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Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Proceedings of the National Academy of Sciences - PNAS, 2015-10, Vol.112 (41), p.12705-12710 [Peer Reviewed Journal]

Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles ;Copyright National Academy of Sciences Oct 13, 2015 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1508073112 ;PMID: 26417073

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  • Title:
    Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness
  • Author: Ribeiro, Alexandre J. S. ; Ang, Yen-Sin ; Fu, Ji-Dong ; Rivas, Renee N. ; Mohamed, Tamer M. A. ; Higgs, Gadryn C. ; Srivastava, Deepak ; Pruitt, Beth L.
  • Subjects: Biological Sciences ; Calcium Signaling ; Cardiovascular system ; Cell Differentiation ; Cell Shape ; Cells, Cultured ; Humans ; Mitochondria, Heart ; Models, Biological ; Muscular system ; Myocardial Contraction ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - metabolism ; Pluripotent Stem Cells - cytology ; Pluripotent Stem Cells - metabolism ; Stem cells ; Tension
  • Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2015-10, Vol.112 (41), p.12705-12710
  • Description: Single cardiomyocytes contain myofibrils that harbor the sarcomerebased contractile machinery of the myocardium. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs) have potential as an in vitro model of heart activity. However, their fetallike misalignment of myofibrils limits their usefulness for modeling contractile activity. We analyzed the effects of cell shape and substrate stiffness on the shortening and movement of labeled sarcomeres and the translation of sarcomere activity to mechanical output (contractility) in live engineered hPSC-CMs. Single hPSC-CMs were cultured on polyacrylamide substrates of physiological stiffness (10 kPa), and Matrigel micropatterns were used to generate physiological shapes (2,000-μm² rectangles with length:width aspect ratios of 5:1–7:1) and a mature alignment of myofibrils. Translation of sarcomere shortening to mechanical output was highest in 7:1 hPSC-CMs. Increased substrate stiffness and applied overstretch induced myofibril defects in 7:1 hPSC-CMs and decreased mechanical output. Inhibitors of nonmuscle myosin activity repressed the assembly of myofibrils, showing that subcellular tension drives the improved contractile activity in these engineered hPSC-CMs. Other factors associated with improved contractility were axially directed calcium flow, systematic mitochondrial distribution, more mature electrophysiology, and evidence of transverse-tubule formation. These findings support the potential of these engineered hPSC-CMs as powerful models for studying myocardial contractility at the cellular level.
  • Publisher: United States: National Academy of Sciences
  • Language: English
  • Identifier: ISSN: 0027-8424
    EISSN: 1091-6490
    DOI: 10.1073/pnas.1508073112
    PMID: 26417073
  • Source: Geneva Foundation Free Medical Journals at publisher websites
    MEDLINE
    PubMed Central
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