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“Paint it black”: New method allows in vivo imaging of macrophage dynamics

Macrophages are an essential part of the innate immune system with crucial functions during host defense against pathogens, tissue homeostasis, and during various inflammatory processes in the body caused by infection, allergic reaction or disease. Hence, their visualization, especially on the comprehensive level of following their dynamics in whole animals is an essential contributor to the better understanding of numerous diseases, e.g. cancer. The group for CellEngineering at the Institute for Biological and Medical Imaging at the Helmholtz Zentrum München, in collaboration with the Chair for Biological Imaging at the Technical University of Munich, developed a new method to facilitate such in vivo imaging of macrophage dynamics.

Labeled Macrophages in vivo (arrows) in Optoacoustic tomography (top). Identity of macrophages confirmed on immunofluorescence (middle) and brightfield (bottom) cross-sections. ©Helmholtz Zentrum München/ IBMI

The visualization of macrophages becomes especially interesting if it can be performed on entire animals in vivo since this allows a comprehensive and systemic view of immune cell dynamics, for instance, in response to an infection or cancer. Using a novel imaging method termed Optoacoustic (Photoacoustic) Tomography it is possible to visualize optical contrast in whole organisms in vivo. Unique high-resolution optical images can be obtained through opaque tissues by “listening to light”: Weak laser pulses minimally warm tissue molecules that absorb light and in response generate a temporary volumetric expansion giving rise to ultrasonic signals. Three-dimensional optical images can then be formed at depths of several centimeters by capturing and mathematically processing those ultrasound signals.

However, imaging macrophages is challenging as they are transparent and do not yield optoacoustic contrast. “We aimed at developing bioengineering methods that make macrophages visible to optoacoustic tomography” explains head of the institute Prof. Dr. Vasilis Ntziachristos. Accordingly, a group of researchers around first-author Dr. Ina Weidenfeld and last-author and head of the CellEngineering group Dr. Andre C. Stiel embarked to devise an optoacoustic label for Macrophages, which allows strong light absorption imparting contrast but at the same time does not disturb macrophage functionality.

A new biocompatible contrast agent for optoacoustic imaging

In collaboration with Technical University Munich (TUM) and University of Bonn, the group finally chose a creative approach: They realized that the rare human disease Alkaptonuria is characterized by the enrichment of a pigment in joints and cartilage. As Weidenfeld explains, the pitch-black nature of this pigment, results in high absorbance across the spectrum making it a perfect contrast agent for Optoacoustic. Inspired by this, the researchers then utilized the molecular precursor of this pigment to produce black pigmentation in macrophages thereby facilitating in vivo imaging of macrophage dynamics. The labeling process itself as well as the high solubility of the resulting pigment make it biocompatible allowing the macrophages to preserve their natural activity and function – a crucial achievement compared to many other contrast agents. “Going forward, macrophages marked in such a way can be used in research to visualize, and hence understand, the versatile functions of these immune cells in health and disease”, says Stiel.

Original publication
Weidenfeld et al., 2019: Homogentisic acid-derived pigment as a biocompatible label for optoacoustic imaging of macrophages. Nature Communications, DOI: 10.1038/s41467-019-13041-4