Contractile Deficits in Engineered Cardiac Microtissues as a Result of MYBPC3 Deficiency and Mechanical Overload

Nat Biomed Eng. 2018 Dec;2(12):955-967. doi: 10.1038/s41551-018-0280-4. Epub 2018 Sep 10.

Abstract

The integration of in vitro cardiac tissue models, human induced pluripotent stem cells (hiPSCs) and genome-editing tools allows for the enhanced interrogation of physiological phenotypes and recapitulation of disease pathologies. Here, using a cardiac tissue model consisting of filamentous three-dimensional matrices populated with cardiomyocytes derived from healthy wild-type (WT) hiPSCs (WT hiPSC-CMs) or isogenic hiPSCs deficient in the sarcomere protein cardiac myosin-binding protein C (MYBPC3-/- hiPSC-CMs), we show that the WT microtissues adapted to the mechanical environment with increased contraction force commensurate to matrix stiffness, whereas the MYBPC3-/- microtissues exhibited impaired force development kinetics regardless of matrix stiffness and deficient contraction force only when grown on matrices with high fibre stiffness. Under mechanical overload, the MYBPC3-/- microtissues had a higher degree of calcium transient abnormalities, and exhibited an accelerated decay of calcium dynamics as well as calcium desensitization, which accelerated when contracting against stiffer fibres. Our findings suggest that MYBPC3 deficiency and the presence of environmental stresses synergistically lead to contractile deficits in cardiac tissues.

Publication types

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

MeSH terms

  • Calcium / metabolism
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / physiopathology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • E1A-Associated p300 Protein / metabolism
  • GATA4 Transcription Factor / metabolism
  • Gene Knockout Techniques
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Myocardial Contraction* / genetics
  • Myocardial Contraction* / physiology
  • Myocardium / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Sarcomeres / metabolism
  • Stress, Mechanical*
  • Tissue Engineering*

Substances

  • Carrier Proteins
  • GATA4 Transcription Factor
  • GATA4 protein, human
  • myosin-binding protein C
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Calcium