Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis

Authors

Lindsey R. Conroy, University of KentuckyFollow
Harrison A. Clarke, University of Florida
Derek B. Allison, University of KentuckyFollow
Samuel Santos Valenca, University of Kentucky
Qi Sun, University of Kentucky
Tara R. Hawkinson, University of FloridaFollow
Lyndsay E. A. Young, University of KentuckyFollow
Juanita E. Ferreira, University of Kentucky
Autumn V. Hammonds, University of Kentucky
Jaclyn B. Dunne, Medical University of South Carolina
Robert J. McDonald, University of Kentucky
Kimberly J. Absher, University of Kentucky
Brittany Dong, University of KentuckyFollow
Ronald C. Bruntz, University of KentuckyFollow
Kia H. Markussen, University of KentuckyFollow
Jelena A. Juras, University of KentuckyFollow
Warren J. Alilain, University of KentuckyFollow
Jinze Liu, Virginia Commonwealth University
Matthew S. Gentry, University of KentuckyFollow
Peggi M. Angel, Medical University of South Carolina
Christopher M. Waters, University of KentuckyFollow
Ramon C. Sun, University of KentuckyFollow

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.

Document Type

Article

Publication Date

5-2023

Notes/Citation Information

© The Author(s) 2023

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41467-023-38437-1

Funding Information

This study was supported by National Institute of Health (NIH) grants R01AG066653, R01CA266004, R01AG078702, CureAlz fund, St Baldrick’s Career Development Award, V-Scholar Grant, Rally Foundation Independent Investigator Grant to R.C.S., HL131526 and HL151419 to C.M.W., R21NS121966 to W.J.A., R35NS116824 to M.S.G., L.E.A.Y. was supported by NIH/NCI F99CA264165, L.R.C. was supported by NIH/NCI training grant T32CA165990, and J.B.D. was supported by NIH training grant T32GM132055. This research was also supported by funding from the University of Kentucky Markey Cancer Center and the NIH-funded Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center P30CA177558. S.S.V. was granted with a sabbatical from Federal University of Rio de Janeiro, Brazil.

Repository Citation

Conroy, Lindsey R.; Clarke, Harrison A.; Allison, Derek B.; Valenca, Samuel Santos; Sun, Qi; Hawkinson, Tara R.; Young, Lyndsay E. A.; Ferreira, Juanita E.; Hammonds, Autumn V.; Dunne, Jaclyn B.; McDonald, Robert J.; Absher, Kimberly J.; Dong, Brittany; Bruntz, Ronald C.; Markussen, Kia H.; Juras, Jelena A.; Alilain, Warren J.; Liu, Jinze; Gentry, Matthew S.; Angel, Peggi M.; Waters, Christopher M.; and Sun, Ramon C., "Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis" (2023). Saha Cardiovascular Research Center Faculty Publications. 97.
https://uknowledge.uky.edu/cvrc_facpub/97