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

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

doi:10.1016/j.cell.2022.03.011

Cited by 78 publications

(91 citation statements)

References 54 publications

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“…A recent study by Gur et al (8), in which an expanded cell population, referred to as nonclassical, CD16+ monocytes, was described but not characterized in detail, confirmed our key observations of altered myeloid populations in dcSSc skin. Upon reanalysis of the myeloid cells in the data set from Gur et al using Uniform Manifold Approximation and Projection (UMAP) clustering, we found cell populations similar to cell populations described in our article (Figures 1A-C).…”

Section: Replysupporting

confidence: 84%

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Lafyatis

Tabib

2022

Arthritis & Rheumatology

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shared gene expression profile and potential similar function between skin FCN-1+ cells in dcSSc patients and colonic Inf-Mo-like cells in CD patients. In Xue et al, bulk RNA-sequencing analysis of dcSSc skin highlighted the expression of TREM1, which was also in the list of discriminating genes identified in cluster E in the colon of CD patients (log 2 fold change >1.2, area under the curve >0.75) (3). Interestingly, colonic Inf-Mo-like cells promoted autologous Th17/Th1 responses in an interleukin-1b-dependent manner; in cluster 5, which was enriched in FCN-1+ myeloid cells, IL1B displayed differential gene expression in dcSSc skin.The precise nature and classification of FCN-1+ myeloid cells in skin and Inf-Mo-like cells in the colon remain unclear. A consensus appears to have been reached regarding their monocyte origin. Whether these 2 CD163-negative cell types that share a molecular signature can be classified as mo-DCs, Inf-Mo-like cells, inflammatory macrophages, or inflammatory DCs warrants further clarification (5). A trajectory analysis of skin FCN-1+ cells by Xue et al suggested that these cells are closely related to mo-DCs, whereas Inf-Mo-like cells in inflamed colon did not fulfill criteria to be classified as DCs. Ginhoux and colleagues argue in favor of developing detailed transcriptomic cell atlases that would integrate cellular heterogeneity and status of tissue in health and disease (6). This strategy might enable a common nomenclature to be proposed for mononuclear phagocytes. Furthermore, cells displaying a shared molecular signature with FCN-1+ cells were observed in skin blisters after acute inflammation (7), suggesting that these cells are not dcSSc-specific but characterize the cellular infiltrate in inflamed skin.We suggest that meta-analyses across different tissue (e.g., joints, heart, lungs), particularly in chronic skin inflammatory disorders that include psoriasis and atopic dermatitis, are needed before a pathogenic role or disease specificity can be attributed to a particular monocyte-derived cell type.

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Section: Replysupporting

confidence: 84%

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Lafyatis

Tabib

2022

Arthritis & Rheumatology

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“…Finally, to examine possible more subtle relationships between tofacitinib treatment and gene expression, we hierarchically clustered SFRP2/DPP4 gene expression and samples by changes in mRSS at 6 or 24 weeks (Figure S7). Examining the genes most closely with the mRSS change at 24 weeks, revealed LGR5 a marker gene of SSc fibroblasts (21), IL6 and PDGFRA (22,23), implicated in SSc pathogenesis. LGR5 has recently been implicated as a marker gene.…”

Section: Tofacitinib Inhibits Ifn-regulated Gene Expression By Ssc Sf...mentioning

confidence: 99%

Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial

Khanna¹,

Padilla²,

Tsoi³

et al. 2022

JCI Insight

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Background: Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. Methods:We randomized 15 participants with early diffuse cutaneous SSc to tofacitinib 5 mg twice a day or matching placebo in a Phase I/II double-blind, placebo-controlled trial. The primary outcome measure was safety and tolerability at or before Week 24. In order to understand the changes in gene expression associated with tofacitinib treatment in each skin cell populations, we compared single cell gene expression in punch skin biopsies obtained at baseline and 6 weeks following the initiation of treatment. Results: Tofacitinib was well tolerated; there were no participants, who experienced Grade 3 or higher adverse effects (AEs) before or at Week 24. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicates interferon (IFN) activated gene expression. Tofacitinib inhibited IFN-regulated gene expression in the SFRP2/DPP4 fibroblasts (progenitors of myofibroblasts) and MYOC and CCL19, representing adventitial fibroblasts (p< 0.05), as well as in the basal and keratinized layers of the epidermis. Gene expression in macrophages and dendritic cells indicated inhibition of STAT3 by tofacitinib (p<0.05). No clinically meaningful inhibition of T cells and endothelial cells in the skin tissue was observed. Conclusion:These results indicate that mesenchymal and epithelial cells of a target organ in SSc, not the infiltrating lymphocytes, may be the primary focus for therapeutic effects of a janus kinase inhibitor.

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“…We showed previously that the stromal cells at the mouse proximal prostatic ducts highly express Axin2 and Lgr5 ( Wei et al, 2019 ), which was corroborated by a recent single cell RNA sequencing (scRNA-seq) analysis ( Joseph et al, 2021 ). Lgr5 is a stem cell marker but was also reported to be expressed in the stromal cells in the lung ( Lee et al, 2017 ; Zepp et al, 2017 ), small intestine ( Bahar Halpern et al, 2020 ), and skin ( Gur et al, 2022 ). The biological function of the Lgr5-expressing stromal cells in those organs is not completely understood.…”

Section: Resultsmentioning

confidence: 99%

“…LGR5 is recently reported to be expressed by an abundant fibroblast subset in human skin tissues ( Gur et al, 2022 ). Nevertheless, we did not find any stromal cells that express LGR5 in human periurethral prostates by RNA in situ analysis (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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

Cited by 78 publications

References 54 publications

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Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial

Ablating Lgr5-expressing prostatic stromal cells activates the ERK-mediated mechanosensory signaling and disrupts prostate tissue homeostasis

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