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      Single-Cell Transcriptomics Reveals that Differentiation and Spatial Signatures Shape Epidermal and Hair Follicle Heterogeneity

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          Summary

          The murine epidermis with its hair follicles represents an invaluable model system for tissue regeneration and stem cell research. Here we used single-cell RNA-sequencing to reveal how cellular heterogeneity of murine telogen epidermis is tuned at the transcriptional level. Unbiased clustering of 1,422 single-cell transcriptomes revealed 25 distinct populations of interfollicular and follicular epidermal cells. Our data allowed the reconstruction of gene expression programs during epidermal differentiation and along the proximal-distal axis of the hair follicle at unprecedented resolution. Moreover, transcriptional heterogeneity of the epidermis can essentially be explained along these two axes, and we show that heterogeneity in stem cell compartments generally reflects this model: stem cell populations are segregated by spatial signatures but share a common basal-epidermal gene module. This study provides an unbiased and systematic view of transcriptional organization of adult epidermis and highlights how cellular heterogeneity can be orchestrated in vivo to assure tissue homeostasis.

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          Highlights

          • Single-cell RNA-seq analysis identifies 25 populations of epidermal cells

          • Differentiation and spatial gene expression signatures can be defined

          • Interplay of differentiation and spatial signatures explains most heterogeneity

          • Stem cell populations are divided by spatial signatures and only share basal identity

          Abstract

          Joost et al. use high-throughput single-cell RNA-seq to describe gene expression in mouse epidermis and hair follicles at unprecedented detail and explain epidermal heterogeneity as the interplay of differentiation-related and spatial gene expression signatures.

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          Most cited references51

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          Quantitative single-cell RNA-seq with unique molecular identifiers.

          Single-cell RNA sequencing (RNA-seq) is a powerful tool to reveal cellular heterogeneity, discover new cell types and characterize tumor microevolution. However, losses in cDNA synthesis and bias in cDNA amplification lead to severe quantitative errors. We show that molecular labels--random sequences that label individual molecules--can nearly eliminate amplification noise, and that microfluidic sample preparation and optimized reagents produce a fivefold improvement in mRNA capture efficiency.
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            Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis.

            Inconsistent with the view that hair follicle stem cells reside in the matrix area of the hair bulb, we found that label-retaining cells exist exclusively in the bulge area of the mouse hair follicle. The bulge consists of a subpopulation of outer root sheath cells located in the midportion of the follicle at the arrector pili muscle attachment site. Keratinocytes in the bulge area are relatively undifferentiated ultrastructurally. They are normally slow cycling, but can be stimulated to proliferate transiently by TPA. Located in a well-protected and nourished environment, these cells mark the lower end of the "permanent" portion of the follicle. Our findings, plus a reevaluation of the literature, suggest that follicular stem cells reside in the bulge region, instead of the lower bulb. This new view provides insights into hair cycle control and the possible involvement of hair follicle stem cells in skin carcinogenesis.
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              Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.

              In adult skin, each hair follicle contains a reservoir of stem cells (the bulge), which can be mobilized to regenerate the new follicle with each hair cycle and to reepithelialize epidermis during wound repair. Here we report new methods that permit their clonal analyses and engraftment and demonstrate the two defining features of stem cells, namely self-renewal and multipotency. We also show that, within the bulge, there are two distinct populations, one of which maintains basal lamina contact and temporally precedes the other, which is suprabasal and arises only after the start of the first postnatal hair cycle. This spatial distinction endows them with discrete transcriptional programs, but surprisingly, both populations are growth inhibited in the niche but can self-renew in vitro and make epidermis and hair when grafted. These findings suggest that the niche microenvironment imposes intrinsic "stemness" features without restricting the establishment of epithelial polarity and changes in gene expression.
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                Author and article information

                Contributors
                Journal
                Cell Syst
                Cell Syst
                Cell Systems
                Cell Press
                2405-4712
                2405-4720
                28 September 2016
                28 September 2016
                : 3
                : 3
                : 221-237.e9
                Affiliations
                [1 ]Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet, Novum, 141 83 Huddinge, Sweden
                [2 ]Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, 171 77 Stockholm, Sweden
                Author notes
                []Corresponding author sten.linnarsson@ 123456ki.se
                [∗∗ ]Corresponding author maria.kasper@ 123456ki.se
                [3]

                Lead Contact

                Article
                S2405-4712(16)30265-4
                10.1016/j.cels.2016.08.010
                5052454
                27641957
                62f41c5a-e591-4c25-8eb7-6f5d8bbc4562
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 4 February 2016
                : 11 May 2016
                : 11 August 2016
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