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

doi:10.1016/j.celrep.2023.113505

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

Cell Rep. 2023 Dec 26;42(12):113505. doi: 10.1016/j.celrep.2023.113505. Epub 2023 Dec 2.

Authors

Affiliations

¹ 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.
² Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA.
³ Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA.
⁴ 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.
⁵ 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.
⁶ Institute for Regenerative Cures and Stem Cell Program, University of California, Davis, Sacramento, CA 95817, USA.
⁷ 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.
⁸ 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. Electronic address: dklieu@ucdavis.edu.

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.

Keywords: CP: Cell biology; CP: Developmental biology; calcium transients; cardiomyocytes; extracellular matrix; human induced pluripotent stem cells; pacemaker; sinoatrial node.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Heart Ventricles
Mice
Myocytes, Cardiac* / metabolism
Phenotype
Sinoatrial Node*
Swine

Abstract

Publication types

MeSH terms

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