1800190 (1 of 15)
2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Quantitative Proteomics Study Reveals Changes
in the Molecular Landscape of Human Embryonic Stem
Cells with Impaired Stem Cell Differentiation upon
Exposure to Titanium Dioxide Nanoparticles
Lei Pan, Yew Mun Lee, Teck Kwang Lim, Qingsong Lin,* and Xiuqin Xu*
L. Pan, Prof. X. Q. Xu
Institute of Stem Cell and Regenerative Medicine
Chengzhi Building, Xiang’an Campus
Xiamen, Fujian Province 361100, P. R. China
Dr. Y. M. Lee, T. K. Lim, Dr. Q. S. Lin
Department of Biological Sciences
National University of Singapore
14 Science Drive 4, Singapore 117543, Singapore
Prof. X. Q. Xu
Shenzhen Research Institute of Xiamen University
Shenzhen, Guangdong Province 518000, P. R. China
materials (ENMs) and nanotechnology-
based applications in various industries
that includes food manufacturing and
Nanoparticles (NPs) make up
the bulk of all ENMs and are compounds
with all three of their dimensions between
1 and 100 nm.
Amongst the many NPs
manufactured, titanium dioxide (TiO
are one of the most well documented NPs.
is a white powder with low solubility
and is widely used as a white pigment in
various industries, accounting for 70% of
global total pigment production.
is also the top ﬁve NPs used in consumer
products, ranging from cosmetics and phar-
maceutics to food manufacturing. The most
signiﬁcance of TiO
NPs’ uses is its appli-
cation in biomedical applications such as
a carrier material for delivery of drugs like
valproic acid for mental disorders and dau-
norubicin for cancer treatment.
NPs are already clinically used as a
component in prosthetic implants in ortho-
pedics and dentistry.
Such a wide applica-
tion of TiO
NPs has added to our concerns
of its safety on humans.
NPs have been extensively studied to determine its
toxicity on humans both in vitro and in vivo, where most in
vitro studies demonstrated the induction of genotoxicity and
carcinogenicity, oxidative stress, and inﬂammation.
these efforts, gray areas remain. One such important area is
how NPs could cause developmental toxicity, especially since
Wick et al.
found that NPs with the diameter of up to 240 nm
were able to cross the blood-placenta barrier. NPs were
also found to pass the blood-testis barrier,
NPs which led to perturbed neurogenesis.
eral studies have found that TiO
NPs could also penetrate
the blood placenta barrier, leading to defective gene expres-
sion, and genital and cranial nerve system defects in the mice
Another study by Yamashita et al.
found pregnancy complications after exposure of TiO
pregnant mice, where TiO
NPs were found in the placenta,
the liver, and the brain of the fetus. However, the mechanistic
details of how TiO
NPs could have led to these observations
remain unknown. Of interest, ENMs are increasingly studied
in the ﬁeld of regenerative medicine.
For instance, studies
The increasing number of nanoparticles (NPs) being used in various
industries has led to growing concerns of potential hazards that NP exposure
can incur on human health. However, its global effects on humans and the
underlying mechanisms are not systemically studied. Human embryonic
stem cells (hESCs), with the ability to differentiate to any cell types, provide
a unique system to assess cellular, developmental, and functional toxicity
in vitro within a single system highly relevant to human physiology. Here,
the quantitative proteomics approach is adopted to evaluate the molecular
consequences of titanium dioxide NPs (TiO
NPs) exposure in hESCs.
The study identiﬁes ≈328 unique proteins signiﬁcantly affected by TiO
NPs exposure. Proteomics analysis highlights that TiO
NPs can induce
DNA damage, elevated oxidative stress, apoptotic responses, and cellular
differentiation. Furthermore, in vivo analysis demonstrates remarkable
reduction in the ability of hESCs in teratoma formation after TiO
exposure, suggesting impaired pluripotency. Subsequently, it is found that
NPs can disrupt hESC mesoderm differentiation into cardiomyocytes.
The study unveils comprehensive changes in the molecular landscape of
hESCs by TiO
NPs and identiﬁes the impact which TiO
NPs can have on
the pluripotency and differentiation properties of human stem cells.
The advancement of nanotechnology over the last few decades has
correlated with the increasing number of new engineered nano-
Small 2018, 14, 1800190