biology.

[6]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[7]  J. Reiter,et al.  Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration , 2015, Cell cycle.

[8]  G. Cotsarelis,et al.  Epithelial stem cells and implications for wound repair. , 2012, Seminars in cell & developmental biology.

[9]  A. Joyner,et al.  Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. , 2011, Cell stem cell.

[10]  Fiona M. Watt,et al.  Epithelial stem cells, wound healing and cancer , 2012, Nature Reviews Cancer.

[11]  T. Schepeler,et al.  Heterogeneity and plasticity of epidermal stem cells , 2014, Development.

[12]  B. Treutlein,et al.  Human organomics: a fresh approach to understanding human development using single-cell transcriptomics , 2017, Development.

[13]  S. Linnarsson,et al.  Stem Cell Reports , 2022 .

[14]  Hans Clevers,et al.  Lgr5 marks cycling, yet long-lived, hair follicle stem cells , 2008, Nature Genetics.

[15]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  E. Fuchs,et al.  Dynamics between Stem Cells, Niche, and Progeny in the Hair Follicle , 2011, Cell.

[17]  H. Clevers,et al.  Lgr6 Marks Stem Cells in the Hair Follicle That Generate All Cell Lineages of the Skin , 2010, Science.

[18]  C. Blanpain,et al.  Defining stem cell dynamics and migration during wound healing in mouse skin epidermis , 2017, Nature Communications.

[19]  Piero Carninci,et al.  A draft network of ligand–receptor-mediated multicellular signalling in human , 2015, Nature Communications.

[20]  A. Regev,et al.  Scaling single-cell genomics from phenomenology to mechanism , 2017, Nature.

[21]  Cole Trapnell,et al.  The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells , 2014, Nature Biotechnology.

[22]  Hans Clevers,et al.  Single-cell messenger RNA sequencing reveals rare intestinal cell types , 2015, Nature.

[23]  Maria Kasper,et al.  Single-Cell Transcriptomics Reveals that Differentiation and Spatial Signatures Shape Epidermal and Hair Follicle Heterogeneity , 2016, Cell systems.

[24]  Y. Bellaïche,et al.  Tissue-scale coordination of cellular behavior promotes epidermal wound repair in live mice , 2017, Nature Cell Biology.

[25]  S. Werner,et al.  Wound repair and regeneration , 1994, Nature.

[26]  Olivier Elemento,et al.  Stem Cell Lineage Infidelity Drives Wound Repair and Cancer , 2017, Cell.

[27]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[28]  Berthold Göttgens,et al.  The Epidermis Comprises Autonomous Compartments Maintained by Distinct Stem Cell Populations , 2013, Cell stem cell.

[29]  R. Sandberg Entering the era of single-cell transcriptomics in biology and medicine , 2013, Nature Methods.

[30]  Junhyong Kim,et al.  Reconstructing the Temporal Ordering of Biological Samples Using Microarray Data , 2003, Bioinform..