Biology subjects

Orange, D.

Publications and source records attributed to Orange, D..

3 recordsLinked to original sources

bioRxiv2026

Conserved Fibroblast Subsets Drive Shared Fibrotic Mechanisms in Osteoarthritis Synovium and Systemic Sclerosis Skin

Osteoarthritis (OA) and systemic sclerosis (SSc) are diseases with distinct etiologies but similar disease phenotypes, most prominently fibrosis, a process governed by the pathological activation of fibroblasts. Mechanisms underpinning fibrosis in these diseases are widely studied, though have yet to be directly compared. We employed single-cell RNA-seq and high-resolution spatial transcriptomics to describe the functional plasticity and the range of fibroblast activation states in both diseases. We identified disease-enriched fibroblast subsets conserved in both diseases, including fibrogenic myofibroblast-like cells, chemokine- and cytokine-expressing inflammatory fibroblasts, and lining-like fibroblasts. These subsets exhibited convergent fibrotic programs also observed in idiopathic pulmonary fibrosis, as well as overlapping osteochondral transcriptional programs. Xenium 5K spatial transcriptomics revealed that conserved, disease-associated fibroblasts reside in highly similar anatomic niches in OA synovium and SSc skin. These consisted of a fibrotic ECM-rich niche harboring myofibroblast-like cells and an inflammatory niche containing inflammatory fibroblasts adjacent to infiltrating immune cells. Disease-associated transcriptional remodeling converged on shared functional pathways and common putative upstream molecular regulators. These findings identify conserved cellular states, spatial niches, and regulatory programs across OA and SSc, suggesting that fibrotic disease is underpinned by shared pathogenic stromal states and candidate targets for therapeutic strategies are applicable across both diseases.

cell biology↗

bioRxiv2026

SPP1hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium

In chronic inflammatory diseases, maladaptive tissue remodelling is driven by a complex interplay of resident cells, immune filtrates and the extracellular matrix. In the autoimmune disorder rheumatoid arthritis (RA), synovial tissue undergoes assive expansion to form an invasive pannus that drives the erosion of cartilage and bone. The mechanisms mediating this ggressive growth are incompletely defined. Using spatial transcriptomics profiling of patient tissue, we detected an bundance of proliferating fibroblasts near the synovial tissue lining surface and adjacent to SPP1hi macrophages. Notably, ese synovial lining regions were also distinctly marked by deposits of the clot-forming protein fibrin. While the SPP1hi acrophages phenotypically resemble pro-fibrotic macrophages that drive lung and liver fibrosis, these niches were devoid f the dense highly ordered collagen that marks fibrosis. Functionally, we found that SPP1hi macrophages degrade and hagocytose fibrin matrices and promote fibroblast proliferation. As fibrin provides transient matrices for de novo tissue eneration in the context of wound healing, these data support a model of hyperplastic tissue outgrowth involving SPP1hi acrophages, fibroblasts and fibrin matrices adhered to the exterior synovial tissue surface. While current RA therapies rimarily aim to dampen pro-inflammatory responses, our findings provide rationale for targeting pro-generative pathways nd SPP1hi macrophages. Once Sentence SummarySPP1hi macrophages in RA synovial fibrin deposits promote tissue hyperplasia.

immunology↗

bioRxiv2021

Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identified a unique B cell population in the synovium characterized by co-expression of a family of orphan nuclear receptors, NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1), that is highly enriched at both early and late stages of RA. NR4A B cells are rare in healthy peripheral blood, RA blood, and SLE kidney, but share markers with blood transcriptomic signatures that peak during RA disease flare. Using combined single cell transcriptomics and B cell receptor (BCR) sequencing, we demonstrate that NR4A synovial B cells have an activated transcriptomic profile that significantly overlaps with germinal center (GC) light zone (LZ) B cells and an accrual of somatic hypermutation that correlates with loss of naive B cell status. NR4A B cells uniquely co-express lymphotoxin {beta} and IL6, supporting important functions in ELS promotion and pro-inflammatory cytokine production. Further, the presence of shared clones in this activated B cell state and NR4A expressing synovial plasma cells (PC) and the rapid up-regulation with BCR stimulation points to in situ differentiation. Taken together, we identified a dynamic progression of B cell activation in RA synovial ELS, with NR4A transcription factors having an important role in antigen activation and local adaptive immune responses. One sentence summaryB cells in the rheumatoid arthritis synovium undergo a spectrum of in situ activation, with the NR4A family of transcription factors having an important role in antigen stimulation, local adaptive immunity, and pathological B cell responses.

immunology↗