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Imaging mass spectrometry enables molecular profiling of mouse and human
Prentice BM, Hart NJ, Phillips N, Haliyur R, Judd A, Armandala R, Spraggins JM,
Lowe CL, Boyd KL, Stein RW, Wright CV, Norris JL, Powers AC, Brissova M,
Submitted Externally on 6/24/2019
Volume : Pages
62 : 1036 - 1047
The molecular response and function of pancreatic islet cells during metabolic
stress is a complex process. The anatomical location and small size of
pancreatic islets coupled with current methodological limitations have prevented
the achievement of a complete, coherent picture of the role that lipids and
proteins play in cellular processes under normal conditions and in diseased
states. Herein, we describe the development of untargeted tissue imaging mass
spectrometry (IMS) technologies for the study of in situ protein and, more
specifically, lipid distributions in murine and human pancreases., We developed
matrix-assisted laser desorption/ionisation (MALDI) IMS protocols to study
metabolite, lipid and protein distributions in mouse (wild-type and ob/ob mouse
models) and human pancreases. IMS allows for the facile discrimination of
chemically similar lipid and metabolite isoforms that cannot be distinguished
using standard immunohistochemical techniques. Co-registration of MS images with
immunofluorescence images acquired from serial tissue sections allowed accurate
cross-registration of cell types. By acquiring immunofluorescence images first,
this serial section approach guides targeted high spatial resolution IMS
analyses (down to 15 µm) of regions of interest and leads to reduced time
requirements for data acquisition., MALDI IMS enabled the molecular
identification of specific phospholipid and glycolipid isoforms in pancreatic
islets with intra-islet spatial resolution. This technology shows that subtle
differences in the chemical structure of phospholipids can dramatically affect
their distribution patterns and, presumably, cellular function within the islet
and exocrine compartments of the pancreas (e.g. 18:1 vs 18:2 fatty acyl groups
in phosphatidylcholine lipids). We also observed the localisation of specific
GM3 ganglioside lipids [GM3(d34:1), GM3(d36:1), GM3(d38:1) and GM3(d40:1)]
within murine islet cells that were correlated with a higher level of GM3
synthase as verified by immunostaining. However, in human pancreas, GM3
gangliosides were equally distributed in both the endocrine and exocrine tissue,
with only one GM3 isoform showing islet-specific localisation., The development
of more complete molecular profiles of pancreatic tissue will provide important
insight into the molecular state of the pancreas during islet development,
normal function, and diseased states. For example, this study demonstrates that
these results can provide novel insight into the potential signalling mechanisms
involving phospholipids and glycolipids that would be difficult to detect by
targeted methods, and can help raise new hypotheses about the types of
physiological control exerted on endocrine hormone-producing cells in islets.
Importantly, the in situ measurements afforded by IMS do not require a priori
knowledge of molecules of interest and are not susceptible to the limitations of
immunohistochemistry, providing the opportunity for novel biomarker discovery.
Notably, the presence of multiple GM3 isoforms in mouse islets and the
differential localisation of lipids in human tissue underscore the important
role these molecules play in regulating insulin modulation and suggest species,
organ, and cell specificity. This approach demonstrates the importance of both
high spatial resolution and high molecular specificity to accurately survey the
molecular composition of complex, multi-functional tissues such as the pancreas.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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