Decoding the cellular crosstalk between obesity and osteoarthritis through single-cell transcriptomics

Hang, Wei 2025. Decoding the cellular crosstalk between obesity and osteoarthritis through single-cell transcriptomics. PhD Thesis, Cardiff University. Item availability restricted.

	PDF (Thesis) - Accepted Post-Print Version Restricted to Repository staff only until 21 September 2027 due to copyright restrictions. Download (5MB)
	PDF (Cardiff University Electronic Publication Form) - Supplemental Material Restricted to Repository staff only Download (224kB)

Abstract

Background: Obesity increases osteoarthritis (OA) risk by more than twofold, yet the underlying mechanisms remain poorly understood. Although the epidemiological association is well-established, the specific cellular populations and molecular pathways linking obesity to OA have not been fully characterized. Single-cell RNA sequencing (scRNA-seq) provides a unique opportunity to dissect cellular heterogeneity and uncover the cell type-specific molecular perturbations that drive OA in the context of obesity. Methods: We established an integrated single-cell transcriptomic and experimental framework to investigate obesity-associated OA. Computational analyses incorporated stringent quality control, batch integration, unsupervised clustering,functional characterization, trajectory inference and ligand–receptor interaction analysis to define synovial fibroblast heterogeneity and state dynamics. Functional validation was performed using fatty acid-treated human fibroblast-like synoviocytes, siRNA-mediated gene silencing and a high-fat diet murine model. We also developed ScellPortal (https://hvgogogo.github.io/Scellportal/), an open-access platform for reproducible scRNA-seq analysis. Results: Using integrated scRNA-seq data of 64,125 synovial fibroblasts from 14 subjects, we identified CD34+ sub-lining synovial fibroblasts (SLSFs) as a previously uncharacterized protective population selectively depleted in obese OA. These cells decreased by 54.49% in patients with obese OA compared to healthy controls, accompanied by enhanced hypoxia signaling, dysregulated adipogenic programming, and altered extracellular matrix (ECM) degradation. Trajectory and cell-cell communication analyses further suggested that obesity reprograms CD34+ SLSFs toward hypoxic, matrix-degrading phenotypes. Functional validation using in vitro human fibroblast-like synoviocytes, siRNA knockdown experiments, and in vivo high-fat diet mouse models confirmed that CD34+ SLSF depletion drives metabolic stress, as evidenced by increased expression of markers for hypoxia (HIF1A),adipogenesis (PPARG), and ECM degradation (MMP3, MMP13). Therapeutic intervention with Tirzepatide, a GLP-1/GIP receptor agonist, demonstrated efficacy in restoring CD34 expression and reversing this metabolic stress in fibroblast-like synoviocytes. Conclusion: This work identifies CD34+ SLSFs as a key cell population linking obesity to OA progression, providing mechanistic insights into obesity-associated joint disease and establishing CD34+ SLSFs as a potential stromal therapeutic target.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	24 September 2026
Last Modified:	24 Sep 2026 13:41
URI:	https://orca.cardiff.ac.uk/id/eprint/189751

Actions (repository staff only)

Edit Item