Kupffer cells (KCs), potent scavenger cells located in hepatic sinusoids, constantly phagocytize and degrade foreign materials to maintain metabolism and clearance. Understanding the strategic KC arrangement which links to their spatial location and function in hepatic lobules, the basic functional unit in the liver, is highly valuable for characterizing liver function. However, selectively labeling KCs and characterizing their function in vivo remains challenging. Herein, a fast self-assembled pomegranate structure-like nanoparticle with "nanopomegranate seeds" of dye aggregates has been developed, which has dual-modality "off/on" capability. This nanopomegranate shows good photostability, a high extinction coefficient, a high KC labeling efficiency (98.8%), and better visualization of KC morphology than commercial FluoSpheres. In vivo photoacoustic (PA) and fluorescence imaging consistently visualize that KCs are strategically distributed along the central vein (CV)−portal triad (PT) axis in each liver lobule: more and larger KCs exist in areas closer to the PTs. The high-resolution PA quantitative data further revealed that the density of KCs was linearly dependent on the r n /r max ratio (their relative location along the CV−PT axis) (R 2 = 0.7513), and the KC density at the outermost layer is almost 246-fold that at the innermost layer (each layer is 8 μm). Notably, the phagocytic ability of KCs located in layers with r n /r max ratios of 0.167−0.3 varies in a zigzag pattern, as evidenced by their different PA intensities. Additionally, the fluorescence imaging quantitation suggests similar fluorescence activation of nanopomegranate in KCs. Nanopomegranates combined with dual-modality imaging reveal the strategic arrangement of KCs in vivo, greatly extending our understanding of liver physiology.
The liver has a unique vascular structure and regional immunosuppressive characteristics closely linked to the occurrence and development of diseases. There are no long-term, large-field, and high-quality imaging methods to simultaneously obtain the structure of blood vessels and movement activities of immune cells in abdominal organs in vivo. This research developed a drawer-type abdominal window with an acrylic/resin coverslip named DAWarc and applied it to the intravital fluorescence/photoacoustic imaging of the liver for over 10 days. The liver lobe was inserted into the drawer holder of the DAWarc to physically fix the liver, which decreased the imaging artifacts. The acrylic/resin material used as the coverslip has a high compatibility for fluorescence/photoacoustic imaging. Through intravital fluorescence/photoacoustic imaging, information on the structure of hepatic lobules, spatial distribution of nanopomegranate labeled Kupffer cells (KCs), the movement behavior of invariant natural killer T cells, and morphology of KCs were obtained. We also used a self-organizing map neural network to detect tumor metastases in the photoacoustic images automatically. Conclusively, the DAWarc model provided a powerful tool for intravital fluorescence/photoacoustic imaging of the liver; it helped us to better understand the structure of hepatic lobules and the distribution and function of immune cells during the occurrence and development of liver diseases.
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