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Journal article
LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma
Cell, Vol.185(8), pp.1373-1388
Apr/2022
PMID: 35381199
Abstract
Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.
Details
- Title
- LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma
- Creators
- Chamutal Gur - 972WIS_INST___121Shuang-Yin Wang (Corresponding Author) - 972WIS_INST___121Fadi Sheban - 972WIS_INST___121Mor Zada - 972WIS_INST___121Baoguo Li - 972WIS_INST___121Fadi Kharouf - Hebrew University of JerusalemHagit Peleg - Hebrew University of JerusalemSuhail Aamar - Hadassah Medical CenterAdam Yalin - 972WIS_INST___121Daniel Kirschenbaum - 972WIS_INST___121Yolanda Braun-Moscovici - Technion – Israel Institute of TechnologyDiego Adhemar Jaitin - 972WIS_INST___121Tomer Meir-Salame - 972WIS_INST___113Efrat Hagai - 972WIS_INST___113Bjørt K Kragesteen - 972WIS_INST___121Batia Avni - Hebrew University of JerusalemSigal Grisariu - Hebrew University of JerusalemChamutal Bornstein - 972WIS_INST___121Shir Shlomi-Loubaton - 972WIS_INST___121Eyal David - 972WIS_INST___121Rony Shreberk-Hassidim - Hebrew University of JerusalemVered Molho-Pessach - Hebrew University of JerusalemDalit Amar - Hebrew University of JerusalemTomer Tzur - Hebrew University of JerusalemRottem Kuint - Hebrew University of JerusalemMoshe Gross - Hebrew University of JerusalemOren Barboy - 972WIS_INST___121Adi Moshe - 972WIS_INST___121Liat Fellus-Alyagor - 972WIS_INST___130Dana Hirsch - 972WIS_INST___130Yoseph Addadi - 972WIS_INST___113Shlomit Erenfeld - Hebrew University of JerusalemMoshe Biton - 972WIS_INST___120Tehila Tzemach - Hebrew University of JerusalemAnat Elazary - Hebrew University of JerusalemYaakov Naparstek - Hebrew University of JerusalemReut Tzemach - 972WIS_INST___121Assaf Weiner - 972WIS_INST___121Amir Giladi - 972WIS_INST___121Alexandra Balbir-Gurman - Technion – Israel Institute of TechnologyIdo Amit (Corresponding Author) - 972WIS_INST___121
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.185(8), pp.1373-1388; Apr/2022
- Number of pages
- 16
- Publisher
- Elsevier Inc
- Language
- English
- DOI
- https://doi.org/10.1016/j.cell.2022.03.011
- PMID
- 35381199
- Grant note
- We would like to thank the patients and their families for their endless support and the clinical study research teams across all participating sites. We thank Vika Shataylo and Adi Mashiah, the clinical research coordinators from Rheumatology Institute of Rambam Health Care Campus; Issa Mualem, head nurse of day care of Internal Medicine, Hadassah Medical Center; Tal Wiesel, Efrat Davidson, and Genia Brodsky for the scientific illustration, and Dr. Inna Goliand and Dr. Ekaterina Petrovich-Kopitman from the Life Science Core Facilities. The research of I.A. is supported by the National Scleroderma Foundation (grant 132309), Seed Networks for the Human Cell Atlas of the Chan Zuckerberg Initiative, Merck KGaA, Darmstadt, the Eden and Steven Romick Professorial Chair, the HHMI International Scholar Award, the European Research Council Consolidator Grant (no. 724471-HemTree2.0), an MRA Established Investigator Award (no. 509044), DFG (no. SFB/TRR167), the ISF Israel Precision Medicine Program (IPMP) 607/20 grant—P128245, the Helen and Martin Kimmel awards for innovative investigation, and the SCA award of the Wolfson Foundation and Family Charitable Trust. S.-Y.W. is an EMBO long-term fellow (ALTF 263-2018) and received the NWO Rubicon award (019.181EN.038). Author contributions : C.G. conceived, designed, and conducted the experiments; collected participant samples; and wrote the paper. S.-Y.W. designed the experiments, performed the analysis, and wrote the paper. F.S. performed the ATAC-seq experiment. F.K., H.P., S.A., and Y.B.-M. collected participant samples. A.W. designed the study and performed the analysis. A.G. performed the receptor-ligand interaction analysis. A.B.-G. designed the study, collected the participant samples, wrote the paper, and supervised the clinical aspect of the project. I.A. conceived, designed, and supervised the project and wrote the paper.
- Record Identifier
- 993357259303596
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