1206-A 13 MARCH 2020 • VOL 367 ISSUE 6483 sciencemag.org SCIENCE
PHOTO: COURTESY OF A. SHARMAINSIGHTS
REGENERATIVE MEDICINEStem cells to help the heart
Cardiac tissue derived from stem cells holds promise for
modeling, screening, and therapy
PRIZE ESSAY
FINALIST
Arun Sharma
Arun Sharma
received his under-
graduate degree
from Duke University
and a Ph.D. from
Stanford University. Having com-
pleted a postdoctoral fellowship at
the Harvard Medical School, Sharma
is now a senior research fellow jointly
appointed at the Smidt Heart Institute
and Board of Governors Regenerative
Medicine Institute at the Cedars-Sinai
Medical Center in Los Angeles. His
research seeks to develop in vitro
platforms for cardiovascular disease
modeling and drug cardiotoxicity
assessment. http://www.sciencemag.org/
content/367/6483/1206.1
By Arun Sharma1,2S
hinya Yamanaka’s 2006 discovery
of induced pluripotent stem cells
(iPSCs) ignited a revolution in the field
of stem cell biology ( 1 ). For the first
time, nearly all human somatic tissues
could be produced from iPSCs repro-
grammed from blood or skin cells, in a pro-
cess that took only weeks. This advance was
particularly crucial for obtaining surrogate
tissues from cell types that are otherwise dif-
ficult to procure and do not readily expand
in vitro, such as cardiac or neural cells. Ad-
ditionally, many ethical concerns are avoided,
because this technology uses a patient’s own
genetic material to create iPSCs rather than
relying on embryonic stem cells. In the af-
termath of Yamanaka’s discovery, entire bio-
medical industries have developed around
the promise of using human iPSCs (hiPSCs)
and their derivatives for in vitro disease mod-
eling, drug screening, and cell therapy ( 2 ).
The hiPSC technology has had a par-
ticularly notable impact in cardiac regen-erative medicine, a field where scientists
and clinicians have been working to devise
new methods to better understand how
cardiovascular disease manifests and how
to restore cardiovascular function after
disease strikes ( 3 ). The heart is limited in
its ability to regenerate lost cardiomyo-
cytes (beating heart muscle cells), follow-
ing an adverse event such as a heart attack
( 4 ). Cardiomyocytes derived from hiPSCs
(hiPSC-CMs) may represent a potential re-
placement option for dead cells in such a
scenario. However, certain issues remain to
be addressed, such as whether hiPSC-CMs
can integrate with host myocardial tissue in
the long term ( 5 ).
While using hiPSC-CMs for in vivo cell
therapy may become practical in the future,employing hiPSC-CMs for high-throughput
drug discovery and screening is becoming
a reality in the present ( 6 ). Cardiovascular
diseases can be recapitulated “in a dish”
with patient-specific hiPSC-CMs. For ex-
ample, if a patient exhibits a cardiac ar-
rhythmia caused by a genetic abnormality
in a sarcomeric protein or ion channel, that
same rhythm problem can be recapitulated
in vitro ( 7 ). Thanks to advances in hiPSC
differentiation protocols, hiPSC-CMs can
now be mass-produced to study cardiovas-
cular disease mechanisms in vitro ( 8 ).
My graduate thesis in the laboratories
of Joseph Wu and Sean Wu at Stanford
University focused on in vitro applications
of hiPSC-CMs for cardiovascular disease
modeling and for high-throughput screen-
ing of chemotherapeutic compounds to
predict cardiotoxicity. I initially embarked
on a project using hiPSC-CMs to model viral
myocarditis, a viral infection of the heart,
caused by the B3 strain of coxsackievirus ( 9 ).
I began by demonstrating that hiPSC-CMs
express the receptors necessary for viral
internalization and subsequently found
that hiPSC-CMs were highly susceptible to
coxsackievirus infection, exhibiting viral
cytopathic effect within hours of infection.
I also identified compounds that could al-
leviate coxsackievirus infection on hiPSC-
CMs, a translationally relevant finding, as
there remains a shortage of treatments for
viral myocarditis.
Using a genetically modified variant of
coxsackievirus B3 expressing luciferase, I
developed a screening platform for assess-
ing the efficacy of antiviral compounds.
Pretreatment with interferon-b, ribavirin,
or pyrrolidine dithiocarbamate markedly
suppressed viral replication on hiPSC-CMs
by activating intracellular antiviral response
and viral protein clearance pathways. These
compounds alleviated viral replication in a
dose-dependent fashion at low concentra-
tions without causing cellular toxicity.
I next sought to use hiPSC-CMs to screen
anticancer chemotherapeutic compounds
for their off-target cardiovascular toxici-
ties ( 10 ). Cardiotoxicity represents a major
cause of drug withdrawal from the phar-
maceutical market, and several chemo-
therapeutic agents can cause unintended
cardiovascular damage ( 11 ). Using cultured
hiPSC-CMs, I evaluated 21 U.S. Food and(^1) Board of Governors Regenerative Medicine Institute, Cedars-
Sinai Medical Center, Los Angeles, CA, 90048, USA.^2 Smidt
Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA,
90048, USA. Email: [email protected]
Published by AAAS