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

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.

SUBMITTER: Gur C

PROVIDER: S-EPMC7612792 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Gur Chamutal C Wang Shuang-Yin SY Sheban Fadi F Zada Mor M Li Baoguo B Kharouf Fadi F Peleg Hagit H Aamar Suhail S Yalin Adam A Kirschenbaum Daniel D Braun-Moscovici Yolanda Y Jaitin Diego Adhemar DA Meir-Salame Tomer T Hagai Efrat E Kragesteen Bjørt K BK Avni Batia B Grisariu Sigal S Bornstein Chamutal C Shlomi-Loubaton Shir S David Eyal E Shreberk-Hassidim Rony R Molho-Pessach Vered V Amar Dalit D Tzur Tomer T Kuint Rottem R Gross Moshe M Barboy Oren O Moshe Adi A Fellus-Alyagor Liat L Hirsch Dana D Addadi Yoseph Y Erenfeld Shlomit S Biton Moshe M Tzemach Tehila T Elazary Anat A Naparstek Yaakov Y Tzemach Reut R Weiner Assaf A Giladi Amir A Balbir-Gurman Alexandra A Amit Ido I

Cell 20220404 8

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<sup>+</sup>-scle ...[more]

PMID: 35381199

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Project description:BackgroundThe modified Rodnan skin score is a common primary outcome measurement tool in clinical trials of systemic sclerosis (scleroderma). However, it is unknown how often physicians perform the modified Rodnan skin score in clinical practice or what precise approach is most often used when assessing each of the 17 sites included in the modified Rodnan skin score (i.e. "maximizing," "averaging," "representative area"). This study assessed the experiences, perceptions, training, and practices of individuals studying scleroderma with regard to modified Rodnan skin score.MethodsAn invitation with an online survey link was sent electronically to 282 individuals who are part of the Scleroderma Clinical Trials Consortium. The 46-item survey included three sections: participant demographics, modified Rodnan skin score background/training, and modified Rodnan skin score assessment practices. The survey was accessible for 5 weeks (October-November 2019).ResultsThe response rate was 41% (116 of 282 individuals). The majority of participants perform the modified Rodnan skin score in clinical care (>99%) and practice at academic institutions (90%) in North America (41%) or Europe (40%). Nearly all participants felt that the modified Rodnan skin score is either "somewhat important" (43%) or "essential" (56%) to the care of patients with systemic sclerosis. In total, 91% of participants reported having received modified Rodnan skin score training. The majority (60%) of those who had not received training were interested in receiving modified Rodnan skin score training, and 39% of participants felt either "uncomfortable" or only "somewhat comfortable" performing the modified Rodnan skin score. The modified Rodnan skin score approach varied: 44% used "maximizing," 28% used "averaging," and 18% used "representative area."ConclusionA majority of participants feel that the modified Rodnan skin score is "essential" to the care of patients with systemic sclerosis; however, the method used to measure modified Rodnan skin score varies greatly among systemic sclerosis investigators. These results indicate a continued role of modified Rodnan skin score for care and research in systemic sclerosis, support ongoing efforts to increase opportunities for modified Rodnan skin score training, and highlight a potential need to harmonize the technical approach to measuring the modified Rodnan skin score.

Dataset Information

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

Publications

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

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