TY - JOUR
T1 - Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
AU - Birket, Matthew J.
AU - Ribeiro, Marcelo C.
AU - Kosmidis, Georgios
AU - Ward, Dorien
AU - Leitoguinho, Ana Rita
AU - van de Pol, Vera
AU - Dambrot, Cheryl
AU - Devalla, Harsha D.
AU - Davis, Richard P.
AU - Mastroberardino, Pier G.
AU - Atsma, Douwe E.
AU - Passier, Robert
AU - Mummery, Christine L.
PY - 2015/10/27
Y1 - 2015/10/27
N2 - Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM.
AB - Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM.
UR - http://www.scopus.com/inward/record.url?scp=84945580024&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.09.025
DO - 10.1016/j.celrep.2015.09.025
M3 - Article
C2 - 26489474
AN - SCOPUS:84945580024
SN - 2211-1247
VL - 13
SP - 733
EP - 745
JO - Cell reports
JF - Cell reports
IS - 4
ER -