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WIREs Nanomed Nanobiotechnol
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Probing stem cell behavior using nanoparticle‐based approaches

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Stem cells hold significant clinical potential to treat numerous debilitating diseases and injures that currently have no treatment plan. While several advances have been made in developing stem cell platforms and methods to induce their differentiation, there are two critical aspects need to be addressed: (1) efficient delivery of nucleic acids and small molecules for stem cell differentiation, and (2) effective, noninvasive, and real‐time tracking of transplanted stem cells. To address this, there has been a trend of utilizing various types of nanoparticles to not only deliver biomolecules to targeted site but also track the location of transplanted stem cells in real time. Over the past decade, various types of nanoparticles, including magnetic nanoparticles, silica nanoparticles, quantum dots, and gold nanoparticles, have been developed to serve as vehicles for targeted biomolecule delivery. In addition of being biocompatible without causing adverse side effect to stem cells, these nanoparticles have unique chemical and physical properties that allow tracking and imaging in real time using different imaging instruments that are commonly found in hospitals. A summary of the landmark and progressive demonstrations that utilize nanoparticles for stem cell application is described. WIREs Nanomed Nanobiotechnol 2015, 7:759–778. doi: 10.1002/wnan.1346 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Cellular uptake mechanisms. Cells have various energy‐dependent mechanisms for allowing extracellular cargo inside. Depending on the size of the cargo, processes such as caveolae mechanism are induced for small cargo, clathrin mechanism for intermediate cargo, and macropinocytosis for large cargo, are utilized by the cell. Because nanoparticles can vary in size ranging from 5 to 500 nm, different mechanisms are utilized by the cell to enable nanoparticle entry. (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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Designing nanoparticles for stem cell applications. The physical properties of nanoparticles can be selectively designed for specific applications based on the material composition and physical properties. Nanoparticles can be made functionally active depending on the surface chemistry and the functional biomolecules. Nanoparticles are highly tunable and have a modular chemistry, thus enabling their application for desired stem cell applications. (Reprinted with permission from Ref . Copyright 2011 Royal Society of Chemistry)
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Axonal alignment and enhanced neural stem cell (NSC) differentiation on graphene–nanoparticle hybrid substrates. (a) Schematic diagram depicting the influence of nanoparticle (NP) monolayers coated with graphene oxide (GO) on the alignment of axons extending from human NSCs and their differentiation into neurons. (b–d) Aligned growth and extension of axons from differentiated hNSCs, and the compass plots showing the variation in the angle of orientation and length of axons. (e) Quantitative gene expression results for early‐ and late‐stage neuronal markers expressed by the hNSCs differentiated on the different substrates, with the nanoparticle‐hybrid condition having the maximal influence on expression of neuron‐specific genes. (f) Scheme depicting the significance of alignment and growth of axons from differentiating hNSCs. The hNSCs that can be transplanted into the injured region (lesion) of a spinal cord differentiate into neurons and glial cells (image on right). The axons from the neurons (derived from hNSCs) if aligned can hasten the recovery process. Our SiNP–GO hybrid structures can provide the ideal microenvironment to align axons that could potentially improve communication leading to rapid recovery of the injured spinal cord (image on left). (Reprinted with permission from Ref . Copyright 2013 John Wiley and Sons)
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Silica nanoparticles (SNPs) for tracking stem cells in vivo using ultrasound. (a) Schematic of SNPs embedded with FITC for fluorescence imaging and gadolinium for enhancing MRI contrast delivered to mesenchymal stem cells (MSCs) and injected into rat heart tissue. (b) Ultrasound images of human MSCs (hMSCs) after intracardiac implantation in mice. The red arrow represents the bevel of the needle catheter. (c) MRI contract images show enhancement of SNP accumulation. (d) Quantification of the MRI and ultrasound (US) signal as a function of number of injected SNP‐loaded hMSCs. (e) Animals injected (on day 0, red dot) with hMSCs were monitored sequentially for 12 days postinjection. (Reprinted with permission from Ref . Copyright 2013 The American Association for the Advancement of Science)
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Nanotopography‐mediated platform to deliver nucleic acids for stem cell differentiation. (a) Silica nanoparticles (SNPs) are assembled on a film and coated with extracellular matrix (ECM) proteins and nucleic acids (siRNA) to develop the nanotopography‐mediated reverse uptake (NanoRU) platform. Neural stem cells (NSCs) cultured on this platform uptake the siRNA, which induces their differentiation into neurons. (b) Scanning electron microscopy image of neurons (brown) with extended axons cultured on NanoRU wherein the SNPs (blue) are visible. (c) Depending on the size of the SNPs on the surface, the uptake rate of siRNA is affected, which is reflected by the difference in green fluorescent protein (GFP) knockdown. Nanoparticle with 100 nm diameter showed the highest efficiency. (d) Fluorescence images showing the differentiation of NSCs into neurons using the NanoRU platform, and (e) the expression of the specific markers, Tuj1 (neuronal) and GFAP (glial cells), was quantified to reveal that NanoRU is an effective platform to induce stem cell differentiation. (Reprinted with permission from Ref . Copyright 2013 Nature Publishing Group)
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Nontoxic quantum dots (QDs) for stem cell imaging and delivery of nucleic acids. (a) Novel synthesis of ZAIS (Zn, Ag, In, and S) QDs using a sonochemical approach to tune emission properties based on the ratio of starting elements. (b) A library of ZAIS QDs synthesized by varying elemental composition. (c) Cell viability of novel ZAIS QDs compared to conventional CdSe QDs shows that ZAIS QDs are nontoxic to human mesenchymal stem cells (hMSCs). (d) ZAIS QDs are effectively internalized by hMSCs and show a strong fluorescence signal, thus making ZAIS QDs suitable for stem cell tracking applications. (Reprinted with permission from Ref . Copyright 2012 John Wiley and Sons)
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Embryonic stem cells (ESCs) loaded with quantum dots (QDs) can be simultaneously imaged. (a) ESCs were labeled with six different QDs and injected subcutaneously onto the backs of nude mice. These labeled ESCs could be imaged with good contrast with a single excitation wavelength. (b) Different number of QD‐labeled ESCs, 104, 105, and 106, were injected into nude mice and signal was quantified and revealed that the signal of ESCs is proportional to number of cells injected. (c) To evaluate the clearance properties of labeled ESCs, mice were injected with QD‐labeled ESCs and longitudinal imaging revealed that the QD signal can be detected up to 14 days. (Reprinted with permission from Ref . Copyright 2007 BioMed Central)
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Fluorescent quantum dots (QDs) for stem cell labeling and tracking. (a) QDs of different diameters (top row, nm) and the respective emission wavelength (bottom row, nm) are tunable fluorescent probes. (b) QDs incubated in embryonic stem cells (ESCs) show that pluripotent makers such as Oct4 remain unaffected. (c) QD‐treated ESCs can differentiate into three germ layers as evidenced by gene expression of each germ layer. (d) ESCs treated with QDs differentiate into germ layers after 4 days. (e–g) Co‐culture of QDs‐labeled kidney stem cells (KSCs) with green fluorescent protein (GFP)‐labeled KSCs (green) confirms that internalized QDs (red) are not transferred to adjacent cells. (h) Flow cytometry confirms this result. (Reprinted with permission from Ref .)
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Mesoporous silica nanoparticles (SNPs) for cell labeling and differentiating induced pluripotent stem cells (iPSCs). (a) Positively charged mesoporous SNPs were functionalized with an HNF3β‐plasmid‐DNA (pHNF3β) and delivered to iPSCs. The treated iPSCs showed differentiation capacity and differentiated into hepatocyte‐like cells with mature functions within 2 weeks. (b) Comparing uptake efficiency of different charged mesoporous SNPs shows that positively charged SNPs have greatest uptake. (c) Immunofluorescence analysis for the expression of hepatic markers HNF3β (green) and HNF4α (red) in iPSCs treated with loaded mesoporous SNPs. 1/16 and 1/128 refer to ratios of delivery (scale bar = 200 µm). (Reprinted with permission from Ref . Copyright 2013 American Chemical Society)
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Magnetic core–shell nanoparticles (MCNPs) for stem cell differentiation and imaging. (a) Schematic of MCNPs functionalized with mercaptoundecanoic acid (MUA) followed by electrostatic conjugation of polyamide and nucleic acids for regulating gene expression in stem cells. (b) A representative image showing that MCNPs with a composition of ZnFe2O4 are attracted to a magnet. (c) TEM image of MCNPs (scale bar = 10 nm). (d) MCNPs were incubated in green fluorescent protein (GFP)‐labeled rat neural stem cells (rNSCs) and exposed to magnetofection (MF). The resulting GFP knockdown was quantified and is directly correlated to the gene‐regulating efficiency of the MCNPs. The greater the GFP knockdown, the greater its effect. (e) Schematic of rNSCs undergoing MF with MCNPs coated with nucleic acids targeting specific stem cell differentiation. (f) Immunofluorescence images showing the differentiation into neurospecific lineages with particular markers, TUJ1 (neuronal), GFAP (glial cells), and MBP (oligodendrocytes), based on the type of nucleic acid delivered. (Reprinted with permission from Ref . Copyright 2013 John Wiley and Sons)
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Guiding in vivo localization of magnetic nanoparticles (MNPs) using external magnets. (a) To demonstrate that MNPs are precisely controlled by the location of a magnetic field, a magnet array with spherical patterns was placed underneath a solution of MNPs, and resulted in MNPs localizing to locations of highest magnetic strength. (b) To simulate MNPs flowing in the bloodstream, a MNP solution passed through the tube with a magnet underneath and the localization of the MNP (red) is dictated by the flow rate of the solution. (c) MNPs were intravenously injected into the distal portion of the mouse tail vein while a magnet was placed at the injection site. High signal in the tail vein of the mice with the magnet confirms that localization of MNPs can be externally controlled by a magnet. (Reprinted with permission from Ref . Copyright 2013 John Wiley and Sons)
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Tracking transplanted stem cells using magnetic resonance imaging (MRI) in vivo. Mesenchymal stem cells (MSCs) were loaded with magnetic nanoparticles (MNPs) and transplanted into rat brains. The loaded MSCs migrate toward the cortical lesion. (a–c) Time course of weighted MRI of rats that were induced with cortical damage. (d) Axial three‐dimensional images showing accumulation of MSCs in the cortex and striatum. (e) Enlargement of the white box in (d). Throughout the time period, high‐resolution MRI revealed that cells migrated along the distant route toward the lesion. The black circles represent the location of the induced lesion. White arrows point to MNP‐loaded MSCs. (Reprinted with permission from Ref . Copyright 2008 John Wiley and Sons)
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