Recent Advances in Single-cell MALDI Mass Spectrometry Imaging and Potential Clinical Impact

Kristin J Boggio; Emmanuel Obasuyi; Ken Sugino; Sacha B Nelson; Nathalie YR Agar; Jeffrey N Agar

Disclosures

Expert Rev Proteomics. 2011;8(5):591-604. 

In This Article

Introduction to MALDI Mass Spectrometry Imaging

Matrix-assisted laser desorption/ionization mass spectrometry (MS) imaging, also referred to as MALDI imaging MS and MS imaging, is a method that allows for the visualization of the spatial distribution of compounds across tissue sections. This method does not require specific antibodies such as those required by immunohistochemistry, thus allowing for a direct discovery approach to tissue analysis. This is achieved by obtaining an array of mass spectra using a pulsed laser. Once an array of spectra is obtained, it is possible to create an ion image of a particular mass-to-charge (m/z) ratio. This image represents the spatial distribution and relative abundance of that particular ion. An array of MALDI mass spectra (MS image) therefore contains hundreds of ion images, each representative of a different molecule of interest in the same tissue section. MS images can be correlated with various imaging modalities such as fluorescence, histological stains and MRI.[1] An overview of this process is shown in Figure 1.

Figure 1.

MALDI mass spectrometry imaging process. The tissue/cell of interest is placed onto a MALDI target or an indium tin oxide-coated glass slide. A matrix is applied to the tissue/cell and mass spectra are acquired in a raster pattern across the tissue section. The spatial distribution of a single m/z can be represented as a 2D ion density map. Reprinted with permission from [118].

The MALDI MS imaging experiment described in Figure 1 is a suitable approach for biomarker discovery, and can detect molecules that would not otherwise be detected in tissue homogenates. For example, as a result of the limited dynamic range of MS, a molecule that is confined to a relatively small area of the brain would be detected by MS imaging, but not necessarily in a whole-brain homogenate. The mass lists from MALDI MS images can be used to create classes of compounds to be analyzed by statistical methods such as principal component analysis or hierarchical clustering.[2,3] Principal component analysis reduces high-dimensional data into a working set of principle components that are representative of the highest amount of variance in the data set. These components can be visualized in order to determine how specific data points relate to one another.[2] An a priori approach can also be taken to tissue analysis, such as histology-directed analysis where regions of interest are identified by a histopathology expert.

Another form of analysis that will not be discussed in this article, but merits acknowledgement is secondary-ion MS (SIMS). SIMS boasts higher spatial resolution (˜500 nm on tissues) than MALDI MS imaging, allowing for subcellular resolution. SIMS can therefore be applied to the characterization of individual organelles, and most often detects elemental composition or small molecules (such as vitamin E[4]) and metabolites, but generally does not detect peptides, proteins and most lipids.[4,5] SIMS should therefore be regarded as a technique that is complementary to MALDI MS imaging. Ambient MS imaging methods, such as desorption electrospray ionization[6,7] and laser ablation electrospray ionization,[8,9] have a significant advantage of minimal sample preparation, but their discussion lies outside the scope of this article.

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