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

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.

Survivin as a mediator of stiffness-induced cell cycle progression and proliferation of vascular smooth muscle cells

“…However, the level of smooth muscle actin, the least specific contractile marker, 19 was significantly upregulated on stiff hydrogels. Conversely, the upregulation of Myh10 46 and osteopontin 47 on stiff hydrogels indicates that high stiffness promotes a synthetic phenotype. These findings demonstrate that, within our hydrogel system, ECM stiffness selectively modulates gene and protein expression associated with VSMC phenotype.…”

Smooth Muscle Heterogeneity and Plasticity in Health and Aortic Aneurysmal Disease

“…The prevalence of inflammation-related histologic changes underscores the pivotal role of the inflammatory response in the pathophysiology of TAAs. VSMCs that exhibit similar characteristics of monocyte/macrophage and T-lymphocyte are identified in TAAs and referred to as immune-related VSMCs [111,112,117]. Additionally, an intermediate state, which expresses interferon-induced genes, has the potency to switch to T-cell-like VSMCs or macrophagelike VSMCs, suggesting that VSMCs are activated by inflammation [111].…”

“…These VSMCs simultaneously decreased the levels of VSMC markers, cell adhesion, the calciummediated signaling pathway, the cGMP metabolism, as well as the translation and RNA metabolism process. Due to the extremely low differentiation potential and the high expression of metallothionein, we speculate that these are also senescent VSMCs, although they are not annotated by the author [117].…”