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 David; Rony 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

doi:10.1016/j.cell.2022.03.011

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 David

Rony 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 journal › Article › peer-review

107 Citations (Scopus)

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 language	English
Pages (from-to)	1373-1388.e20
Number of pages	36
Journal	Cell
Volume	185
Issue number	8
DOIs	https://doi.org/10.1016/j.cell.2022.03.011
Publication status	Published - 14 Apr 2022

Funding

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 ).

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2022.03.011

Cite this

Gur, C., Wang, S.-Y., Sheban, F., Zada, M., Li, B., Kharouf, F., Peleg, H., Aamar, S., Yalin, A., Kirschenbaum, D., Braun-Moscovici, Y., Jaitin, D. A., Meir-Salame, T., Hagai, E., Kragesteen, B. K., Avni, B., Grisariu, S., Bornstein, C., Shlomi-Loubaton, S., ... Amit, I. (2022). LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma. Cell, 185(8), 1373-1388.e20. https://doi.org/10.1016/j.cell.2022.03.011

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title = "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. ",

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

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Gur, C, Wang, S-Y, Sheban, F, Zada, M, Li, B, Kharouf, F, Peleg, H, Aamar, S, Yalin, A, Kirschenbaum, D, Braun-Moscovici, Y, Jaitin, DA , Meir-Salame, T, Hagai, E, Kragesteen, BK, Avni, B, Grisariu, S, Bornstein, C, Shlomi-Loubaton, S , David, E, Shreberk-Hassidim, R, Molho-Pessach, V, Amar, D, Tzur, T, Kuint, R, Gross, M, Barboy, O, Moshe, A, Fellus-Alyagor, L , Hirsch, D , Addadi, Y, Erenfeld, S, Biton, M, Tzemach, T, Elazary, A, Naparstek, Y, Tzemach, R, Weiner, A, Giladi, A, Balbir-Gurman, A & Amit, I 2022, 'LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma', Cell, vol. 185, no. 8, pp. 1373-1388.e20. https://doi.org/10.1016/j.cell.2022.03.011

TY - JOUR

T1 - LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma

AU - Gur, Chamutal

AU - Wang, Shuang-Yin

AU - Sheban, Fadi

AU - Zada, Mor

AU - Li, Baoguo

AU - Kharouf, Fadi

AU - Peleg, Hagit

AU - Aamar, Suhail

AU - Yalin, Adam

AU - Kirschenbaum, Daniel

AU - Braun-Moscovici, Yolanda

AU - Jaitin, Diego Adhemar

AU - Meir-Salame, Tomer

AU - Hagai, Efrat

AU - Kragesteen, Bjørt K

AU - Avni, Batia

AU - Grisariu, Sigal

AU - Bornstein, Chamutal

AU - Shlomi-Loubaton, Shir

AU - David, Eyal

AU - Shreberk-Hassidim, Rony

AU - Molho-Pessach, Vered

AU - Amar, Dalit

AU - Tzur, Tomer

AU - Kuint, Rottem

AU - Gross, Moshe

AU - Barboy, Oren

AU - Moshe, Adi

AU - Fellus-Alyagor, Liat

AU - Hirsch, Dana

AU - Addadi, Yoseph

AU - Erenfeld, Shlomit

AU - Biton, Moshe

AU - Tzemach, Tehila

AU - Elazary, Anat

AU - Naparstek, Yaakov

AU - Tzemach, Reut

AU - Weiner, Assaf

AU - Giladi, Amir

AU - Balbir-Gurman, Alexandra

AU - Amit, Ido

PY - 2022/4/14

Y1 - 2022/4/14

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85127965765

U2 - 10.1016/j.cell.2022.03.011

DO - 10.1016/j.cell.2022.03.011

M3 - Article

C2 - 35381199

SN - 0092-8674

VL - 185

SP - 1373-1388.e20

JO - Cell

JF - Cell

IS - 8

ER -

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

Abstract

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