Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis
Kartik Bhamidipati, Alexa B. R. McIntyre, Shideh Kazerounian, Ce Gao, Soon Wei Wong, Miles Tran, Sean A. Prell, Rachel Lau, Vikram Khedgikar, Christopher Altmann, Annabelle Small, Roopa Madhu, Sonia Presti, Ksenia S. Anufrieva, PHILIP E. BLAZAR, Jeffrey K. Lange, Jennifer A. Seifert, Accelerating Medicines Partnership RA/SLE Network, L. Donlin, Accelerating Medicines Partnership: Autoimmune and Immune-Mediated Diseases Network (AMP-AIM), L. Donlin, Melanie H. Smith, Ranjeny Thomas, Michael J. Zuscik, Michael R. Clay, Andrew Clauw, Melissa Griffith, Terrin Geohring, PATRICK M. CARRY, V. Michael Holers, Cherl L. Ackert-Bicknell, Daniel K. Moon, Craig A. Hogan, Rachel M. Frank, Michael R. Dayton, Fraser J. Leversedge, Adam J. Seidl, Larry W. Moreland, Adam Croft, Melanie H. Smith, L. Donlin, Myles J. Lewis, Anna H Jonsson, C. Pitzalis, Ranjeny Thomas, Ellen M. Gravallese, Michael B. Brenner, Ilya Korsunsky, Mihir D. Wechalekar, Kevin Wei
Abstract
Treatment-refractory rheumatoid arthritis (RA) is a major unmet need, and the underlying mechanisms are poorly understood. To identify molecular determinants of refractory RA, we performed spatial transcriptomic profiling on synovial tissue biopsy samples taken 6 months before and after treatment. In the baseline biopsy samples of non-remitting patients, we identified increased fibrogenic signaling within vascular tissue niches, marked by high fibroblast COMP expression. We uncovered a role of endothelial-derived Notch signaling as an upstream regulator of fibroblast transforming growth factor beta (TGFβ) signaling via its opposing ability to induce TGFβ isoform expression while suppressing TGFβ receptors, generating a proximal-to-distal gradient of TGFβ sensitivity that can be altered with disruption of steady-state Notch signaling. In posttreatment biopsy samples, we observed significant immune depletion with expansion of fibrogenic niches, a process that can be reversed by inhibition of Notch and TGFβ signaling in RA patient-derived organoids. Collectively, our data implicate targeting of TGFβ signaling to prevent exuberant synovial tissue fibrosis as a potential therapeutic strategy for refractory RA. Wei et al. perform spatial transcriptomic profiling on synovial tissue biopsy samples from individuals with recent-onset rheumatoid arthritis, finding TGFβ signaling and fibrogenic fibroblast activation drive a treatment-refractory tissue phenotype.