Distinct landscapes of fibroblast subtypes in arteries of patients with giant cell arteritis.

Abstract

Giant cell arteritis (GCA) is a systemic vasculitis of large- and medium-sized arteries characterized by granulomatous inflammation and vascular remodelling. Although fibroblasts are the predominant cell type in the adventitia, their role in GCA pathogenesis is largely unknown. This study aimed to investigate the distribution of fibroblast subtypes in relation to vascular remodelling in GCA. Temporal artery biopsies (TAB) from patients with GCA (n = 9) and controls (n = 15) and aorta tissues from GCA (n = 9)- and atherosclerosis (n = 11)-related aneurysms were examined. Immunohistochemical and immunofluorescence staining for fibroblast subtype markers (CD90, platelet-derived growth factor receptor α [PDGFRA], fibroblast activation protein [FAP], podoplanin [PDPN], CD248, α-smooth muscle actin [α-SMA]), cellular proliferation (Ki67) and remodelling-related growth factors (TGF-β, fibroblast growth factor 21 [FGF21], platelet-derived growth factor B [PDGFB]) were performed to evaluate the distribution of fibroblast subtypes in relation to active remodelling pathways. To evaluate the role of FAP in TGF-β-induced fibroblast proliferation, human aortic adventitial fibroblasts (HAoAF) were stimulated in vitro with TGF-β and transfected with small interfering RNA targeting FAP. In GCA-TAB, CD90+FAP+ activated fibroblasts and CD90+PDPN+ immunofibroblasts were predominantly located in the adventitia. CD90+α-SMA+ myofibroblasts were observed mainly in the intima, and CD90+CD248+ fibroblasts in the adventitia-media border and intima. High FGF21 and PDGFB expression in the intima was associated with intimal hyperplasia in GCA-positive TAB. GCA-affected aortas showed a different landscape of fibroblast subtypes: CD90+FAP+ activated fibroblasts, CD90+PDPN+ immunofibroblasts and CD90+CD248+ fibroblasts accumulated especially in structurally disrupted media. Approximately 80% of proliferative fibroblasts in TAB and aorta were FAP positive. FAP knockdown suppressed TGFβ-induced proliferation of HAoAF in vitro. This study documents a distinct spatial distribution pattern of fibroblast subtypes in GCA-affected arteries. The data suggest different roles for fibroblasts in remodelling of specific arterial vascular beds in GCA.