Single cell analysis identifies a distinct population of fibroblasts that mediate increased cell-cell communication in murine aortopathy of Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS), caused by heterozygous loss-of-function mutations in members of transforming growth factor β (TGFβ) pathway, results in frequent aortic root aneurysms and type A dissections in human.

METHODS: To unveil the mechanism of pathogenesis, the present study utilized single cell RNA sequencing (scRNAseq) from the proximal aortas (aortic root and ascending aorta) of 20 weeks old LDS (Tgfbr2G357W/+) and wild type (Tgfbr2+/+) mice. Histological and immunofluorescence studies were performed on 30 weeks old mice.

RESULTS: ScRNAseq study identifies presence of an exclusive fibroblast population (remodeling fibroblasts) in the proximal aortas of LDS mice, which differentially expressed increased extracellular matrix remodeling genes (Mmp3, Col6a5, Col3a1, and Fn1), and macrophage recruiting chemokines (Saa3, Ccl7, Ccl8, and Cxcl11). These remodeling fibroblasts are focally localized with macrophages at the adventitia of dilated aortic roots of LDS mice. LDS aortas showed increased accumulation of Ccr2 expressing infiltrating macrophages, which are functionally involved in phagocytosis, immune responses and antigen processing and presentation. Ligand-receptor based interaction model recognizes remodeling fibroblasts as a major mediator for signaling communications with resident and recruited macrophages in the proximal aortopathies of LDS mice.

CONCLUSION: Our study highlights the presence of a specialized fibroblast population in the dilated aortic roots of LDS mice at 20 weeks and provides a deeper insight for involvement of remodeling fibroblasts in cellular heterogeneity and cell-cell communications in LDS aortopathies.