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 7

Modulation of the Hippo pathway in primary HS FBs.

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Modulation of the Hippo pathway in primary HS FBs. (A) Illustration of H...
(A) Illustration of Hippo pathway, created with BioRender (biorender.com). (B) Quantitative PCR results showing the effect of TRULI or verteporfin (both 10 μM) on ACTA2, COL1A1, and CTGF expression in HS FBs (n = 5; *P < 0.05, ****P < 0.0001; mean ± SD; ANOVA/Kruskal-Wallis test). (C) Effect of TRULI or verteporfin (both 10 μM) on smooth muscle actin (SMA) and collagen I levels in HS FBs by Western blotting (n = 5; *P < 0.05; mean ± SD; Kruskal-Wallis test [collagen I], ANOVA [SMA]). (D) Verteporfin blocked gel contraction in HS FBs. Data normalized to the corresponding NT (untreated) group (n = 5; *P < 0.05; mean ± SD). (E) TRULI significantly increased cell proliferation while verteporfin dose-dependently blocked cell growth among HS FBs (n = 3; *P < 0.05, ***P < 0.0001; mean ± SEM; 2-way repeated-measures ANOVA). The same NT group is shown in both panels. Cell proliferation was monitored by analysis of the area occupied by cells over time, using IncuCyte S3 Analysis software. (F) Verteporfin showed a dose-dependent reduction in cell migration of HS FBs (n = 3; **P < 0.01, ***P < 0.001; mean ± SEM; 2-way repeated-measures ANOVA). The same NT group is shown in both panels. (G) Expression of cytokines and chemokines among untreated (NT), IL-1β–stimulated (10 ng/mL), and TNF-α–stimulated (10 ng/mL) primary HS FBs treated or not treated with TRULI or verteporfin (n = 5; *P < 0.05, **P < 0.01, ***P < 0.001; mean ± SD; 1-way repeated-measures ANOVA).