Form meets function in synovium: Did the evolution of power and precision grip drive development of rheumatoid arthritis?

Project No: #OxKEN-2023/8
Intake: OxKEN 2023

themes

2, (5)

project overview

Rheumatoid arthritis (RA) and osteoarthritis (OA) have very different underlying biological pathways and process driving disease pathology leading to either bone destruction (RA) or bone creation (OA). RA is a classically leukocyte driven inflammatory disease leading to expansion of sublining layer stroma with inflammatory monocyte and lymphocytic inflammation and loss of synovial lining layer integrity. OA involves a non-lymphocytic disease process with inflammation and expansion of the lining layer leading to a mechanical fibrotic like disease. Interestingly in the human fingers OA occurs in the distal interphalangeal (DIP) joint in contrast RA occurs in the proximal interphalangeal (PIP) joint, implying anatomical and physiological differences inherent to the individual joints is as important as genetic and underlying immunological processes are in disease formation. One of the key observations about the PIP joint is it is a uniquely human joint providing hominids with two key properties that drove brain enlargement, power grip and precision control permitting tool usage. Thus, this unique joint in the animal kingdom not only made us human but might act as the triggering microenvironment to precipitate rheumatoid arthritis through anatomical features that act as a disease trigger point.

To develop a mechanistic understanding of human joint formation and function we have developed a transcriptomic atlas of developing human DIP and PIP joints using single cell genomics and cytometry. This has been performed at three different human developmental stages. Even at early stages of development differences in cellular composition and gene expression were revealed indicating that mechanics alone are not responsible for disease formation. This work is now being extended to normal human finger DIP and PIP joints to develop a comprehensive atlas of a human joint. In this project this atlas will be used to map and test gene function in the DIP vs PIP joints. Specifically, in this project a combination of spatial genomics and functional assays to dissect the anatomical and physiological differences between DIP and PIP joints.

Project Aims:

To develop a spatial genomic map of human DIP and PIP joints: Using a combination of multi-plex high dimensional imaging, light sheet microscopy and transcriptomics to develop a spatial map of the joints characterizing cell – cell interactions in the developing joints and 3 dimensional organization of neurons, vasculature and synovial tissues.
Utilize human joint organoid models to analyse developmental differences in DIP and PIP synovium: We will utilise the cartographical map of the DIP and PIP joints to test gene expression and function in vitro using organoid culture systems and observing effect of cytokines and mechanical stresses.
Analyse the differential role of neurons, vasculature and synovium in disease formation: Patients with denervation lead to resolution of rheumatoid arthritis in the effected limb, in mouse models localized vasculature has been shown to be important in RA like disease induction. Organotypic cultures containing either neuronal in growth and/or vasculature to determine the roles of these cell types in development of differential susceptibility to disease.

keywords

Rheumatoid-Arthritis, human-developmental, systems-biology, imaging

TRAINING OPPORTUNITIES

The student will be based in the Kennedy Institute of Rheumatology taking advantage of world leading technologies in the institute including confocal microscopy, high dimensional Cell Dive imaging and 3D light sheet microscopy. obtain training in key cutting-edge technologies including: 3D light sheet and multi-plex high dimensional imaging; Spatial genomics and big data analysis; Organoid culture systems; biomechanical forces; Human Developmental Biology

KEY PUBLICATIONS

Cosgrove J, Novkovic M, Albrecht S, Pikor NB, Zhou Z , Onder L, Mörbe U, Cupovic J, Miller H, Alden K, Thuery A, O'Toole P, Pinter R, Jarrett S, Taylor E, Venetz D, Heller M, Uguccioni M, Legler DF, Lacey CJ, Coatesworth A, Polak WG, Cupedo T, Manoury B, Thelen M, Stein JV, Wolf M, Leake MC, Timmis J, Ludewig B, Coles MC, B-cell Zone Reticular Cell Microenvironments Shape CXCL13 Gradient Formation, Nature Communications, 2020, Jul 22;11(1):3677. doi: 10.1038/s41467-020-17135-2.
Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Perlman H, Barone F, McGettrick HM, Fearon DT, Wei K, Raychaudhuri S, Lorsunsky I, Brenner MB, Coles M, Sansom SN, Filer A, Buckley CD, Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis, Nature. 2019 Jun;570(7760):246-251. doi: 10.1038/s41586-019-1263-7
Nayar S, Campos J, Smith CG, Iannizzotto V, Gardner DH, Mourcin F, Roulois D, Turner J, Sylvestre M, Asam S, Glaysher B, Bowman SJ, Fearon DT, Filer A, Tarte K, Luther SA, Fisher BA, Buckley CD, Coles MC, Barone F, Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proc Natl Acad Sci U S A. 2019 Jun 18. pii: 201905301. doi: 10.1073/pnas.1905301116.
Juan-Colás J, Hitchcock IS, Coles M, Johnson S, Krauss TF.Quantifying single-cell secretion in real time using resonant hyperspectral imaging. Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):13204-13209. doi: 10.1073/pnas.1814977115. Epub 2018 Dec 10.
Yang J, Cornelissen F, Papazian N, Reijmers RM, Llorian M, Cupedo T, Coles M, Seddon B. IL-7-dependent maintenance of ILC3s is required for normal entry of lymphocytes into lymph nodes. J Exp Med. 2018 Apr 2;215(4):1069-1077. doi: 10.1084/jem.20170518.