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Title: Langhans-type multinucleated giant cells in giant cell arteritis
Authors: Maunder, Daniel Joseph
Issue Date: 2022
Publisher: Newcastle University
Abstract: Langhans-type multinucleated giant cells (LMGCs) are observed in a selection of seemingly disparate idiopathic pathologies including sarcoidosis, Crohn’s disease, granulomatosis with polyangiitis, and giant cell arteritis (GCA). The origin of LMGCs is unclear, though two different formation mechanisms have been proposed; cell-to-cell fusion and modified cell division with failed cytokinesis involving DNA damage signalling. Present across species, they may possess as yet undiscovered functional adaptations, and evidence suggests that they may play a destructive role in GCA. The tissue microenvironment of GCA-affected arteries is also poorly understood, in particular, the molecular pathways involved in driving intimal hyperplasia remain elusive. To facilitate the characterisation of LMGCs in the context of GCA, an in vitro LMGC culture system was developed using GM-CSF and IFNγ to differentiate primary monocytes, and subsequently interrogated using single cell RNA sequencing. Cultured LMGCs were shown to be morphologically representative of those in disease, and transcriptional analysis revealed upregulation of gene modules relating to leukocyte activation, smooth muscle cell proliferation, cell-extracellular matrix interactions and chemokine activity. With fluorescent imaging techniques and electron microscopy it was shown that cultured LMGCs and those from GCA-affected temporal artery tissue contain large chromatin bridges, indicative of cytokinesis failure. Staining for the marker 53BP1 indicated that IFNγ induced DNA damage in these cells, though multinucleation rate was unaffected by additional ROS scavengers. Live confocal imaging revealed the fusion of cultured monocytes to form LMGCs and abnormal cell division. Investigations into the functional adaptations of cultured LMGCs showed that they may enter a state of premature senescence with increased capacity for ROS production. Together these data indicate that LMGCs form by a combination of cell fusion and DNAdamage induced cytokinesis failure, and persist in a senescent state with enhanced capacity for the production of damaging ROS.
Description: PhD Thesis
Appears in Collections:Biosciences Institute

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