Highlights

Researchers at Fleming characterized the functional diversity of structural cells of synovia and addressed the underlying regulatory mechanisms that define the development of murine inflammatory arthritis, at the single cell level.

In a collaborative project between the Armaka, Fousteri and Kollias labs at Fleming, supported by the pMedGR infrastructure at the Medical School of Athens, researchers have assessed a few thousands synovial fibroblast cells of normal and arthritic mice – at the single cell level - to better understand how distinct synovial fibroblastic cells drive the development of rheumatoid arthritis (RA). The results, which were published in Genome Medicine, provide fine-grained mapping of the dynamic changes happening in the synovium during the disease at the transcriptomic and epigenomic level, along with comprehensive comparisons with respective available data from RA patients. 

RA is a highly debilitating disease of the synovial joints, characterized by aberrant immune and stromal (fibroblast) responses. Anti-cytokine therapies, such as those based on anti-TNF antibodies, provide efficient management of RA; however significant remission cannot be achieved long-term. Therefore, efforts for identifying new cellular and/or molecular targets have further intensified in recent years. Novel concepts appreciate the heterogeneity of stromal cells in shaping the homeostatic and the pathogenic responses, while previous work from Fleming researchers highlighted the fundamental role of synovial fibroblasts (SFs) in the orchestration of inflammatory arthritic disease. Yet, we still have limited view of the regulatory mechanisms underlying the arthritogenic potential of synovial fibroblasts.

To address these concerns, M. Armaka, M. Fousteri, G. Kollias and their teams employed high-end technologies to study the functional and epigenomic landscape of SFs in homeostasis and TNF-mediated arthritic pathology. “To get insights on what happens in the synovia when TNF levels become pathogenic, we primarily need multi-parametric data from freshly isolated cells”, says Prof. George Kollias. “In this study, we managed to uncover arthritis-specific differentiation cues of SFs and their regulators”.

The biologists and bioinformaticians of the team determined the activity of SFs in three different conditions: health, early and established arthritic disease, to understand how the loss of homeostatic functions and gain of pathogenic functions happen along disease progression.

Dr. Armaka notes: “We are thrilled that we have identified expansion of specific SF profiles in arthritic mice, which are also present in human RASFs. Strikingly, these mouse and human SF profiles express some unique and targetable/druggable markers, such as Lrrc15. Parallel analysis on the transcription factor activity underlining the expansion of the specific SF profiles led to the identification of novel molecular targets, such as Runx1, in addition to well-appreciated NFkB”.

Zooming in on individual SFs of all three studied conditions, we uncovered that the pathogenic expansion features as a continuum, and it is determined by an unrealized, epigenetically-primed capacity for arthritic gene expression in progenitor SF states of the differentiation continuum. These genes hold promise for targeting them early in disease” says Dr. M. Fousteri.;

M. Armaka: “Our data emphasize the highly structured nature of synovial representations mediated either by specific morphogen cues to maintain homeostasis or by dominant inflammatory cues during RA-like pathology, therefore providing new fibroblast-oriented therapeutic avenues to safely treat arthritis”.

Reference:

Armaka M, Konstantopoulos D, Tzaferis C, Lavigne MD, Sakkou M, Liakos A, Sfikakis PP, Dimopoulos MA, Fousteri M, Kollias G. Single-cell multimodal analysis identifies common regulatory programs in synovial fibroblasts of rheumatoid arthritis patients and modeled TNF-driven arthritis. Genome Med 14, 78 (2022). https://doi.org/10.1186/s13073-022-01081-3 .