Abstract: SA-OR27
Multimodal Single-Cell and Spatial Atlas of Interstitial and Vascular Niches in Reference and Diseased Kidneys
Session Information
- CKD: New Insights into Mechanisms and Treatment Strategies
October 26, 2024 | Location: Room 24, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Lake, Blue, Altos Labs Inc, San Diego, California, United States
- Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
- Melo Ferreira, Ricardo, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Chen, Xi, Flatiron Institute, New York, New York, United States
- Hansen, Jens, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Sealfon, Rachel S., Flatiron Institute, New York, New York, United States
- Schaub, Jennifer A., University of Michigan, Ann Arbor, Michigan, United States
- Rosas, Sylvia E., Joslin Diabetes Center, Boston, Massachusetts, United States
- Gaut, Joseph, Washington University in St Louis, St Louis, Missouri, United States
- Barisoni, Laura, Duke University School of Medicine, Durham, North Carolina, United States
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
- Zhang, Kun, Altos Labs Inc, San Diego, California, United States
- Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States
- Eadon, Michael T., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Jain, Sanjay, Washington University in St Louis, St Louis, Missouri, United States
Group or Team Name
- HuBMAP, KPMP.
Background
Multiomic studies at a single cell and spatial resolution are powerful approaches to define molecular and cellular landscape of the human kidney and understand etiology of failed or successful repair in acute or chronic injury. We expand KPMP AtlasV1 with clinicopathological correlations and maps of immune-fibroblast-vascular niches with insights into AKI-CKD transition.
Methods
We generated data from >250 kidney KPMP and HuBMAP tissue samples (reference, AKI, CKD) using snRNA-seq, paired snRNA-ATAC-seq and scRNA-seq technologies and performed integrated analyses. 10X Visium, Slide-Seq2, CosMx and Xenium spatial transcriptomics (ST) assays were used to validate and discover putative niches, pathways associated with altered states and their associations with clinicopathological features.
Results
Analysis of 1.5M+ datasets revealed 160 cellular identities including more than ~40 immune, 20 stromal, 20 endothelial and > 70 nephron cell clusters along the cortico-medullary depth. There were ~60 unique niches identified by ST including cellular neighborhoods of profibrogenic and reparative fibroblasts associated with distinct myeloid and altered tubular cells. Several of the cell states were associated with tubular inflammation, interstitial fibrosis or reduced eGFR. This led to the identification of cellular identities that were associated with AKI or CKD. For example, two spatially distinct groups of fibroblasts localized either to perivascular or interstitial sites. Perivascular fibroblasts showed a distinct trajectory from reference fibroblasts to myofibroblasts reminiscent of failed repair and fibrosis. Cell-level functions enriched in altered states include translation, cytoskeleton dynamics, immune response activities and ECM turnover. Paired RNA-ATAC analysis revealed key transcriptional factors, regulatory circuits and accessible chromatin regions that were linked to CKD-associated GWAS variants, identifying genes potentially associated with disease pathogenesis.
Conclusion
We provide a comprehensive blueprint of spatially resolved altered cellular identities, regulatory circuits and molecular codes that inform on mechanisms of unsuccessful repair and acute and chronic kidney dysfunction.
Funding
- NIDDK Support