The sinoatrial node extracellular matrix promotes pacemaker phenotype and protects automaticity in engineered heart tissues from cyclic strain.

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Public Summary:
Pacemaking muscle cells residing in the sinoatrial node, or the native pacemaking tissue, are the cells responsible for initiating heartbeats in the heart. The matrix scaffold in the sinoatrial node of the heart likely best supports the native pacemaking heart muscle cells. To test the roles of the matrix scaffold on the pacemaking heart muscle cell phenotype and function, we engineered heart tissues by seeding the matrix scaffolds derived from the pig sinoatrial node with human stem cell-derived pacemaking muscle cells. The same cells were also seeded on the matrix scaffold from the left ventricle of the heart for comparison. The pacemaking muscle cells in the sinoatrial node matrix self-organized into clusters, expressed pacemaking genes, and were able to generate electrical impulses resembling the native pacemaking tissue. These pacemaking characteristics were also maintained even after transplantation into mice and subjected to condition of continuous stretch. Those cells seeded on the ventricular matrix scaffold were unable to retain these pacemaking characteristics. Our findings highlight the promotive and protective roles of the sinoatrial node matrix scaffold and provide valuable insights for engineering biopacemakers that may someday replace the electronic pacemakers.
Scientific Abstract:
The composite material-like extracellular matrix (ECM) in the sinoatrial node (SAN) supports the native pacemaking cardiomyocytes (PCMs). To test the roles of SAN ECM in the PCM phenotype and function, we engineered reconstructed-SAN heart tissues (rSANHTs) by recellularizing porcine SAN ECMs with hiPSC-derived PCMs. The hiPSC-PCMs in rSANHTs self-organized into clusters resembling the native SAN and displayed higher expression of pacemaker-specific genes and a faster automaticity compared with PCMs in reconstructed-left ventricular heart tissues (rLVHTs). To test the protective nature of SAN ECMs under strain, rSANHTs and rLVHTs were transplanted onto the murine thoracic diaphragm to undergo constant cyclic strain. All strained-rSANHTs preserved automaticity, whereas 66% of strained-rLVHTs lost their automaticity. In contrast to the strained-rLVHTs, PCMs in strained-rSANHTs maintained high expression of key pacemaker genes (HCN4, TBX3, and TBX18). These findings highlight the promotive and protective roles of the composite SAN ECM and provide valuable insights for pacemaking tissue engineering.