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Afterload promotes maturation of human induced pluripotent stem cell derived cardiomyocytes in engineered heart tissues.

Authors
  • Leonard, Andrea1
  • Bertero, Alessandro2
  • Powers, Joseph D3
  • Beussman, Kevin M1
  • Bhandari, Shiv4
  • Regnier, Michael3
  • Murry, Charles E5
  • Sniadecki, Nathan J6
  • 1 Department of Mechanical Engineering, University of Washington, Seattle 98107, WA, USA; Center for Cardiovascular Biology, University of Washington, Seattle 98109, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle 98109, WA, USA.
  • 2 Department of Pathology, University of Washington, Seattle 98109, WA, USA; Center for Cardiovascular Biology, University of Washington, Seattle 98109, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle 98109, WA, USA.
  • 3 Department of Bioengineering, University of Washington, Seattle 98107, WA, USA; Center for Cardiovascular Biology, University of Washington, Seattle 98109, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle 98109, WA, USA.
  • 4 Department of Medicine, University of Washington, Seattle 98195, WA, USA.
  • 5 Department of Pathology, University of Washington, Seattle 98109, WA, USA; Department of Bioengineering, University of Washington, Seattle 98107, WA, USA; Center for Cardiovascular Biology, University of Washington, Seattle 98109, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle 98109, WA, USA; Department of Medicine, University of Washington, Seattle 98195, WA, USA; Division of Cardiology, University of Washington, Seattle 98195, WA, USA. Electronic address: [email protected]
  • 6 Department of Mechanical Engineering, University of Washington, Seattle 98107, WA, USA; Department of Bioengineering, University of Washington, Seattle 98107, WA, USA; Center for Cardiovascular Biology, University of Washington, Seattle 98109, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle 98109, WA, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Molecular and Cellular Cardiology
Publisher
Elsevier
Publication Date
May 01, 2018
Volume
118
Pages
147–158
Identifiers
DOI: 10.1016/j.yjmcc.2018.03.016
PMID: 29604261
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) grown in engineered heart tissue (EHT) can be used for drug screening, disease modeling, and heart repair. However, the immaturity of hiPSC-CMs currently limits their use. Because mechanical loading increases during development and facilitates cardiac maturation, we hypothesized that afterload would promote maturation of EHTs. To test this we developed a system in which EHTs are suspended between a rigid post and a flexible one, whose resistance to contraction can be modulated by applying braces of varying length. These braces allow us to adjust afterload conditions over two orders of magnitude by increasing the flexible post resistance from 0.09 up to 9.2 μN/μm. After three weeks in culture, optical tracking of post deflections revealed that auxotonic twitch forces increased in correlation with the degree of afterload, whereas twitch velocities decreased with afterload. Consequently, the power and work of the EHTs were maximal under intermediate afterloads. When studied isometrically, the inotropy of EHTs increased with afterload up to an intermediate resistance (0.45 μN/μm) and then plateaued. Applied afterload increased sarcomere length, cardiomyocyte area and elongation, which are hallmarks of maturation. Furthermore, progressively increasing the level of afterload led to improved calcium handling, increased expression of several key markers of cardiac maturation, including a shift from fetal to adult ventricular myosin heavy chain isoforms. However, at the highest afterload condition, markers of pathological hypertrophy and fibrosis were also upregulated, although the bulk tissue stiffness remained the same for all levels of applied afterload tested. Together, our results indicate that application of moderate afterloads can substantially improve the maturation of hiPSC-CMs in EHTs, while high afterload conditions may mimic certain aspects of human cardiac pathology resulting from elevated mechanical overload. Copyright © 2018 Elsevier Ltd. All rights reserved.

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