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

2022; Cell Press; Volume: 39; Issue: 2 Linguagem: Inglês

10.1016/j.celrep.2022.110685

2639-1856

Julius L. Decano, Yukio Iwamoto, Shinji Goto, Janey Y. Lee, Joan T. Matamalas, Arda Halu, Mark C. Blaser, Lang Ho Lee, Brett Pieper, Sarvesh Chelvanambi, Jessica Silva-Nicolau, Francesca Bartoli‐Leonard, Hideyuki Higashi, Haruki Shibata, Payal Vyas, Jianguo Wang, Elena V. Gostjeva, Simon C. Body, Sasha A. Singh, Masanori Aikawa, Elena Aïkawa,

Aortic Disease and Treatment Approaches

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.