Aging- and alcohol-associated spatial transcriptomic signature in mouse acute pancreatitis reveals heterogeneity of inflammation and potential pathogenic factors

Rachel R. Tindall, Department of Surgery, UTHealth at Houston, Houston, TX, 77030, USA.
Yuntao Yang, McWilliams School of Biomedical Informatics, UTHealth at Houston, Houston, TX, 77030, USA.
Isabella Hernandez, Department of Surgery, UTHealth at Houston, Houston, TX, 77030, USA.
Amy Qin, Department of Surgery, UTHealth at Houston, Houston, TX, 77030, USA.
Jiajing Li, Department of Surgery, UTHealth at Houston, Houston, TX, 77030, USA.
Yinjie Zhang, Department of Surgery, UTHealth at Houston, Houston, TX, 77030, USA.
Thomas H. Gomez, Center for Laboratory Animal Medicine and Care, UTHealth at Houston, Houston, TX, 77030, USA.
Mamoun Younes, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
Qiang Shen, Department of Interdisciplinary Oncology, Louisiana State Univ. Health Sciences Center, New Orleans, LA, 70112, USA.
Jennifer M. Bailey-Lundberg, Department of Anesthesiology, Critical Care and Pain Medicine, UTHealth at Houston, Houston, TX, 77030, USA.
Zhongming Zhao, Center for Precision Health, McWilliams School of Biomedical Informatics, UTHealth at Houston, Houston, TX, 77030, USA.
Daniel Kraushaar, Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, TX, 77030, USA.
Patricia Castro, Human Tissue Acquisition & Pathology Core, Baylor College of Medicine, Houston, TX, 77030, USA.
Yanna Cao, Department of Surgery, UTHealth at Houston, Houston, TX, 77030, USA. Yanna.Cao@uth.tmc.edu.
W Jim Zheng, McWilliams School of Biomedical Informatics, UTHealth at Houston, Houston, TX, 77030, USA. Wenjin.J.Zheng@uth.tmc.edu.
Tien C. Ko, Department of Surgery, UTHealth at Houston, Houston, TX, 77030, USA. Tien.C.Ko@uth.tmc.edu.

Document Type

Journal Article

Publication Date

6-28-2024

Journal

Journal of molecular medicine (Berlin, Germany)

DOI

10.1007/s00109-024-02460-6

Keywords

Acute pancreatitis; Aging; Alcohol; Alcohol-associated acute pancreatitis mouse model; Differentially expressed genes; Visium spatial transcriptomics

Abstract

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via Visium spatial transcriptomics, eight distinct tissue clusters were revealed from aggregated transcriptomes of aging and young AAP mice: five acinar, two stromal, and one islet, which were then merged into three clusters: acinar, stromal, and islet for the comparative analysis. Compared to young AAP mice, > 1300 differentially expressed genes (DEGs) and approximately 3000 differentially regulated pathways were identified in aging AAP mice. The top five DEGs upregulated in aging AAP mice include Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp with heterogeneous distributions among the clusters. Taken together, this study demonstrates spatial heterogeneity of inflammatory processes in aging AAP mice, offering novel insights into the mechanisms and potential drivers for AAP development. KEY MESSAGES: Mechanisms regarding high mortality of AAP in aging remain undefined. An aging AAP mouse model was developed recapturing clinical exhibition in humans. Spatial transcriptomics identified contrasted DEGs in aging vs. young AAP mice. Top five DEGs were Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp in aging vs. young AAP mice. Our findings shed insights for identification of molecular drivers in aging AAP.

Department

Pathology

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