LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma

Chamutal Gur, Shuang Yin Wang*, Fadi Sheban, Mor Zada, Baoguo Li, Fadi Kharouf, Hagit Peleg, Suhail Aamar, Adam Yalin, Daniel Kirschenbaum, Yolanda Braun-Moscovici, Diego Adhemar Jaitin, Tomer meir-salame, Efrat Hagai, Bjørt K. Kragesteen, Batia Avni, Sigal Grisariu, Chamutal Bornstein, Shir Shlomi-Loubaton, Eyal DavidRony Shreberk-Hassidim, Vered Molho-Pessach, Dalit Amar, Tomer Tzur, Rottem Kuint, Moshe Gross, Oren Barboy, Adi Moshe, Liat Fellus-Alyagor, Dana Hirsch, Yoseph Addadi, Shlomit Erenfeld, Moshe Biton, Tehila Tzemach, Anat Elazary, Yaakov Naparstek, Reut Tzemach, Assaf Weiner, Amir Giladi, Alexandra Balbir-Gurman, Ido Amit*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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.

Original languageEnglish
Pages (from-to)1373-1388.e20
JournalCell
Volume185
Issue number8
DOIs
StatePublished - 14 Apr 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • autoimmune
  • fibroblast
  • fibrosis
  • FOS
  • GVHD
  • LGR5
  • skin
  • systemic sclerosis
  • TWIST1

Fingerprint

Dive into the research topics of 'LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma'. Together they form a unique fingerprint.

Cite this