Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes
Junaid Afzal,
Yamin Liu,
Wenqiang Du,
Yasir Suhail,
Pengyu Zong,
Jianlin Feng,
Visar Ajeti,
Wasim A. Sayyad,
Joerg Nikolaus,
Maya Yankova,
Alix C. Deymier,
Lixia Yue,
Kshitiz
Affiliations
Junaid Afzal
Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
Yamin Liu
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA
Wenqiang Du
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA
Yasir Suhail
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA; Center for Cellular Analysis and Modeling, University of Connecticut Health, Farmington, CT 06032, USA
Pengyu Zong
Department of Cell Biology, University of Connecticut Health, Farmington, CT 06032, USA; Calhoun Cardiology Center, University of Connecticut Health, Farmington, CT 06032, USA
Jianlin Feng
Department of Cell Biology, University of Connecticut Health, Farmington, CT 06032, USA; Calhoun Cardiology Center, University of Connecticut Health, Farmington, CT 06032, USA
Visar Ajeti
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA; Center for Cellular Analysis and Modeling, University of Connecticut Health, Farmington, CT 06032, USA
Wasim A. Sayyad
Department of Cell Biology, Yale University, New Haven, CT 06510, USA
Joerg Nikolaus
West Campus Imaging Core, Yale University, New Haven, CT 06477, USA
Maya Yankova
Electron Microscopy Core, University of Connecticut Health, Farmington, CT 06032, USA
Alix C. Deymier
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA
Lixia Yue
Department of Cell Biology, University of Connecticut Health, Farmington, CT 06032, USA; Calhoun Cardiology Center, University of Connecticut Health, Farmington, CT 06032, USA
Kshitiz
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA; Center for Cellular Analysis and Modeling, University of Connecticut Health, Farmington, CT 06032, USA; Department of Cell Biology, University of Connecticut Health, Farmington, CT 06032, USA; Corresponding author
Summary: The vast potential of human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) in preclinical models of cardiac pathologies, precision medicine, and drug screening remains to be fully realized because hiPSC-CMs are immature without adult-like characteristics. Here, we present a method to accelerate hiPSC-CM maturation on a substrate, cardiac mimetic matrix (CMM), mimicking adult human heart matrix ligand chemistry, rigidity, and submicron ultrastructure, which synergistically mature hiPSC-CMs rapidly within 30 days. hiPSC-CMs matured on CMM exhibit systemic transcriptomic maturation toward an adult heart state, are aligned with high strain energy, metabolically rely on oxidative phosphorylation and fatty acid oxidation, and display enhanced redox handling capability, efficient calcium handling, and electrophysiological features of ventricular myocytes. Endothelin-1-induced pathological hypertrophy is mitigated on CMM, highlighting the role of a native cardiac microenvironment in withstanding hypertrophy progression. CMM is a convenient model for accelerated development of ventricular myocytes manifesting highly specialized cardiac-specific functions.
