Science - USA (2020-03-13)

SCIENCE sciencemag.org 13 MARCH 2020 • VOL 367 ISSUE 6483 1206-A

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SCIENCE

Drug Administration–approved tyrosine

kinase inhibitors (TKIs), commonly pre-

scribed anticancer compounds, for their

cardiotoxic potential. HiPSC-CMs express

the major tyrosine kinase receptor proteins

such as the insulin, insulin-like growth fac-

tor (IGF), vascular endothelial growth fac-

tor (VEGF), and platelet-derived growth

factor (PDGF) receptors, lending validity to

this cellular model.

With data from a battery of cellular apo-

ptosis, contractility, electrophysiology, and

signaling assays, I generated a “cardiac

safety index” to help align in vitro toxicity

data to clinical drug safety guidelines ( 12 ).

From the safety index, I determined that a

subclass of VEGF receptor 2/PDGF recep-

tor–inhibiting tyrosine kinase inhibitors,

some of which exhibit toxicity clinically,

also elicited cardiotoxicities in hiPSC-CMs.

These manifested as substantial alterations

in cellular electrophysiology, contractility,

and viability when administered at clini-

cally relevant concentrations. I also dis-

covered that cotreatment with either IGF

or insulin partially rescued TKI-induced

toxicity by up-regulating antiapoptotic sig-

naling pathways. This work could prove

useful for groups aiming to develop effec-

tive screening platforms to assess new che-

motherapeutic compounds for cardiotoxic

side effects.

I also collaborated with the Center for the

Advancement of Science in Space (CASIS)

to send a sample of hiPSC-CMs to the

International Space Station. As humankind

ventures beyond our home planet, it is im-

perative that we better understand how the

heart functions for long

periods of time in micro-

gravity. Analysis of these

hiPSC-CMs revealed mi-

crogravity-induced altera-

tions in metabolic gene

expression and calcium

handling ( 13 ).

In recent years, the

stem cell field has expe-

rienced an explosion of

studies using hiPSC-CMs

as a model cellular sys-

tem to study cardiovas-

cular biology. As im-

provements in hiPSC-CM

mass production continue,

we will see a rise in studies

using these cells for dis-

ease modeling and drug

screening. Thus, although hiPSC-CM tech-

nology is in its infancy, it holds great po-

tential to improve cardiovascular health. j

REFERENCES AND NOTES

1. K. Takahashi, S. Yamanaka, Cell 126 , 663 (2006).


2. M. Rao, Cell Stem Cell 12 , 149 (2013).


3. A. S. Go et al., Circulation 127 , e6 (2013).


4. M. A. Laflamme, C. E. Murry, Nature 473 , 326 (2011).


5. J. J. Chong et al., Nature 510 , 273 (2014).


6. A. Sharma, J. C. Wu, S. M. Wu, Stem Cell Res. Ther. 4 , 150
   (2013).


7. I. Itzhaki et al., Nature 471 , 225 (2011).


8. P. W. Burridge et al., Nat. Methods 11 , 855 (2014).


9. A. Sharma et al., Circ. Res. 115 , 556 (2014).


10. A. Sharma et al., Sci. Transl. Med. 9 , eaaf2584 (2017).


11. J. D. Groarke, S. Cheng, J. Moslehi, N. Engl. J. Med. 369 ,
    1779 (2013).


12. A. Sharma et al., Nat. Protoc. 13 , 3018 (2018).


13. A. Wnorowski et al., Stem Cell Reports 13 , 960 (2019).

10.1126/science.aba6111

Patient

Biopsy Cardiac

diferentiation

Reprogramming

Tissue sample

(skin fbroblast,

blood, etc.)

iPSC colonies

iPSC-cardiomyocytes

Autologous cell

therapy

Drug screening and discovery

Disease

modeling

Applications of hiPSC-CM technology

Initially, human induced pluripotent stem cells (hiPSCs) can be produced by reprogramming

skin or blood cells by nonviral or viral reprogramming methods. Cardiac differentiation protocols

allow for the creation of cardiomyocytes derived from hiPSCs (hiPSC-CMs) for downstream

applications, including in vitro disease modeling, drug screening, and regenerative cell therapy.

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