Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 24, Pages 9770-9775Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1304913110
Keywords
organs on chips; mechanotransduction; muscular thin films; microarray; contraction
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Funding
- American Heart Association Predoctoral Fellowship [0815729D]
- National Institutes of Health [1 R01 HL079126, 1 UH2 TR000522-01]
- Harvard Materials Research Science and Engineering Center
- National Science Foundation Division of Materials Research Grant [DMR-0213805]
- Harvard Stem Cell Institute
- GlaxoSmithKline
- Harvard School of Engineering and Applied Sciences
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The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structure-function relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased alpha- to beta-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart.
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