Spatial Metabolomics of the Human Kidney Using MALDI Trapped Ion Mobility Imaging Mass Spectrometry Elizabeth K

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Spatial Metabolomics of the Human Kidney Using MALDI Trapped Ion Mobility Imaging Mass Spectrometry Elizabeth K Spatial Metabolomics of the Human Kidney using MALDI Trapped Ion Mobility Imaging Mass Spectrometry Elizabeth K. Neumann,1,2 Lukasz G. Migas,3 Jamie L. Allen,2 Richard M. Caprioli,1,2,4-6 Raf Van de Plas,1-3 and Jeffrey M. Spraggins1,2,6* 1Department of Biochemistry, Vanderbilt University, 607 Light Hall, Nashville, TN 37205, USA 2Mass Spectrometry Research Center, Vanderbilt University, 465 21st Ave S #9160, Nashville, TN 37235, USA 3Delft Center for Systems and Control, Delft University of Technology, Mekelweg 2 Building 34, 2628 CD Delft, The Neth- erlands 4Department of Pharmacology, Vanderbilt University, 2220 Pierce Avenue, Nashville, TN 37232, USA 5Department of Medicine, Vanderbilt University, 465 21st Ave S #9160, Nashville, TN 37235, USA 6Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, TN 37235, USA KEYWORDS. Metabolomics, Human Kidney, Imaging mass spectrometry, Matrix-assisted laser desorption/ionization, Trapped ion mobility spectrometry, Ion mobility mass spectrometry, High spatial resolution imaging ABSTRACT: Small metabolites are essential for normal and diseased biological function but are difficult to study because of their inherent structural complexity. MALDI imaging mass spectrometry (IMS) of small metabolites is particularly challenging as MALDI matrix clusters are often isobaric with metabolite ions, requiring high resolving power instrumentation or derivatization to circumvent this issue. An alternative to this is to perform ion mobility separation before ion detection, enabling the visualization of metabolites without the interference of matrix ions. Here, we use MALDI timsTOF IMS to image small metabolites at high spatial resolution within the human kidney. Through this, we have found metabolites, such as arginic acid, acetylcarnitine, and choline that localize to the cortex, medulla, and renal pelvis, respectively. We have also demonstrated that trapped ion mobility spectrometry (TIMS) can resolve matrix peaks from metabolite signal and separate both isobaric and isomeric metabolites with different localizations within the kidney. The added ion mobility data dimension dramatically increased the peak capacity for molecular imaging experiments. Future work will involve further exploring the small metabolite profiles of human kidneys as a function of age, gender, and ethnicity. Small metabolites are essential for normal biological function from small metabolites, lipids and peptides to glycans and pro- as well as in transition to a disease state. The localization of teins, often informing biological processes.22-26 In summary, these metabolites is important for cellular function and may per- frozen tissue is cryosectioned into micron thick sections, coated haps provide insight into the (dis)functional state of human or- with an ultraviolet (UV) light-absorbing chemical matrix, and gans.1 Despite their importance, small metabolites are particu- rastered under a UV laser.24,27 While exceptionally powerful for larly difficult to study within tissue matrices because of their small metabolite analysis,28-31 the application of the organic ma- structural complexity and abundance of isomers.2,3 Traditional trix complicates small molecule analysis by MALDI IMS.32 Pri- means of exploring small metabolites include capillary electro- marily, matrix ions are often isobaric with small metabolites33 phoresis,3-6 electrochemistry,7-9 spectroscopy,10-12 liquid chro- and, secondarily, application of the MALDI matrix can cause matography,13-15 and microscopy.16-18 The discrete metabolites delocalization of easily soluble small molecules, preventing ac- identified from each of these analyses have been integrated into curate visualization of each molecular species at cellular spatial databases, such as Metlin19 and Human Metabolome Data- resolutions. 20 base. Each of these technical approaches have provided im- Several approaches exist for enhancing the detection portant insights into biological functions; however, these tech- of small metabolites within a MALDI IMS experiment, gener- niques are often limited by throughput, specificity, sensitivity, ally by reducing matrix isobaric interferences. The most or cannot be performed in an imaging regime. straightforward is to use high resolving power instruments, such Imaging mass spectrometry (IMS) is a powerful tool as Fourier transform ion cyclotron resonance or Orbitrap mass that enables untargeted, spatial analysis of hundreds of chemi- spectrometers, to mass resolve the metabolites from matrix cals within a biological sample.21 Matrix-assisted laser desorp- ions.34-38 However, these systems cannot resolve isomeric com- tion/ionization (MALDI) IMS is a laser-based imaging system pounds and imaging times tend to be longer at sufficiently long used to study a variety of different chemical classes, ranging transient times. Alternatively, other labs have explored derivat- field is progressively decreased, allowing the trapped ions to elute as a function of their differential mobility (K), which is dependent on the mass, charge, and size of the ion.52,53 TIMS is capable of resolving powers greater than 250, enabling separa- tion of lipid isomeric and isobaric species.54 Other types of ion mobility spectrometry, such as traveling-wave55,56 and drift tube57, can discriminate and differentiate small molecule iso- mers, but has not been done in an imaging context. Here, we explore the metabolic composition of the hu- man kidney with MALDI trapped ion mobility IMS. Ultimately, we have demonstrated that the use of TIMS enhances the dis- crimination and peak capacity of small molecule analysis within quadrupole-time of flight (qTOF) MS, enabling high spatial res- olution IMS analysis of small molecules (m/z 50-650) without significant interference from MALDI matrix ions. Beyond im- proving discrimination of metabolites from matrix ions, we also demonstrate that additional metabolite isomers and isobars can be visualized with ion mobility separations compared to qTOF only mode. As such, this developed technology enables imag- ing-based metabolomics with enhanced sensitivity and specific- ity at high spatial resolution. METHODS Materials: α-Cyano-4-hydroxycinnamic acid (CHCA) was purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). HPLC- Figure 1: Average mass spectra of metabolites detected within grade acetonitrile, isopropanol, and methanol were purchased the human kidney in qTOF-only mode (A) and with TIMS en- from Fisher Scientific (Pittsburgh, PA, USA). abled (B). Hundreds of metabolites are detected in both modes, but TIMS increases the number of detectable ions with the ad- Sample Preparation: ditional ion mobility component as seen in the mass spectra (B) and gel view image (C). The addition of TIMS separation re- Human kidney tissue was surgically removed during a full ne- duces the detectability of ions below an m/z value of 150. phrectomy and remnant tissue was processed for research pur- poses by the Cooperative Human Tissue Network at Vanderbilt ization of the small metabolites themselves to enhance ioniza- University Medical Center. Remnant biospecimens were col- tion or increase their respective mass-to-charge ratios (m/z), re- lected in compliance with the Cooperative Human Tissue Net- 39-46 ducing isobaric interferences by matrix ions. Derivatization work standard protocols and National Cancer Institute’s Best methods are generally targeted in nature and limit the number Practices for the procurement of remnant surgical research ma- of different metabolite classes that can be simultaneously visu- terial. Participants were consented for remnant tissue collection alized. The derivatization step may also affect localization of in accordance to institutional IRB policies. The excised tissue the small metabolites within tissue, resulting in limited spatial resolutions. Further, others have synthesized matrices that have fewer isobaric interferences.33,47 These matrices either form clusters that have m/z values higher than metabolites of interest or do not effectively cluster, limiting the number of potential isobars. While effective, matrix choice affects the types of de- tectable molecules, so there is a benefit to developing methods compatible with a wide variety of matrices, particularly com- mon matrices that have been extensively studied. By broaden- ing small metabolite analysis to include a variety of sampling approaches, we can expand and maximize the information ob- tained from a sample. Ion mobility spectrometry is a gas phase analytical ap- proach that enables the separation of ions based on their appar- ent size, shape, and charge state.48-50 Specifically, trapped ion mobility spectrometry (TIMS) is a fast, high resolution ion mo- bility technique that we have recently shown is compatible with imaging experiments and time scales, unlike gas or liquid chro- matography.51 In brief, ions are initially trapped against oncom- ing gas using an electric field. The magnitude of the electric 2 Figure 2: Selected ion images of small metabolites at 20 µm pixel size in comparison to autofluorescence (AF) microscopy (A), showing the spatial and size diversity of the detectable analytes (B-H). Each metabolite localizes to different regions within the kidney, such as the cortex, medulla, and renal pelvis. The selected ion images demonstrate our molecular coverage from smaller m/z values (A) to larger values (H) with many ions detected between those values (C-G). Scale bars are 1.5 mm. was flash frozen over
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