Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis

Lindsey R. Conroy, Harrison A. Clarke, Derek B. Allison, Samuel Santos Valenca, Qi Sun, Tara R. Hawkinson, Lyndsay E. A. Young, Juanita E. Ferreira, Autumn V. Hammonds, Jaclyn B. Dunne, Robert J. McDonald, Kimberly J. Absher, Brittany E. Dong, Ronald C. Bruntz, Kia H. Markussen, Jelena A. Juras, Warren J. Alilain, Jinze Liu, Matthew S. Gentry, Peggi M. Angel, Christopher M. Waters () and Ramon C. Sun ()
Additional contact information
Lindsey R. Conroy: University of Kentucky College of Medicine
Harrison A. Clarke: College of Medicine, University of Florida
Derek B. Allison: Markey Cancer Center
Samuel Santos Valenca: University of Kentucky College of Medicine
Qi Sun: University of Kentucky College of Medicine
Tara R. Hawkinson: College of Medicine, University of Florida
Lyndsay E. A. Young: University of Kentucky College of Medicine
Juanita E. Ferreira: University of Kentucky College of Medicine
Autumn V. Hammonds: University of Kentucky College of Medicine
Jaclyn B. Dunne: Department of Cell & Molecular Pharmacology & Experimental Therapeutics at the Medical University of South Carolina
Robert J. McDonald: University of Kentucky College of Medicine
Kimberly J. Absher: University of Kentucky College of Medicine
Brittany E. Dong: University of Kentucky College of Medicine
Ronald C. Bruntz: University of Kentucky College of Medicine
Kia H. Markussen: University of Kentucky College of Medicine
Jelena A. Juras: University of Kentucky College of Medicine
Warren J. Alilain: University of Kentucky College of Medicine
Jinze Liu: Virginia Commonwealth University
Matthew S. Gentry: Markey Cancer Center
Peggi M. Angel: Department of Cell & Molecular Pharmacology & Experimental Therapeutics at the Medical University of South Carolina
Christopher M. Waters: University of Kentucky College of Medicine
Ramon C. Sun: University of Kentucky College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application of high-dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed blunted N-linked glycan levels and nearly 90% reduction in endpoint fibrosis when compared to WT animals. Collectively, we provide conclusive evidence that lysosomal utilization of glycogen is required for pulmonary fibrosis progression. In summary, our study provides a roadmap to leverage spatial metabolomics to understand foundational biology in pulmonary diseases.

Date: 2023
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DOI: 10.1038/s41467-023-38437-1

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