Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function

Birket, M.J.; Ribeiro, M.C.; Kosmidis, G.; Ward, D.; Leitoguinho, A.R.; Pol, V. van de; ... ; Mummery, C.L. (2015)

Article / Letter to editor

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 iden- tify 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 cardiomyop- athy (HCM). A simple screen revealed the collabora- tive effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the elec- trophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condi- tion, 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 hap- loinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM

• All authors: Birket, M.J.; Ribeiro, M.C.; Kosmidis, G.; Ward, D.; Leitoguinho, A.R.; Pol, V. van de; Dambrot, C.; Devalla, H.D.; Davis, R.P.; Mastroberardino, P.G.; Atsma, D.E.; Passier, R.; Mummery, C.L.
• Date: 2015
• Journal: Cell Reports
• DOI: doi:10.1016/j.celrep.2015.09.025
• Link: http://dx.doi.org/10.1016/j.celrep.2015.09.025