Single-cell transcriptomic analysis reveals differential cell subpopulations and distinct phenotype transition in normal and dissected ascending aorta

Abstract

Abstract Background Acute thoracic aortic dissection (ATAD) is a fatal condition characterized by tear of intima, formation of false lumen and rupture of aorta. However, the subpopulations of normal and dissected aorta remain less studied. Methods Single-cell RNA sequencing was performed including 5 patients with ATAD and 4 healthy controls. Immunohistochemistry and immunofluorescence were used to verify the findings. Results We got 8 cell types from human ascending aorta and identified 50 subpopulations including vascular smooth muscle cells (VSMCs), endothelial cells, fibroblasts, neutrophils, monocytes and macrophages. Six transmembrane epithelial antigen of prostate 4 metalloreductase (STEAP4) was identified as a new marker of synthetic VSMCs. CytoTRACE identified subpopulations with higher differentiation potential in specified cell types including synthetic VSMCs, enolase 1+ fibroblasts and myeloid-derived neutrophils. Synthetic VSMCs-derived C-X-C motif chemokine ligand 12 (CXCL12) might interact with neutrophils and fibroblasts via C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), respectively, which might recruit neutrophils and induce transdifferentitation of fibroblasts into synthetic VSMCs. Conclusion We characterized signatures of different cell types in normal and dissected human ascending aorta and identified a new marker for isolation of synthetic VSMCs. Moreover, we proposed a potential mechanism that synthetic VSMCs might interact with neutrophils and fibroblasts via CXCL12-CXCR4/ACKR3 axis whereby deteriorating the progression of ATAD, which might provide new insights to better understand the development and progression of ATAD.

Keywords

• Single-cell RNA sequencing
• Acute thoracic aortic dissection
• Cell differentiation trajectory
• CXCL12
• Cell–cell interaction
• Phenotypic switch