TY - JOUR
T1 - Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload
AU - Ma, Zhen
AU - Huebsch, Nathaniel
AU - Koo, Sangmo
AU - Mandegar, Mohammad A.
AU - Siemons, Brian
AU - Boggess, Steven
AU - Conklin, Bruce R.
AU - Grigoropoulos, Costas P.
AU - Healy, Kevin E.
N1 - Funding Information:
This work was supported in part by the NIH NHLBI (R01HL096525, R01HL108677, U01HL100406 and U01HL098179), NIH NIBIB (R21EB021003) and NIH NCATS (UH3TR000487). Z.M. acknowledges support from NSF (1804875), American Heart Association postdoctoral fellowship (16POST27750031) and the Nappi Family Foundation Research Scholar Project. N.H. acknowledges support from NIH T32 (HL007544). M.A.M. acknowledges support from the Canadian Institute of Health Research Postdoctoral Fellowship (129844). B.S. acknowledges support from the California Institute for Regenerative Medicine (TBI-01197). We acknowledge assistance from the Berkeley CIRM/QB3 Shared Stem Cell Facility for flow cytometry, Biological Imaging Facility for confocal microscopy (supported by NIH S10 programme 1S10RR026866-01) and Biomolecular Nanotechnology Center for scanning electron microscopy. We thank E. Nora and P. Devine (Gladstone Institute of Cardiovascular Disease) for helpful discussions and advice regarding p300 expression analysis. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the California Institute for Regenerative Medicine and/or other agencies of the State of California.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41551-018-0280-4
DO - 10.1038/s41551-018-0280-4
M3 - Article
C2 - 31015724
AN - SCOPUS:85053024136
SN - 2157-846X
VL - 2
SP - 955
EP - 967
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 12
ER -