Matrix architecture in the perivascular niche: a master regulator of lymphocyte infiltration in inflammatory disease?

Project No: #OxKEN-2023/18
Intake: OxKEN 2023

project overview

Rheumatoid arthritis (RA) is an autoimmune disease of poorly understood aetiology, primarily characterised by inflammation and swelling of the joints, and which can lead to loss of function and disability (1). Under pathological conditions both the architecture and cellular landscape of the synovium, the primary site of RA inflammation, are significantly altered (2,3). The ingress and accumulation of lymphocytic cell subsets is a key feature of the histopathology of inflammatory arthritides and plays a crucial role in the establishment of a tissue-specific chronic inflammatory milieu (4). The primary focus of the Midwood group is on extracellular matrix (ECM) immunology in disease settings. While the ECM was long thought of as simply an inert scaffold in which cells are embedded, it is now evident that it plays key roles in defining tissue properties, cell spatial organisation and functional polarisation. ECM compositional biases are associated with growth, metastatic potential, and treatment refraction in cancer (5), and matrix dysregulation is also emerging as a key driver of inflammatory conditions, including RA (6,7).

Work focusing on elucidating the spatial and temporal dynamics of the poorly characterised ECM of the inflamed arthritic synovium reveals two distinct classes of matrix architecture that define blood and lymphatic vasculature respectively. This perivascular organization is conserved in different synovial diseases, and matrix composition in this niche significantly correlates with tissue lymphocyte levels in arthritis patient synovial biopsy sections. This project will investigate the hypothesis that the vascular architecture plays a key role in bidirectional lymphocytic trafficking in and out of inflamed tissues.

In this project, the DPhil student will assess whether type I and type II perivascular architecture is specific to the synovium, or a universal feature of blood and lymphatic vessels across human pathology, including inflammatory bowel disease, fibrotic diseases, and tumours. We will characterise the cellular landscape within each type of perivascular niche using multiplexed immunofluorescence to delineate cell lineage, phenotype and activation status, and spatial transcriptomics to uncover transcriptional conversations between niche-specific endothelial- or lymphatic-lymphocytic interaction networks. Analysis of T cell migration in vitro using artificial basement membrane constructs to recapitulate type I and II vasculature will provide a tractable model for gene expression and pathway validation and to understand the mechanisms by which matrix composition controls lymphocyte trafficking.

keywords

ECM, inflammation, arthritis, lymphocyte infiltration, omics

training opportunities

Spatial transcriptomics and proteomics, multiplexed tissue imaging, bioinformatic analysis of omics data from published and generated datasets, developing expertise in in vivo and in vitro models of inflammation, expert understanding of links between tissue microenvironment and inflammation, presenting and networking in high profile academic settings.

key publications

Gulati M, Farah Z, Mouyis M. Clinical features of rheumatoid arthritis. Medicine. 2018 Apr 1;46(4):211–5.
Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019 Jul;20(7):928–42.
Kurowska-Stolarska M, Alivernini S. Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission. Nat Rev Rheumatol. 2022 Jul;18(7):384–97.
Zhang F, Jonsson AH, Nathan A, Wei K, Millard N, Xiao Q, et al. Cellular deconstruction of inflamed synovium defines diverse inflammatory phenotypes in rheumatoid arthritis. bioRxiv; 2022. p. 2022.02.25.481990.
Henke E, Nandigama R, Ergün S. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy. Frontiers in Molecular Biosciences. 2020;6.
Friedrich M, Pohin M, Jackson MA, Korsunsky I, Bullers SJ, Rue-Albrecht K, et al. IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med. 2021 Nov;27(11):1970–81.
Aungier SR, Cartwright AJ, Schwenzer A, Marshall JL, Dyson MR, Slavny P, et al. Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy? Ann Rheum Dis. 2019 Feb;78(2):186–91.