Effects of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers on the proliferation and cell cycle progression of embryonic stem cells
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Embryonic stem cells (ESCs) can uniquely proliferate indefinitely and differentiate into all cell lineages. ESCs may therefore provide an unlimited supply of cells for cell-based therapies. Previous study reported the presence of hyperpolarization-activated inward currents in undifferentiated mouse (m) ESCs, but the functional role of this hyperpolarization-activated current in mESCs is unknown. In this study, the role of this current in maintaining the proliferative capacity and the cell cycle progression of ESCs was investigated. In D3 mESCs, this hyperpolarization-activated inward current can be blocked by HCN channel blocker ZD7288. Application of the HCN channel blockers, cesium (1–10 mM) or ZD7288 (0.1–30 μM), attenuated cell proliferation in a concentration-dependent manner. Both HCN blockers were found to be non-cytotoxic to mESCs as determined by cell viability test. Interestingly, ZD7288 at 10 and 30 μM was found to decrease the proportion of cells in G0/G1 phase and increase the proportion of cells in S phase. This suggests that this hyperpolarization-activated current can affect the cell cycle progression in mESCs. In summary, the present investigation suggests that ESC proliferation and cell cycle progression can be regulated by this hyperpolarization-activated current.
KeywordsIon channels Hyperpolarization-activated channels Stem cell Cell cycle Excitability
Embryonic stem cells
- HCN channel
Hyperpolarization-activated cyclic nucleotide-gated channel
TATA-box binding protein
This study was supported by the Direct Grant for Research from the Chinese University of Hong Kong (CUHK) and the Lee Hysan Foundation Research Grant. Y.T.L. and C.K.W. were supported by postgraduate studentships from the CUHK. We would like to thank Ms Cecilia Sze-Lee Leung and Dr. Winnie Poon for their excellent technical support.
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