Format

Send to

Choose Destination
Sci Rep. 2016 Sep 28;6:34154. doi: 10.1038/srep34154.

Non-cell autonomous cues for enhanced functionality of human embryonic stem cell-derived cardiomyocytes via maturation of sarcolemmal and mitochondrial KATP channels.

Keung W1,2, Ren L1,2, Sen Li1,2, Wong AO1,2, Chopra A3,4, Kong CW1,2, Tomaselli GF5, Chen CS3,4, Li RA1,6,7.

Author information

1
Stem Cell &Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.
2
Department of Physiology, The University of Hong Kong, Hong Kong.
3
Department of Bioengineering, Boston University, Boston, MA, USA.
4
Harvard Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
5
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, M.D., United States of America.
6
Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaborations in Regenerative Medicine, The University of Hong Kong, Hong Kong.
7
Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Sweden.

Abstract

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 sarcKATP and mitoKATP in hESC-VCM. We showed that SarcIK, ATP in 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, ATP displayed a ~3-fold increase after treatment with hypoxia (5% O2). MitoIK, ATP was 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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center