Am J Physiol Cell Physiol 303: C113–C114, 2012;
doi:10.1152/ajpcell.00160.2012.
Editorial Focus
“Ether-à-go-go” proliferation of iPSC-derived mesenchymal stem cells.
Focus on “Regulation of cell proliferation of human induced pluripotent
stem cell-derived mesenchymal stem cells via ether-à-go-go 1 (hEAG1)
potassium channel”
Amy L. Firth1 and Jason X.-J. Yuan2
1
The Salk Institute of Biological Studies, La Jolla, California; and 2Departments of Medicine and Pharmacology, Institute of
Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois
Address for reprint requests and other correspondence: J.X.-J. Yuan, Dept.
of Medicine, Univ. of Illinois at Chicago, COMRB 3131 (MC 719), 909 S.
Wolcott Ave., Chicago, IL 60612 (e-mail: [email protected]).
http://www.ajpcell.org
MSCs, including mouse, rat, rabbit, and human bone marrow
(BM)-MSCs and human umbilical cord-derived MSCs (1– 6).
A summary of the data from these studies is shown in Fig. 1,
A and B, and is important in understanding the vast heterogeneity in MSC ion channel expression and function between
species, and origin within a species. In the comprehensive
study by Zhang et al. (10), transcript was found for several ion
channels in both iPSC-MSCs and BM-MSCs (KCa1.1,
KCa3.1, KCNH1, Kir2.1, SCN9A, CACNA1C, and Clcn3); two
further Kir transcripts (2.2 and 2.3) were only found in iPSCMSCs. Interestingly, functional currents reflecting all five families of transcripts were found in iPSC-MSCs but no chloride
channel currents were evident in BM-MSCs. The importance
of ion channels in the proliferation rate of MSCs is no secret
(7). Inhibition of K⫹ channels in rat MSCs with tetraethyl
ammonium, amioderone, verapamil or elevated extracellular
K⫹ decreases proliferation by preventing cells from entering S
phase (increased cells in G0/G1 phase) (8). Likewise in mouse
MSCs, inhibition of Ca2⫹-activated K⫹ currents (IKCa) with
clotrimazole and of volume-sensitive Cl⫺ currents (IClvol) with
5-nitro-1-(3-phenylpropylamino)benzoic acid (NPPB) inhibits
proliferation by decreasing cells in S phase through altered
cyclin D1 and cyclin E expression (7). In the current study,
Zhang et al. (10) find a novel regulator of MSC proliferation
(Fig. 1C); they use astemizole, originally an antihistamine, and
a short hairpin RNA to inhibit hEAG1 activity. This decreased
proliferation rates in both iPSC-derived and BM-derived MSCs
but to a much greater extent in the iPSC-MSCs, suggesting a
crucial role for hEAG1 in regulating the proliferation rate of
iPSC-MSCs. It seems likely that the mechanism will be, in
part, due to the ion flow through the channel, but a role for a
conformational change and other intracellular signaling cannot
be ruled out at this stage. Further investigation is necessary to
elucidate this intracellular signaling pathway. Unlike previous
studies, Zhang et al. (10) were unable to demonstrate that
blockade of KCa1.1-encoded channels (or decrease in IKCa) by
paxilline could significantly reduce proliferation. It seems
likely that iPSC-derived MSCs, while having the same differentiation capacity as BM-MSCs, have ion channel expression
that is favorable to in vitro clonogenic expansion.
It is widely accepted now that individual iPSC lines and even
clones of lines have different properties; in particular their differentiation capacity has a tendency to be primed to have a greater
propensity to differentiate to a specific germ layer. It will be
interesting to see whether the data or Zhang and colleagues’ study
holds across a variety of iPSC lines generated from different tissue
sources and using different reprogramming techniques. Evidence
thus far from a handful of studies investigating ion channels in
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C113
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the selective transport of ions and are
fundamental to numerous physiological processes; including,
but not limited to, muscle contraction, neuron firing and cellular homeostasis.
The EAG or “ether-a-go-go” gene encodes a family of depolarization-activated or voltage-gated K⫹ channels. These channels, while predominantly expressed in cardiac tissues being
responsible for repolarization and action potential termination, are
also known to have oncogenic properties due to their influence on
cell proliferation potential. The precise nature of their involvement in cell proliferation is still to be fully consolidated. Pharmacologically speaking, the role of K⫹ channels in cell proliferation
is indirect and explained by either their regulation of intracellular
Ca2⫹ concentration or their role in cell volume control. This is,
however, not always the case. In cancer, the role of ion channels
is relatively novel, with a number of identified functions including
the regulation of cell proliferation and apoptosis. These oncogenic
properties of human EAG channels (hEAG) are more frequently
attributed to signaling mechanisms modulated by ion channel
proteins and independent of ion flux. For example, hEAG1 activity has been shown to be regulated by EGF receptor kinase, and
another study indicates a role for the extracellular matrix, in
particular actin filaments accounting for proliferative properties in
their respective assays (9). Similar oncogenic/pro-proliferative
effects have been observed in several cancers including ovarian
cancer, acute myeloid leukemia, and gliomas. In the current issue,
Zhang and colleagues (10) investigate ion channel expression and
function and demonstrate a critical role for the hEAG1 channel in
the proliferation of induced pluripotent stem cell (iPSC)-derived
mesenchymal stem cells (MSCs).
Mesenchymal stem cells’ capacity for self-renewal and differentiation is unquestionable; however, with age or time in
culture there is a notable decrease in their proliferative potential. Why this occurs is currently unknown though recent
evidence suggests that ion channels may play a pertinent role.
A lack of allorecognition and a homing capacity to specific
niches make MSCs particularly attractive as therapeutic approaches, whether this be as a vehicle for gene delivery or as
a reparative cell. It is thus essential to discover the cellular and
molecular mechanisms that would enhance their undifferentiated proliferation potential in vitro. This is the issue that Zhang
et al. (10) start to tackle in their study.
Over the past decade, there have been several studies investigating the properties of ion channels present in a variety of
ION CHANNELS REGULATE
Editorial Focus
C114
MSCs indicates a distinct heterogeneity likely to be influenced
substantially by the specific microenvironments the cells reside in.
In the case of human iPSC-derived MSCs, the specific culture
conditions are likely to have a significant impact on the cells’
phenotype: media, cell source, splitting frequency and density,
and culture substrate.
The study by Zhang et al. (10) should forge the way for many
future studies investigating a role for ion channels, like EAG1encoded channels, in MSC clonogenic expansion. Given the
known therapeutic potential of MSCs, especially in diseases like
ischemia, these studies could be pertinent to the advancement of
such approaches.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
A.L.F. and J.X.-J.Y. prepared the figures; A.L.F. and J.X.-J.Y. drafted the
manuscript; A.L.F. and J.X.-J.Y. edited and revised the manuscript; J.X.-J.Y.
approved the final version of the manuscript.
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Fig. 1. Ion channels expressed in mesenchymal stem cells (MSCs; A and B) and regulation of induced pluripotent stem cell (iPSC)-derived MSC proliferation
by human ether-à-go-go 1 (hEAG1; C). A and B: ion channels identified by mRNA expression (A) and function (B, or whole cell currents) in bone marrow
(BM)-derived, umbilical vein (UV)-derived, and iPSC-derived MSCs (1– 6, 10). Resting membrane potential (RMP) in rat and human BM- and iPSC-derived
MSC is shown in B (right) (1– 6, 10). H, human; Rb, rabbit; R, rat; M, mouse; IKV, voltage-gated K⫹ current; IKCa, Ca2⫹-activated K⫹ current; INa, voltage-gated
Na⫹ current; ICaL, L-type voltage-dependent Ca2⫹ current; IKir, inwardly rectifying K⫹ current; ICl, Cl⫺ current; MaxiK, large-conductance Ca2⫹-activated K⫹
(KCa) channel. C: iPSCs are generated from adult somatic cells and differentiated in vitro to MSC-like cells. The expression and function of hEAG1-encoded
K⫹ channels enhance the expansion of iPSC-MSCs in vitro either directly via cell cycle regulation or via regulation of intracellular ion (e.g., Ca2⫹) concentration.
hEAG1 inhibition by astemizole inhibits this MSC proliferation. PAS, Per-Arnt-Sim; NLS, nuclear localization signal; NES, nuclear export signal.