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Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug screening

Olya Mastikhina, Byeong-Ui Moon, Kenneth Williams, Rupal Hatkar, Dakota Gustafson, Xuetao Sun, Margaret Koo, Alan Y.L. Lam, Yu Sun, Jason E. Fish, Edmond W.K. Young, View ORCID ProfileSara S. Nunes
doi: https://doi.org/10.1101/632406
Olya Mastikhina
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
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Byeong-Ui Moon
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
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Kenneth Williams
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
3Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, Canada
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Rupal Hatkar
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
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Dakota Gustafson
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
3Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, Canada
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Xuetao Sun
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
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Margaret Koo
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
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Alan Y.L. Lam
2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
4Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Canada
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Yu Sun
5Department of Mechanical & Industrial Engineering, University of Toronto, Toronto, Canada
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Jason E. Fish
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
3Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, Canada
6Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada
7Peter Munk Cardiac Center, Toronto General Hospital, Toronto, Canada
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Edmond W.K. Young
2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
5Department of Mechanical & Industrial Engineering, University of Toronto, Toronto, Canada
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Sara S. Nunes
1Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, Canada, M5G 1L7
2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
3Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, Canada
6Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada
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  • ORCID record for Sara S. Nunes
  • For correspondence: sara.vasconcelos@utoronto.ca
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Abstract

While interstitial fibrosis plays a significant role in heart failure, our understanding of disease progression in humans is limited. To address this limitation, we have engineered a cardiac-fibrosis-on-a-chip model consisting of a microfabricated device with live force measurement capabilities using co-cultured human cardiac fibroblasts and pluripotent stem cell-derived cardiomyocytes. Transforming growth factor-β was used as a trigger for fibrosis. Here, we have reproduced the classic hallmarks of fibrosis-induced heart failure including high collagen deposition, increased tissue stiffness, BNP secretion, and passive tension. Force of contraction was significantly decreased in fibrotic tissues that displayed a transcriptomic signature consistent with human cardiac fibrosis/heart failure. Treatment with an anti-fibrotic drug decreased tissue stiffness and BNP secretion, with corresponding changes in the transcriptomic signature. This model represents an accessible approach to study human heart failure in vitro, and allows for testing anti-fibrotic drugs while facilitating the real-time assessment of cardiomyocyte function.

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Posted May 13, 2019.
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Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug screening
Olya Mastikhina, Byeong-Ui Moon, Kenneth Williams, Rupal Hatkar, Dakota Gustafson, Xuetao Sun, Margaret Koo, Alan Y.L. Lam, Yu Sun, Jason E. Fish, Edmond W.K. Young, Sara S. Nunes
bioRxiv 632406; doi: https://doi.org/10.1101/632406
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Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug screening
Olya Mastikhina, Byeong-Ui Moon, Kenneth Williams, Rupal Hatkar, Dakota Gustafson, Xuetao Sun, Margaret Koo, Alan Y.L. Lam, Yu Sun, Jason E. Fish, Edmond W.K. Young, Sara S. Nunes
bioRxiv 632406; doi: https://doi.org/10.1101/632406

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