The Impact of Metallic Nanoparticles on Stem Cell Proliferation and Differentiation

Abstract

Nanotechnology has a wide range of medical and industrial applications. The impact of metallic nanoparticles (NPs) on the proliferation and differentiation of normal, cancer, and stem cells is well-studied. The preparation of NPs, along with their physicochemical properties, is related to their biological function. Interestingly, various mechanisms are implicated in metallic NP-induced cellular proliferation and differentiation, such as modulation of signaling pathways, generation of reactive oxygen species, and regulation of various transcription factors. In this review, we will shed light on the biomedical application of metallic NPs and the interaction between NPs and the cellular components. The in vitro and in vivo influence of metallic NPs on stem cell differentiation and proliferation, as well as the mechanisms behind potential toxicity, will be explored. A better understanding of the limitations related to the application of metallic NPs on stem cell proliferation and differentiation will afford clues for optimal design and preparation of metallic NPs for the modulation of stem cell functions and for clinical application in regenerative medicine.

Keywords: differentiation; metallic nanoparticles; proliferation; regenerative medicine; stem cells; toxicity.

Figure 1

Representative diagram depicting the main types and sources of stem cells and their potential to differentiate into various lineages.

Figure 2

Schematic diagram describes the main pathways of NP uptake (endocytosis) and release (exocytosis) (Reproduced from [100] with permission from American Chemical Society).

Figure 3

(A) AgNPs promoted the osteogenic differentiation of mMSCs in a dose-dependent manner as shown by alizarin red staining. (B) The healing of mouse bone fracture after the exposure to AgNPs is highlighted by the plain X-ray radiographic analysis of the location of fracture and the graphic data that represent the fracture gap closure. (C) Histological analysis of the fracture site in mice scarified after 21 days was carried out using hematoxylin and eosin staining of the middle section of the fracture. This figure was reproduced from Reference [105] with permission from Elsevier.

Figure 4

IONPs promoted the osteogenic differentiation of hBM-MSCs. (A) IONP-exposed hBM-MSCs showed high ALP activity in a dose-dependent manner (* p < 0.05; ** p < 0.01; *** p < 0.001). Scale bar: 100 μm. (B) Calcium mineralization indicated by alizarin red S staining. (C) Quantification of alizarin red S staining (** p < 0.01; *** p < 0.001). (D) The quantitative real-time PCR data showed the upregulation of the osteogenic differentiation-specific genes when exposed for one week to IONPs at 100 μg/mL (*** p < 0.001). (E) The downregulation of the MSC-specific markers after exposure to IONPs at 100 μg/mL for one week (*** p < 0.001). (F) Upregulation of the protein level of the osteogenesis-associated proteins in IONP-treated hBM-MSCs. (G) The quantitative real-time PCR analysis results displayed the significant increase in the expression levels of mRNAs of the classical MAPK-related genes upon exposure to IONPs (100 μg/mL) for one week (*** p < 0.001). (H) Western blot analysis showed the phosphorylation of MAPK-associated proteins. This figure is reproduced from [154] with Elsevier’s permission.

Figure 5

ZnO NP-induced toxicity in mBM-MSCs in ROS-mediated mechanism. (A) MTT assay data showing dose-dependent cytotoxicity in MSC (* p < 0.05). (B) The quantitative estimation of ROS generation in ZnO NP-exposed MSCs represented in fluorescence units (* p < 0.05). (C) ZnO NP-treated MSCs show abnormal actin filaments. Reproduced from [185] with permission from Taylor & Francis.

Figure 6

hMSC labeled with Ferucarbotran showed a dose-dependent suppression of the osteogenic differentiation and high cell migration. (A) Ferucarbotran (300 μg/mL) suppressed the osteogenic differentiation of hMSC that shown in weak ALP staining. (B) The quantitative analysis of the ALP using the microplate reader and the absorbance was taken at 405 nm (* p < 0.05). (B) The quantitative estimation of ROS generation in ZnO NP-exposed MSCs represented in fluorescence units (* p < 0.05). (C) hMSC exposed to Ferucarbotran (300 μg/mL) during the osteogenic differentiation for 2–3 days showed cell scattering and suspension, while cells adhered to the culture plate without migration under normal medium. (D) Cell migration assay was carried out using Transwell filters, showing the increased migration of Ferucarbotran-exposed cells for 24 h to the lower chamber that validated by the crystal violet staining. Reproduced from [188] with permission from Elsevier.