Non-cell autonomous cues for enhanced functionality of human embryonic stem cell-derived cardiomyocytes via maturation of sarcolemmal and mitochondrial KATPchannels.
Human embryonic stem cells (hESCs) is a potential unlimited ex vivo source of ventricular (V) cardiomyocytes (CMs), but hESC-VCMs and their engineered tissues display immature traits. In adult VCMs, sarcolemmal (sarc) and mitochondrial (mito) ATP-sensitive potassium (KATP) channels play crucial roles in excitability and cardioprotection. In this study, we aim to investigate the biological roles and use of sarcKATPand mitoKATPin hESC-VCM. We showed that SarcIK, ATPin single hESC-VCMs was dormant under baseline conditions, but became markedly activated by cyanide (CN) or the known opener P1075 with a current density that was ~8-fold smaller than adult; These effects were reversible upon washout or the addition of GLI or HMR1098. Interestingly, sarcIK, ATPdisplayed a ~3-fold increase after treatment with hypoxia (5% O2). MitoIK, ATPwas absent in hESC-VCMs. However, the thyroid hormone T3 up-regulated mitoIK, ATP,conferring diazoxide protective effect on T3-treated hESC-VCMs. When assessed using a multi-cellular engineered 3D ventricular cardiac micro-tissue (hvCMT) system, T3 substantially enhanced the developed tension by 3-folds. Diazoxide also attenuated the decrease in contractility induced by simulated ischemia (1% O2). We conclude that hypoxia and T3 enhance the functionality of hESC-VCMs and their engineered tissues by selectively acting on sarc and mitoIK, ATP.
Stem Cell &Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.|Department of Physiology, The University of Hong Kong, Hong Kong.
Wendy
W
Keung
Stem Cell &Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.|Department of Physiology, The University of Hong Kong, Hong Kong.
Lihuan
L
Ren
Stem Cell &Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.|Department of Physiology, The University of Hong Kong, Hong Kong.
Sen Li
Stem Cell &Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.|Department of Physiology, The University of Hong Kong, Hong Kong.
Andy On-Tik
AO
Wong
Department of Bioengineering, Boston University, Boston, MA, USA.|Harvard Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
Anant
A
Chopra
Stem Cell &Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.|Department of Physiology, The University of Hong Kong, Hong Kong.
Chi-Wing
CW
Kong
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, M.D., United States of America.
Gordon F
GF
Tomaselli
Department of Bioengineering, Boston University, Boston, MA, USA.|Harvard Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
Christopher S
CS
Chen
Stem Cell &Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.|Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaborations in Regenerative Medicine, The University of Hong Kong, Hong Kong.|Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Sweden.
Ronald A
RA
Li
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