In Vivo Molecular MR Imaging: Potential and Limits

Abstract

The recent years have seen dramatic progress in molecular imaging across the board of various techniques. Molecular imaging, in the context of the authors’ goals in this chapter, is termed as the non-invasive, in vivo visualization of cellular and molecular events in normal and pathological processes. In particular, optical and in vivo bioluminescence imaging (BLI) techniques [1,2] but also positron emission tomography (PET) [3,4] have set the pace. All these high-resolution imaging modalities are based on the same general idea that the presence of specific contrast agents, incorporated or intracellularly induced by cellular activities, will provide the necessary contrast of the cells or compartments of interest against the background of the host tissue [1,5]. For the purpose of specific contrast generation, either tracers or contrast agents are incorporated in cells or attached via selective antigen–antibody bindings. Alternatively, cells are, in close cooperation with molecular biologists, transfected with the goal of expressing selected markers. These markers are considered “reporter genes,” as the genes responsible for the marker expression are coupled to other predefined genetic expression patterns. Thus, the reporter genes can be chosen to be expressed constitutively (i.e. permanently) or conditionally (i.e. dependent on specific gene activities, linked to particular cellular dynamics or functional activity). Magnetic resonance imaging (MRI) has joined this group of imaging modalities with cellular/molecular focus only very recently. The reason for this “late appearance” as a player in the field of molecular imaging, despite its high spatial three-dimensional (3D) resolution, is based on the fact that labeling strategies of cells for this imaging technique are not as intuitively available and not directly accessible. For example, optical techniques exploit very successfully the existence of naturally occurring chromophores, genetic code of which is transfected in a selected group of cells. The most successful single chromophore to date is probably the green fluorescent protein “GFP,” originally found in certain jellyfish. For MRI applications of microscopic resolution and for the study of cellular dynamical processes, cells can be effectively loaded with iron oxide nanoparticles. This cell loading generates a pronounced contrast in T ∗ 2 -weighted images. This approach is by now well established and has already led to a variety of applications in diverse medical but also in developmental biological areas. In the latter field, individual cells of an embryo have been labeled [6,7] and, consequently, the fate of the labeled cells during further cell division and selective cell migration was followed in vivo. In the medical arena, there are two major application fields: one dealing with the monitoring of macrophage activity during inflammatory processes in various organs including liver [8,9] as well as brain [10–12] and another field dealing with stem cell implantation in the hope of successful tissue regeneration [13–16] (Figure 1). This chapter is not aiming to review the broad application field. For this purpose, the reader is referred to a couple of excellent recent reviews [17,18]. The basis for the success of these applications in animal models rests in all cases on fundamental considerations concerning the reliable detectability of the cells of interest and the monitoring of their fate in space and time. The present chapter will review the methodological and technical aspects of the ultrahigh-resolution MRI technique, and, most of all, the key tool of this strategy: cell labeling. The goal of the present chapter is to provide the reader with an insight into the methodological requirements for successful MolecularMRI, and to prepare an overview of the various strategies from which the reader is then free to determine an optimal strategy for particular applications.