Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis

Feiyang Ma, Pei-Suen Tsou, Mehrnaz Gharaee-Kermani, Olesya Plazyo, Xianying Xing, Joseph Kirma, Rachael Wasikowski, Grace A. Hile, Paul W. Harms, Yanyun Jiang, Enze Xing, Mio Nakamura, Danielle Ochocki, William D. Brodie, Shiv Pillai, Emanual Maverakis, Matteo Pellegrini, Robert L. Modlin, John Varga, Lam C. Tsoi, Robert Lafyatis, J. Michelle Kahlenberg, Allison C. Billi, Dinesh Khanna () and Johann E. Gudjonsson ()
Additional contact information
Feiyang Ma: University of Michigan
Pei-Suen Tsou: University of Michigan
Mehrnaz Gharaee-Kermani: University of Michigan
Olesya Plazyo: University of Michigan
Xianying Xing: University of Michigan
Joseph Kirma: University of Michigan
Rachael Wasikowski: University of Michigan
Grace A. Hile: University of Michigan
Paul W. Harms: University of Michigan
Yanyun Jiang: University of Michigan
Enze Xing: University of Michigan
Mio Nakamura: University of Michigan
Danielle Ochocki: University of Michigan
William D. Brodie: University of Michigan
Shiv Pillai: Massachusetts Institute of Technology and Harvard University
Emanual Maverakis: University of California, Davis
Matteo Pellegrini: University of California Los Angeles
Robert L. Modlin: University of California Los Angeles
John Varga: University of Michigan
Lam C. Tsoi: University of Michigan
Robert Lafyatis: University of Pittsburgh
J. Michelle Kahlenberg: University of Michigan
Allison C. Billi: University of Michigan
Dinesh Khanna: University of Michigan
Johann E. Gudjonsson: University of Michigan

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs function as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs.

Date: 2024
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DOI: 10.1038/s41467-023-44645-6

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