Differential Nanoparticle Sequestration by Macrophages and Scavenger Endothelial Cells Visualized in Vivo in Real-Time and at Ultrastructural Resolution

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DOI

  • Yuya Hayashi
  • Masanari Takamiya, Karlsruhe Institute of Technology (KIT), Germany
  • Pia Bomholt Jensen
  • Isaac Ojea-Jiménez, European Commission - Joint Research Centre, Italy
  • Hélicia Claude, Karlsruhe Institute of Technology (KIT), Germany
  • Claude Antony, Karlsruhe Institute of Technology (KIT), Germany
  • Kasper Kjaer-Sorensen
  • Clemens Grabher, Karlsruhe Institute of Technology (KIT), Germany
  • Thomas Boesen
  • Douglas Gilliland, European Commission - Joint Research Centre, Italy
  • Claus Oxvig
  • Uwe Strähle, Karlsruhe Institute of Technology (KIT), Germany
  • Carsten Weiss, Karlsruhe Institute of Technology (KIT), Germany
Despite the common knowledge that the reticuloendothelial system is largely responsible for blood clearance of systemically administered nanoparticles, the sequestration mechanism remains a "black box". Using transgenic zebrafish embryos with cell type-specific fluorescent reporters and fluorescently-labelled model nanoparticles (70 nm SiO2), we here demonstrate simultaneous three-color in vivo imaging of intravenously injected nanoparticles, macrophages and scavenger endothelial cells (SECs). The trafficking processes were further revealed at ultrastructural resolution by transmission electron microscopy. We also find, using a correlative light-electron microscopy approach, that macrophages rapidly sequester nanoparticles via membrane adhesion and endocytosis (including macropinocytosis) within minutes after injection. In contrast, SECs trap single nanoparticles via scavenger receptor-mediated endocytosis resulting in gradual sequestration with a time scale of hours. Inhibition of the scavenger receptors prevented SECs from accumulating nanoparticles but enhanced uptake in macrophages, indicating the competitive nature of nanoparticle clearance in vivo. To directly quantify the relative contributions of the two cell types to overall nanoparticle sequestration, the differential sequestration kinetics was studied within the first 30 min post-injection. This revealed a much higher and increasing relative contribution of SECs as they by far outnumber macrophages in zebrafish embryos, suggesting the importance of the macrophage:SECs ratio in a given tissue. Further characterizing macrophages on their efficiency in nanoparticle clearance, we show that inflammatory stimuli diminish the uptake of nanoparticles per cell. Our study demonstrates the strength of transgenic zebrafish embryos for intravital real-time and ultrastructural imaging of nanomaterials that may provide mechanistic insights into nanoparticle clearance in rodent models and humans.
Original languageEnglish
JournalACS Nano
Volume14
Issue2
Pages (from-to)1665-1681
Number of pages17
ISSN1936-0851
DOIs
Publication statusPublished - Jan 2020

    Research areas

  • ACCUMULATION, CIRCULATION, CLEARANCE, COLOCALIZATION, IMAGE, LIVER, PROTEIN ADSORPTION, SILICA, SIZE, ZEBRAFISH, correlative light-electron microscopy, intravital confocal microscopy, macrophage polarization, nanoparticles, transmission electron microscopy, uptake kinetics, zebrafish embryos

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