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

doi:10.1016/j.celrep.2022.111146

Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes

Cell Rep. 2022 Jul 26;40(4):111146. doi: 10.1016/j.celrep.2022.111146.

Authors

Junaid Afzal¹, Yamin Liu², Wenqiang Du², Yasir Suhail³, Pengyu Zong⁴, Jianlin Feng⁴, Visar Ajeti³, Wasim A Sayyad⁵, Joerg Nikolaus⁶, Maya Yankova⁷, Alix C Deymier², Lixia Yue⁴, Kshitiz⁸

Affiliations

¹ Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: junaid.afzal@ucsf.edu.
² Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA.
³ 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.
⁴ Department of Cell Biology, University of Connecticut Health, Farmington, CT 06032, USA; Calhoun Cardiology Center, University of Connecticut Health, Farmington, CT 06032, USA.
⁵ Department of Cell Biology, Yale University, New Haven, CT 06510, USA.
⁶ West Campus Imaging Core, Yale University, New Haven, CT 06477, USA.
⁷ Electron Microscopy Core, University of Connecticut Health, Farmington, CT 06032, USA.
⁸ 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. Electronic address: kshitiz@uchc.edu.

PMID: 35905711
DOI: 10.1016/j.celrep.2022.111146

Abstract

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.

Keywords: CP: Developmental biology; CP: cell biology; adult heart like; cardiac maturation; cardiac mimetic; cardiac ultrastructure; hiPSC derived cardiomyocytes; metabolic maturation; oxidative phosphorylation; pathological hypertrophy; redox handling; substrate topography.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Cell Differentiation / physiology
Cells, Cultured
Humans
Hypertrophy / metabolism
Induced Pluripotent Stem Cells* / metabolism
Myocytes, Cardiac* / metabolism

Grants and funding

R01 HL147350/HL/NHLBI NIH HHS/United States