Kinase inhibitor-induced cardiotoxicity assessed in vitro with human pluripotent stem cell derived cardiomyocytes

Xian, Hai-Qing; Blanco, Carmina; Bonham, Kristina; Snodgrass, H. Ralph

doi:10.1016/j.taap.2022.115886

Cited by 1 publication

(2 citation statements)

References 39 publications

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“…Finally, erlotinib, axitinib, trametinib, cabozantinib, mirdametinib, and pazopanib were experimentally and clinically proven to be cardiac safe. 44 , 50 , 56 Consistently, these drugs all had very large IC 50 values (well above 100 μM) (Fig. 6f ).…”

Section: Resultssupporting

confidence: 61%

“…Overall, the IC 50 values in the high-toxicity group did not exceed 30 μM. The medium-toxicity drug group consisted of lestaurtinib, 56 gefitinib, 57 imatinib, 44 , 50 , 56 everolimus, 56 cobimetinib, 58 and lapatinib, 56 , 59 all of which had been shown to show some level of toxicity. Accordingly, the IC 50 values of these inhibitors remained in the range of 30–100 μM (Fig.…”

Section: Resultsmentioning

confidence: 94%

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Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes

Zhou

Shi

Tang

et al. 2022

Sig Transduct Target Ther

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Cardiovascular diseases are the most common cause of death globally. Accurately modeling cardiac homeostasis, dysfunction, and drug response lies at the heart of cardiac research. Adult human primary cardiomyocytes (hPCMs) are a promising cellular model, but unstable isolation efficiency and quality, rapid cell death in culture, and unknown response to cryopreservation prevent them from becoming a reliable and flexible in vitro cardiac model. Combing the use of a reversible inhibitor of myosin II ATPase, (-)-blebbistatin (Bleb), and multiple optimization steps of the isolation procedure, we achieved a 2.74-fold increase in cell viability over traditional methods, accompanied by better cellular morphology, minimally perturbed gene expression, intact electrophysiology, and normal neurohormonal signaling. Further optimization of culture conditions established a method that was capable of maintaining optimal cell viability, morphology, and mitochondrial respiration for at least 7 days. Most importantly, we successfully cryopreserved hPCMs, which were structurally, molecularly, and functionally intact after undergoing the freeze-thaw cycle. hPCMs demonstrated greater sensitivity towards a set of cardiotoxic drugs, compared to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Further dissection of cardiomyocyte drug response at both the population and single-cell transcriptomic level revealed that hPCM responses were more pronouncedly enriched in cardiac function, whereas hiPSC-CMs responses reflected cardiac development. Together, we established a full set of methodologies for the efficient isolation and prolonged maintenance of functional primary adult human cardiomyocytes in vitro, unlocking their potential as a cellular model for cardiovascular research, drug discovery, and safety pharmacology.

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Section: Resultssupporting

confidence: 61%