A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling

Yimu Zhao; Naimeh Rafatian; Nicole T Feric; Brian J Cox; Roozbeh Aschar-Sobbi; Erika Yan Wang; Praful Aggarwal; Boyang Zhang; Genevieve Conant; Kacey Ronaldson-Bouchard; Aric Pahnke; Stephanie Protze; Jee Hoon Lee; Locke Davenport Huyer; Danica Jekic; Anastasia Wickeler; Hani E Naguib; Gordon M Keller; Gordana Vunjak-Novakovic; Ulrich Broeckel; Peter H Backx; Milica Radisic

doi:10.1016/j.cell.2018.11.042

A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling

Cell. 2019 Feb 7;176(4):913-927.e18. doi: 10.1016/j.cell.2018.11.042. Epub 2019 Jan 24.

Authors

Yimu Zhao¹, Naimeh Rafatian², Nicole T Feric³, Brian J Cox⁴, Roozbeh Aschar-Sobbi⁵, Erika Yan Wang⁶, Praful Aggarwal⁷, Boyang Zhang⁸, Genevieve Conant⁸, Kacey Ronaldson-Bouchard⁹, Aric Pahnke⁸, Stephanie Protze¹⁰, Jee Hoon Lee¹¹, Locke Davenport Huyer⁸, Danica Jekic¹², Anastasia Wickeler¹³, Hani E Naguib¹³, Gordon M Keller¹⁴, Gordana Vunjak-Novakovic¹⁵, Ulrich Broeckel⁷, Peter H Backx¹⁶, Milica Radisic¹⁷

Affiliations

¹ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada.
² Division of Cardiology and Peter Munk Cardiac Center, University of Health Network; Toronto, ON M5G 2N2, Canada.
³ TARA Biosystems, Inc., New York, NY 10016, USA; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
⁴ Department of Physiology, Faculty of Medicine; University of Toronto; Toronto; Ontario, M5S 1A8, Canada; Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ Division of Cardiology and Peter Munk Cardiac Center, University of Health Network; Toronto, ON M5G 2N2, Canada; TARA Biosystems, Inc., New York, NY 10016, USA.
⁶ Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
⁷ Section of Genomic Pediatrics, Department of Pediatrics and Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁸ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
⁹ TARA Biosystems, Inc., New York, NY 10016, USA; Department of Biomedical Engineering and Department of Medicine, Columbia University, New York, NY 10032, USA.
¹⁰ Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
¹¹ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; BlueRock Therapeutics, MaRS Discovery District, Toronto, ON M5G 1L7, Canada.
¹² Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Department of Anatomy and Cell Biology, Faculty of Science, McGill University, Montreal, QC H3A 2K6, Canada.
¹³ Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3G8, Canada.
¹⁴ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
¹⁵ Department of Biomedical Engineering and Department of Medicine, Columbia University, New York, NY 10032, USA.
¹⁶ Division of Cardiology and Peter Munk Cardiac Center, University of Health Network; Toronto, ON M5G 2N2, Canada; Department of Physiology, Faculty of Medicine; University of Toronto; Toronto; Ontario, M5S 1A8, Canada; Department of Biology; York University, Toronto, ON M3J 1P3, Canada; Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada. Electronic address: p.backx@utoronto.ca.
¹⁷ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada. Electronic address: m.radisic@utoronto.ca.

Abstract

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca²⁺ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.

Keywords: Cardiomyocyte; action potential; atrial; calcium transient; contractility; drug testing; electrophysiology; heart; polygenic cardiac disease; tissue engineering; ventricular.

Publication types

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

MeSH terms

Action Potentials
Cell Differentiation
Cells, Cultured
Electrophysiological Phenomena
Humans
Induced Pluripotent Stem Cells / cytology
Models, Biological
Myocardium / cytology
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / metabolism
Pluripotent Stem Cells / cytology
Tissue Culture Techniques / instrumentation*
Tissue Culture Techniques / methods
Tissue Engineering / methods*

Abstract

Publication types

MeSH terms

Grants and funding