Phospholipid composition and functional implications of bone-derived extracellular vesicles in osteogenic differentiation

Dribika, Lujien 2025. Phospholipid composition and functional implications of bone-derived extracellular vesicles in osteogenic differentiation. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Bone-derived extracellular vesicles (EVs), particularly small EVs (sEVs), have emerged as important mediators of skeletal regeneration. While nucleic acids and proteins have been extensively studied, little is known about the role of sEV lipids in osteogenesis. This thesis presents a comprehensive investigation of the phospholipid composition of bone cell-derived sEVs and explores their functional relevance using biomimetic liposomal models. Serum depletion protocols were first optimised in Saos-2 osteoblast-like cells, revealing that serum-free conditions impaired cell viability and altered the phospholipid profile of sEVs. Lipid profiling, performed using mass spectrometry, identified phosphatidylcholine (PC) as the predominant class, with lower levels of phosphatidylserine (PS) and phosphatidylethanolamine (PE). sEVs derived from undifferentiated human bone marrow stem cells (hBMSCs) showed conserved lipid class distributions across donors but revealed donor-dependent variability in individual lipid species, particularly those containing polyunsaturated fatty acid chains, such as PS 38:4 and PE O-40:7. Upon osteogenic differentiation, hBMSCs produced fewer sEVs, accompanied by notable compositional changes in their lipidome. These included a depletion of polyunsaturated PE species (e.g., PE 40:6) and the emergence of ether lipids (e.g., PE O-36:2), indicating membrane remodelling and metabolic reprogramming. To assess biological relevance, liposomes mimicking sEV phospholipid composition were used to treat hBMSCs. Gene expression analysis showed that PS and PE liposomes upregulated osteogenic genes such as TRIB3 and ASNS, revealing lipid-specific signalling effects. Notably, PS liposomes also modulated pathways involved in osteogenic commitment, including ERK signalling. This is the first study to integrate lipidomics with functional lipid modelling to investigate the role of sEV phospholipids in bone regeneration. It demonstrates that specific phospholipid species are not merely structural components but may actively contribute to the osteogenic potential of sEVs. These novel insights support the development of lipid-informed sEV engineering strategies for acellular bone regenerative therapies.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Dentistry
Subjects:	Q Science > QR Microbiology
Date of First Compliant Deposit:	14 October 2025
Last Modified:	16 Oct 2025 08:14
URI:	https://orca.cardiff.ac.uk/id/eprint/181657

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