||3UH3CA256962-04S1 Interpret this number
||Columbia Univ New York Morningside
||Multimodal Mass Spectrometry Imaging of Mouse and Human Liver
We request an administrative supplement to build the first spatially-resolved 3D map of the human
liver integrating both cellular components and metabolites and the extracellular matrix for the first
time. This collaborative effort between the HuBMAP Transformative Technology Development
team led by Dr. Tian (University of Pittsburgh, Pitt) and Dr. Stockwell (Columbia University, CU)
and the Demonstration Program team led by Dr. Naba (University of Illinois Chicago, UIC) is in
line with HuBMAP’s vision for comprehensive organ mapping, providing an unprecedented view
into liver architecture with a depth never achieved before.
An extensive effort has been made to profile the extracellular matrix (ECM) composition – or
matrisomes – of various organs; however, there is still lack of study on the spatial distribution of
ECM components surrounding cells and contributing to functional multicellular structures, their
variation in normal vs. disease, and molecular signaling/crosstalk with cells. The challenges lie in
(1) the lack of panels of validated anti-ECM antibodies, (2) the difficulty in performing multiplexed
mapping of multi-level biomolecules at single-cell resolution, and (3) the difficulty to integrate
datasets generated using multiple “-omic” modalities in a single sample. The team led by Dr. Tian
developed a mass spectrometry imaging (H2O)n>25k-GCIB-SIMS dual-SIMS workflow, integrating
untargeted metabolomics, lipidomics, and targeted proteomics (up to 40 targets) on the same
tissue section at subcellular spatial resolution (1 µm). Together with the team led by Dr. Stockwell,
a robust multimodal imaging workflow has been established to generate a spatially-resolved atlas
of liver tissue, visualizing major tissue structures, cell types, and metabolic states of cell types.
Leveraging the draft of the human liver matrisome obtained by Dr. Naba and the content of
MatrisomeDB, the database of ECM proteomics datasets her team created, we propose to create
a spatially-resolved map of essential human liver matrisome components, along with our current
multiplexed liver map at the single-cell level.
This project will present a new opportunity to delineate the spatial organization of cellular and
extracellular biomolecules, the definition of functional tissue units, including information on
microenvironmental niches. This will allow, in the future, to define the nature of the interactions
and signals established between cells and their surrounding ECM, and to begin to understand
disease-associated dysregulations (e.g., fibrosis, cirrhosis, hepatocellular carcinoma).
None. See parent grant details.