Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa
Kelsey R. van Straalen, … , Lam C. Tsoi, Johann E. Gudjonsson
Kelsey R. van Straalen, … , Lam C. Tsoi, Johann E. Gudjonsson
Published December 5, 2023
Citation Information: J Clin Invest. 2024;134(3):e169225. https://doi.org/10.1172/JCI169225.
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Research Article Dermatology Inflammation

Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.

Authors

Kelsey R. van Straalen, Feiyang Ma, Pei-Suen Tsou, Olesya Plazyo, Mehrnaz Gharaee-Kermani, Marta Calbet, Xianying Xing, Mrinal K. Sarkar, Ranjitha Uppala, Paul W. Harms, Rachael Wasikowski, Lina Nahlawi, Mio Nakamura, Milad Eshaq, Cong Wang, Craig Dobry, Jeffrey H. Kozlow, Jill Cherry-Bukowiec, William D. Brodie, Kerstin Wolk, Özge Uluçkan, Megan N. Mattichak, Matteo Pellegrini, Robert L. Modlin, Emanual Maverakis, Robert Sabat, J. Michelle Kahlenberg, Allison C. Billi, Lam C. Tsoi, Johann E. Gudjonsson

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Figure 5

Identification of HS-associated FB subsets.

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Identification of HS-associated FB subsets. (A) Trichrome staining of HS...
(A) Trichrome staining of HS lesional skin (patient HS1). Blue, collagen. Scale bars: top, 6 mm; bottom, 200 μm. (B) UMAP plot showing 4,459 FBs colored by subtype: SFRP2+, LSP1+, COL11A+, RAMP1+, SFRP4+, and CXCL13+. (C) UMAP plot showing the cells colored by disease condition. NS, healthy control. (D) Dot plot showing the representative marker genes for each subtype. Color scale represents scaled expression; size of the dot represents the percentage of cells expressing the gene. (E) Bar chart showing the cell types as percentage component of disease. (F) Immunofluorescence showing the colocalization of CXCL13 with vimentin (FBs) and to a lesser extent CD3 (T cells). Scale bars: 100 μm; insets, 50 μm. (G) IHC showing FB subsets in HS lesional skin (patient HS1). Scale bars: top, 6 mm; bottom, 200 μm. (H) Dot plot showing the expression of collagen genes for each FB subtype. Color scale represents scaled expression; size of the dot represents the percentage of cells expressing the gene. (I) Extracellular matrix (ECM) module score plotted using ECM pathway gene list from Gene Ontology. (J) Expression of ACTA2 among FB subtypes. (K) Circos plot showing the cytokine and chemokine interactions from the SFRP4+ and CXCL13+ FBs with other cell types: PLC, plasma cells; ML, myeloid cells; BC, B cells; TC, T cells. (L) Dot plot showing the expression of cytokines and chemokines among the FB subsets. (M) Circos plot representing the interactions of MMPs, collagens, and laminins between the most prominent HS-associated cell subtypes: Mac, macrophages; EC4, endothelial cell subcluster 4; EC5, endothelial cell subcluster 5; cDC2B, classical type 2 dendritic cell subset B; SMC6, smooth muscle cell subcluster 6. (N) Dot plot showing the expression of MMPs among the FB subsets.