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      The Use of Single-Cell RNA-Sequencing and Spatial Transcriptomics in Understanding the Pathogenesis and Treatment of Skin Diseases

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          Abstract

          The development of multiomic profiling tools has rapidly expanded in recent years, along with their use in profiling skin tissues in various contexts, including dermatologic diseases. Among these tools, single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) have emerged as widely adopted and powerful assays for elucidating key cellular components and their spatial arrangement within skin disease. In this paper, we review the recent biological insights gained from the use of scRNA-seq and ST and the advantages of combining both for profiling skin diseases, including aberrant wound healing, inflammatory skin diseases, and cancer. We discuss the role of scRNA-seq and ST in improving skin disease treatments and moving toward the goal of achieving precision medicine in dermatology, whereby patients can be optimally matched to treatments that maximize therapeutic response.

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          Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.

          Eric Simpson, Thomas Bieber, Emma Guttman-Yassky … (2016)
          Background Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. Methods In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. Results We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. Conclusions In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).
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            Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion

            Ansuman Satpathy, Jeffrey M Granja, Kathryn Yost … (2019)
            Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here, we assess the performance of a massively parallel droplet-based method for mapping transposase-accessible chromatin in single cells using sequencing (scATAC-seq). We apply scATAC-seq to obtain chromatin profiles of more than 200,000 single cells in human blood and basal cell carcinoma. In blood, application of scATAC-seq enables marker-free identification of cell type-specific cis - and trans -regulatory elements, mapping of disease-associated enhancer activity and reconstruction of trajectories of cellular differentiation. In basal cell carcinoma, application of scATAC-seq reveals regulatory networks in malignant, stromal and immune cells in the tumor microenvironment. Analysis of scATAC-seq profiles from serial tumor biopsies before and after programmed cell death protein 1 blockade identifies chromatin regulators of therapy-responsive T cell subsets and reveals a shared regulatory program that governs intratumoral CD8 + T cell exhaustion and CD4 + T follicular helper cell development. We anticipate that scATAC-seq will enable the unbiased discovery of gene regulatory factors across diverse biological systems.
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              Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics

              Marlon Stoeckius, Shiwei Zheng, Brian Houck-Loomis … (2018)
              Despite rapid developments in single cell sequencing, sample-specific batch effects, detection of cell multiplets, and experimental costs remain outstanding challenges. Here, we introduce Cell Hashing, where oligo-tagged antibodies against ubiquitously expressed surface proteins uniquely label cells from distinct samples, which can be subsequently pooled. By sequencing these tags alongside the cellular transcriptome, we can assign each cell to its original sample, robustly identify cross-sample multiplets, and “super-load” commercial droplet-based systems for significant cost reduction. We validate our approach using a complementary genetic approach and demonstrate how hashing can generalize the benefits of single cell multiplexing to diverse samples and experimental designs. Electronic supplementary material The online version of this article (10.1186/s13059-018-1603-1) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Andrew L. Ji
                Journal
                Journal ID (nlm-ta): JID Innov
                Journal ID (iso-abbrev): JID Innov
                Title: JID Innovations
                Publisher: Elsevier
                ISSN (Electronic): 2667-0267
                Publication date PMC-release: 22 March 2023
                Publication date Collection: July 2023
                Publication date (Electronic): 22 March 2023
                Volume: 3
                Issue: 4
                Electronic Location Identifier: 100198
                Affiliations
                [1 ]Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [2 ]Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [3 ]Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [4 ]Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                Author notes
                [∗ ]Correspondence: Andrew L. Ji, Department of Dermatology, Icahn School of Medicine at Mount Sinai, 1428 Madison Avenue, Atran 7-10F, Box 1048, New York, New York 10029, USA. andrew.ji@ 123456mssm.edu
                Article
                Publisher Item ID: S2667-0267(23)00020-6 Publisher ID: 100198
                DOI: 10.1016/j.xjidi.2023.100198
                PMC ID: 10186616
                PubMed ID: 37205302
                SO-VID: bab796ce-4ae8-4f44-b594-fec91cb06d21
                Copyright © © 2023 The Authors
                License:

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

                History
                Date received : 18 December 2022
                Date revision received : 15 February 2023
                Date accepted : 27 February 2023
                Categories
                Subject: Review

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