Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels

Abstract

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration. We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis and prevention.

Disease-relevant single cell photonic signatures identify S100β stem cells and their myogenic progeny in vascular lesions

“…Based on these data, we conclude there is considerable heterogeneity in the photonic profile of medial SMCs between vascular beds in healthy animals, and yet find that medial SMCs uniformly express SMC contractile markers (SMA and Myh11). Similar conclusions were observed for medial SMCs from various vascular beds of healthy animals using scRNA-seq data as a discriminator 21 . Carotid artery SMCs are atheroprone and are derived from the neural crest 54 whereas medial SMCs from the thoracic aortic are of somatic mesoderm origin 55 and are considered atheroresistant.…”

“…Despite extensive research, their origin remains controversial 67 . In particular, whether these clonal progeny are derived primarily from differentiated medial SMCs 11,21,66 , endothelial cells 20,68 , and/or resident vascular stem cells (mVSc) 15,20,22,59,69,70 .…”

“…In a post-genomic era, information-rich technologies are proving critically important drivers for both fundamental biology and personalised medicine 37 . In particular, scRNA-seq clustering has elucidated cell-to-cell heterogeneity and uncovered cell subgroups and cell dynamics in numerous systems 38 , including vascular 21,22,39 . Label-free technologies for bioanalytical applications have also attracted recent attention with several different classes of label-free sensor detectors now being developed, including plasmonic, photonic, electrical and mechanical sensors 40 .…”

“…While some adventitial progenitors are derived from a parent Myh11 + SMC population 17 , non-SMC derived SRY-related HMG-box 10 (Sox10) adventitial/medial resident multipotent vascular stem cells (MVSC) and Nestin + progenitor cells have also been implicated 19,20 . Single cell RNA sequence analysis (scRNA-seq) further suggested that a rare subpopulation of Myh11-Cre marked SMC that are stem cell antigen-1 positive (Sca1 + ) may be entirely responsible 21 while cell fate mapping and scRNA-seq studies also implicated non-SMC adventitial Sca1 + cells as they expand more rapidly than pre-existing SMCs within severe lesions 22 . Despite these insights, the putative role of resident vascular stem cells that do not originate from medial Myh11 + SMCs in promoting intimal thickening remains controversial.…”

“…Lineage tracing and single cell RNA sequence analysis (scRNA-seq) have provided compelling evidence in various animal models for the involvement of a population of (i) differentiated myosin heavy chain 11 (Myh11) + medial SMC in progressing intimal thickening [7,8] and (ii) adventitial and medial progenitors in progressing intimal thickening [9][10][11][12]. While some adventitial progenitors are derived from a parent Myh11 + SMC population [10], non-SMC derived SRY-related HMG-box 10 (Sox10) adventitial/medial resident multipotent vascular stem cells (mVSc) [13] and Nestin + progenitor cells have also been implicated [14].…”