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

  • Nat Commun. 2024 Jan 3;15(1):210. doi: 10.1038/s41467-023-44645-6.
Feiyang Ma  #  1  2 ,  Pei-Suen Tsou  #  2  3 ,  Mehrnaz Gharaee-Kermani  2 ,  Olesya Plazyo  2 ,  Xianying Xing  2 ,  Joseph Kirma  2 ,  Rachael Wasikowski  2 ,  Grace A Hile  2 ,  Paul W Harms  1  4 ,  Yanyun Jiang  1 ,  Enze Xing  2 ,  Mio Nakamura  1 ,  Danielle Ochocki  2  3 ,  William D Brodie  2 ,  Shiv Pillai  5 ,  Emanual Maverakis  6 ,  Matteo Pellegrini  7 ,  Robert L Modlin  7  8 ,  John Varga  2  3 ,  Lam C Tsoi  1 ,  Robert Lafyatis  9 ,  J Michelle Kahlenberg  2 ,  Allison C Billi  1 ,  Dinesh Khanna  10  11 ,  Johann E Gudjonsson  12
Affiliations
  • 1. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
  • 2. Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 3. University of Michigan Scleroderma Program, Ann Arbor, MI, USA.
  • 4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 5. Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA, USA.
  • 6. Department of Dermatology, University of California, Davis, Sacramento, CA, USA.
  • 7. Dept of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  • 8. Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA, 90095, USA.
  • 9. Division of Rheumatology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 10. Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 11. University of Michigan Scleroderma Program, Ann Arbor, MI, USA. [email protected].
  • 12. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • # Contributed equally.
PMID: 38172207 DOI: 10.1038/s41467-023-44645-6
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.

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