Related Experiment Video

Updated: Jan 18, 2026

Generation of Induced-pluripotent Stem Cells Using Fibroblast-like Synoviocytes Isolated from Joints of Rheumatoid Arthritis Patients
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Generation of Induced-pluripotent Stem Cells Using Fibroblast-like Synoviocytes Isolated from Joints of Rheumatoid Arthritis Patients

Published on: October 16, 2016

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Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis

Kartik Bhamidipati1, Alexa B R McIntyre1,2, Shideh Kazerounian1

  • 1Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital at Harvard Medical School, Boston, MA, USA.

Nature Immunology
|January 16, 2026
PubMed

Insights

Identifying molecular drivers of refractory rheumatoid arthritis (RA) reveals increased fibrogenic signaling and endothelial Notch signaling. Targeting TGFβ signaling may prevent synovial fibrosis in non-remitting RA patients.

Area of Science:

  • Rheumatology
  • Molecular Biology
  • Immunology

Background:

  • Treatment-refractory rheumatoid arthritis (RA) presents a significant clinical challenge with poorly understood mechanisms.
  • Identifying molecular determinants is crucial for developing novel therapeutic strategies for non-remitting RA.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying treatment-refractory RA.
  • To identify molecular targets for preventing synovial fibrosis in refractory RA.

Main Methods:

  • Spatial transcriptomic profiling of synovial tissue biopsies before and after treatment in RA patients.
  • Analysis of fibrogenic signaling, fibroblast COMP expression, and endothelial Notch signaling pathways.
  • Assessment of therapeutic potential using RA patient-derived organoids.

Main Results:

  • Baseline biopsies from non-remitting patients showed increased fibrogenic signaling and fibroblast COMP expression in vascular niches.
  • Endothelial-derived Notch signaling regulates fibroblast TGFβ signaling, influencing TGFβ sensitivity gradients.
  • Post-treatment samples exhibited immune depletion and expanded fibrogenic niches, reversible by inhibiting Notch and TGFβ signaling.

Conclusions:

  • Targeting TGFβ signaling to prevent synovial fibrosis is a potential therapeutic strategy for refractory RA.
  • Endothelial Notch signaling plays a key role in regulating fibrogenic processes in refractory RA.
  • Understanding these mechanisms offers new avenues for treating non-remitting rheumatoid arthritis.

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