The sinoatrial node extracellular matrix promotes pacemaker phenotype and protects automaticity in engineered heart tissues from cyclic strain
Yao-Hui Sun,
Hillary K.J. Kao,
Phung N. Thai,
Regan Smithers,
Che-Wei Chang,
Dalyir Pretto,
Sergey Yechikov,
Sarah Oppenheimer,
Amanda Bedolla,
Brooke A. Chalker,
Rana Ghobashy,
Jan A. Nolta,
James W. Chan,
Nipavan Chiamvimonvat,
Deborah K. Lieu
Affiliations
Yao-Hui Sun
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA
Hillary K.J. Kao
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA
Phung N. Thai
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA
Regan Smithers
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA
Che-Wei Chang
Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA
Dalyir Pretto
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA
Sergey Yechikov
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA
Sarah Oppenheimer
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA; Bridges to Stem Cell Research Program, California State University, Sacramento, Sacramento, CA 95817, USA
Amanda Bedolla
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA; Bridges to Stem Cell Research Program, California State University, Sacramento, Sacramento, CA 95817, USA
Brooke A. Chalker
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA; Bridges to Stem Cell Research Program, Cal Poly Humboldt, Humboldt, CA 95521, USA
Rana Ghobashy
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA; Bridges to Stem Cell Research Program, California State University, Sacramento, Sacramento, CA 95817, USA
Jan A. Nolta
Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA
James W. Chan
Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA
Nipavan Chiamvimonvat
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655, USA
Deborah K. Lieu
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA; Corresponding author
Summary: 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.
