Abstract: FR-PO148
Spatial Transcriptomics Define Injury-Specific Microenvironments in the Adult Mouse Kidney and Novel Cellular Interactions in Regeneration and Disease
Session Information
- AKI: Mechanisms
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Gerhardt, Louisa Maria Sophie, Keck School of Medicine of the University of Southern California, Los Angeles, United States
- Polonsky, Michal, California Institute of Technology, Pasadena, California, United States
- Yun, Jina, California Institute of Technology, Pasadena, California, United States
- Koppitch, Kari A., Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
- Cai, Long, California Institute of Technology, Pasadena, California, United States
- McMahon, Andrew P., Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
Background
Acute kidney injury (AKI) disrupts the highly complex architecture of the kidney resulting in reduced kidney function and triggering intrinsic repair processes. These repair processes can lead to functional recovery of the kidney, but AKI can also invoke inflammation and fibrosis resulting in chronic kidney disease (CKD). Development of targeted treatment strategies to halt disease progression after AKI is still hampered by an incomplete understanding of the underlying pathophysiologic processes. Deciphering molecular and cellular interactions driving injury-invoked inflammation and fibrosis is challenging due to the intricate renal architecture.
Methods
We leveraged sequential Fluorescence In Situ Hybridization (seqFISH) to quantify the expression of 1300 genes within the spatial context at single cell resolution in the mouse kidney during the AKI to CKD transition at day 28 after ischemia-reperfusion injury (n=3). Kidneys from non-surgery mice (n=3) were used as controls.
Results
Clustering 220,753 high-quality cells based on gene expression identified all major cell types in the kidney and revealed changes in the kidneys’ cellular composition at 4 weeks post AKI: While immune cells, fibroblasts and injured proximal tubule cells were abundant in the injured kidney, cortical vasculature and proximal tubule segment 3 cells were reduced. Clustering the cells based on the neighborhood cell type composition revealed injury-specific and spatially-dependent gene expression patterns in distinct cellular microenvironments within the kidney. This analysis also predicted novel cell interactions, such as a molecular interplay between persistently injured proximal tubule cells and neighboring fibroblasts via Clcf1-Crfl1. Immune cell types play a critical role in organ repair and the spatial analysis revealed cellular microenvironments resembling early tertiary lymphoid structures.
Conclusion
Collectively, this study provides a high-resolution characterization of injury-invoked changes in the kidney, highlighting injury-specific cellular microenvironments and cell-cell interactions relevant to inflammation and fibrosis development after AKI.
Funding
- NIDDK Support