Key result
Single-cell RNA sequencing identified Vsnl1 as a highly specific marker for the core pacemaker cell cluster in the mammalian sinoatrial node, and its deficiency reduced the beating rate of cardiomyocytes by 44.8%.
Why the study?
The molecular and cellular features of the sinoatrial node underpinning its critical cardiac function remained uncharted.
Single-cell RNA sequencing of the mammalian sinoatrial node identifies distinct cell clusters and reveals Vsnl1 as a key marker and regulator of pacemaker activity.
Vsnl1 may mark core SAN pacemaker cells; leaves open therapeutic targeting in human sinus node dysfunction.
Bioelectrical impulses intrinsically generated within the sinoatrial node (SAN) trigger the contraction of the heart in mammals. Though discovered over a century ago, the molecular and cellular features of the SAN that underpin its critical function in the heart are uncharted territory. Here, we identify four distinct transcriptional clusters by single-cell RNA sequencing in the mouse SAN. Functional analysis of differentially expressed genes identifies a core cell cluster enriched in the electrogenic genes. The similar cellular features are also observed in the SAN from both rabbit and cynomolgus monkey. Notably, Vsnl1, a core cell cluster marker in mouse, is abundantly expressed in SAN, but is barely detectable in atrium or ventricle, suggesting that Vsnl1 is a potential SAN marker. Importantly, deficiency of Vsnl1 not only reduces the beating rate of human induced pluripotent stem cell - derived cardiomyocytes (hiPSC-CMs) but also the heart rate of mice. Furthermore, weighted gene co-expression network analysis (WGCNA) unveiled the core gene regulation network governing the function of the SAN in mice. Overall, these findings reveal the whole transcriptome profiling of the SAN at single-cell resolution, representing an advance toward understanding of both the biology and the pathology of SAN.
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Liang et al. (2021) studied Normal mammalian sinoatrial node physiology (n=43). Vsnl1 knockdown vs. Control (nonsense siRNA or AAV9-miRNAi-Control) was evaluated on Beating rate of cardiomyocytes and heart rate in mice. Single-cell RNA sequencing identified Vsnl1 as a highly specific marker for the core pacemaker cell cluster in the mammalian sinoatrial node, and its deficiency reduced the beating rate of cardiomyocytes by 44.8%.
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