The ontogeny of myeloid-stromal synovial tissue niches in rheumatoid arthritis.

Recent single-cell multi-omic and spatial analyses of synovial biopsies have transformed our understanding of myeloid cell-driven mechanisms underlying human joint pathology and tissue homeostasis in Rheumatoid arthritis (RA). However, the developmental trajectories of synovial tissue macrophage (STM) subsets in humans remain poorly understood, due in part to the lack of models that faithfully replicate synovial tissue niches. This hinders the exploration of the therapeutic potential of targeting specific synovial myeloid cell clusters. Using multi-omics analyses of synovial tissue from an allogeneic bone marrow transplant recipient, we show that joint-specific tissue-resident STM subsets, including both health- and disease-associated clusters, can derive from peripheral blood monocytes. Analysis of embryonic synovial joints revealed that macrophage localization and maturation in the joints are preceded by local stromal niche specialisation, indicating that synovial fibroblasts (FLS) provide tissue-specific instructive cues to STM precursors. To elucidate human STM developmental trajectories, we established a SNP-based fate-tracking human synovial organoid system by embedding distinct blood-derived myeloid precursors, together with FLS clusters from RA synovial biopsies and endothelial cells, into 3D structures. These organoids reproduced key synovial tissue features, including lining and sublining architecture and stromal-myeloid cell cluster composition. Importantly, they supported differentiation of all resident STM subsets: homeostatic lining TREM2