{
  "abstract": "Introduction Systemic sclerosis (SSc) patients present with diverse trajectories of skin and lung fibrosis progression, while drugs that stabilize lung fibrosis may not affect skin. Herein, we utilize single cell RNA-seq analyses to identify common and/or unique fibroblast subpopulations and cellular states in fibrotic skin and lung of SSc patients. To indirectly assess the role of such fibroblasts in pathogenic tissue activation, single cell RNA-seq analyses of skin and lung tissues derived from an experimental model of bleomycin-induced fibrosis were performed.Material and Methods We analyzed three publicly available single cell RNA-seq (scRNA-seq) datasets of SSc skin (GSE138669 and GSE249279), lung (GSE212109) and respective healthy tissues. After cluster annotation, skin and lung fibroblasts were integrated in a common inter-organ fibroblast dataset using Harmony to identify distinct and shared fibroblast subpopulations. Time-course scRNA-seq analyses in a bleomycin model of concurrent skin and lung fibrosis at baseline and weeks 1,2,4 and 8 post-bleomycin treatment were also performed.Results We first analyzed GSE138669 and GSE212109 scRNA-seq datasets, identifying 11,092 skin and 3,156 lung fibroblasts (42.2% SSc-derived). Among 16 fibroblast clusters identified, 3 were common between skin and lung: the 1st cluster was enriched in stress-response genes, including many mitochondrial genes (‘stressed fibroblasts’); the 2nd cluster was enriched in proinflammatory genes (‘proinflammatory fibroblasts’), while the 3rd cluster (‘profibrotic fibroblasts’) was enriched in genes related to extracellular matrix organization and fibroblast activation (POSTN, MFAP4 and TAGLN). The latter cluster was mainly identified in SSc-derived cells in both skin (80%) and lung (90%). These results were verified in the other SSc skin dataset (GSE249279), where both the ‘proinflammatory’ and ‘profibrotic’ fibroblast clusters were exclusively derived from SSc samples. We next analysed skin and lung derived from an experimental model of fibrosis. Interestingly, ‘stressed fibroblasts’ were universally expressed in both skin and lung, showing a progressive increase in skin from week-1 to week-4 after bleomycin treatment. ‘Proinflammatory fibroblasts’ were identified in both skin and lung at week-1, but not at later stages when tissue fibrosis had been established. In contrast, ‘profibrotic fibroblasts’ were identified in skin only and their number increased as skin fibrosis developed.Conclusions Distinct fibroblast subpopulations with proinflammatory and/or profibrotic properties are enriched and shared between skin and lung in patients with SSc. Commonalities across tissues in both mice and humans enable the design of experimental models to confirm the pathogenic role of these fibroblast clusters in the development and progression of tissue fibrosis.",
  "authors": [
    {
      "affiliations": [
        "First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece"
      ],
      "name": "Nikolaos Vlachogiannis"
    },
    {
      "affiliations": [
        "First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece"
      ],
      "name": "Kleio-Maria Verrou"
    },
    {
      "affiliations": [
        "Department of Biochemistry & Cell Biology and Pulmonary Center, Boston University School of Medicine, Boston, USA"
      ],
      "name": "Konstantinos Kontodimas"
    },
    {
      "affiliations": [
        "Biosciences Institute, Faculty of Medical Sciences, Newcastle University,, Newcastle upon Tyne, United Kingdom"
      ],
      "name": "Eleftherios Zormpas"
    },
    {
      "affiliations": [
        "Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Oliver Distler"
    },
    {
      "affiliations": [
        "Department of Biochemistry & Cell Biology and Pulmonary Center, Boston University School of Medicine, Boston, USA"
      ],
      "name": "Xaralabos Varelas"
    },
    {
      "affiliations": [
        "First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece"
      ],
      "name": "Petros P Sfikakis"
    }
  ],
  "title": "P.014 Common fibroblast subpopulations in skin and lung tissue in systemic sclerosis",
  "uid": "d090f041-2f9d-5511-b811-8ba5efa1c636"
}