A disease-driver population within interstitial cells of human calcific aortic valves identified via single-cell and proteomic profiling

Cell Rep. 2022 Apr 12;39(2):110685. doi: 10.1016/j.celrep.2022.110685.

Abstract

Cellular heterogeneity of aortic valves complicates the mechanistic evaluation of the calcification processes in calcific aortic valve disease (CAVD), and animal disease models are lacking. In this study, we identify a disease-driver population (DDP) within valvular interstitial cells (VICs). Through stepwise single-cell analysis, phenotype-guided omic profiling, and network-based analysis, we characterize the DDP fingerprint as CD44highCD29+CD59+CD73+CD45low and discover potential key regulators of human CAVD. These DDP-VICs demonstrate multi-lineage differentiation and osteogenic properties. Temporal proteomic profiling of DDP-VICs identifies potential targets for therapy, including MAOA and CTHRC1. In vitro loss-of-function experiments confirm our targets. Such a stepwise strategy may be advantageous for therapeutic target discovery in other disease contexts.

Keywords: CP: Molecular biology; CTHRC1; MAOA; aortic valve; calcification; cardiovascular; flow cytometry; human CAVD; networks; proteomics; single-cell analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Valve / pathology
  • Aortic Valve Stenosis*
  • Calcinosis*
  • Cells, Cultured
  • Extracellular Matrix Proteins
  • Humans
  • Osteogenesis
  • Proteomics

Substances

  • CTHRC1 protein, human
  • Extracellular Matrix Proteins

Supplementary concepts

  • Aortic Valve, Calcification of