Heterogeneous Cardiac-Derived and Neural Crest-Derived Aortic Smooth Muscle Cells Exhibit Similar Transcriptional Changes After TGFβ Signaling Disruption

Abstract

Background: Smooth muscle cells (SMCs) of cardiac and neural crest origin contribute to the developing proximal aorta and are linked to disease propensity in adults.

Methods: We analyzed single-cell transcriptomes of aortic SMCs from adult mice to determine basal states and changes after disrupting TGFβ (transforming growth factor-β) signaling necessary for aortic homeostasis.

Results: A minority of Myh11 lineage-marked SMCs differentially expressed genes suggestive of embryological origin. Additional analyses in Nkx2-5 and Wnt1 lineage-marked SMCs derived from cardiac and neural crest progenitors, respectively, showed both lineages contributed to a major common cluster and each lineage to a minor distinct cluster. Common cluster SMCs extended from root to arch, cardiac subset cluster SMCs from root to ascending, and neural crest subset cluster SMCs were restricted to the arch. The neural crest subset cluster had greater expression of a subgroup of TGFβ-dependent genes. Nonetheless, conditional deletion of TGFβ receptors resulted in similar transcriptional changes among all SMC clusters. Several disease-associated transcriptional responses were comparable among SMC clusters in a mouse model of Marfan syndrome aortopathy, while many embryological markers of murine aortic SMCs were not detected in adult human aortas.

Conclusions: There are multiple subtypes of cardiac-derived and neural crest-derived SMCs with shared or distinctive transcriptional profiles; neural crest subset cluster SMCs with increased expression of certain TGFβ-inducible genes are not spatially linked to the aortic root predisposed to aneurysms from aberrant TGFβ signaling; and loss of TGFβ responses after receptor deletion is uniform among SMC clusters.

Keywords: aneurysm; aorta; heart; mice; neural crest; transcriptome.