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

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.