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Scissor-CIBERSORTx Deconvolution Reveals Functional Heterogeneity of CTAL/aTAL Cells and Associated Biomarkers in
Hengping Wang1, Yuan Zhang1, Jiale Li1
1Jilin Collaborative Innovation Center for Antibody Engineering, Jilin Medical University, Jilin 132013, China.
Abstract:
Renal fibrosis (RF) represents a major pathological outcome of chronic kidney disease, currently accompanied by extremely limited therapeutic strategies. To decipher key cellular and molecular drivers, we integrated single-cell and bulk transcriptomic profiles for comprehensive analysis. Based on the RF-related single-cell and bulk transcriptomic data, key cell subtypes were identified through Scissor analysis, custom signature matrix construction via CIBERSORTx, and Weighted Gene Co-Expression Network Analysis (WGCNA). Subsequently, key subtype-related biomarkers were identified through the expression analysis, and functional enrichment analysis for biomarkers was conducted to elucidate the potential mechanisms by which biomarkers regulate RF. Through comprehensive profiling, thick ascending limb (TAL) cells were predominant and displayed marked heterogeneity in renal fibrosis (RF), with cortical TAL (CTAL) and adaptive TAL (aTAL) identified as principal subtypes. A set of candidate biomarkers was identified. Quantitative polymerase chain reaction (qPCR) validation in mouse models confirmed aberrant expression of these biomarkers, with STAT1 and PARP8 upregulated and HS6ST2, PTGER3, and TMEM207 downregulated in RF. Furthermore, functional enrichment analyses indicated that these biomarkers were associated with pathways underlying metabolic reprogramming and immune perturbation. Our study implicates CTAL and aTAL as central cellular players in RF and identifies their associated biomarkers. These experimentally validated biomarkers provide novel targets and repurposing opportunities for RF therapeutic intervention.
Insights
New research identifies specific kidney cell subtypes, cortical TAL (CTAL) and adaptive TAL (aTAL), as key drivers of renal fibrosis (RF). This discovery offers novel therapeutic targets for chronic kidney disease treatment.
Area of Science:
- Nephrology
- Molecular Biology
- Genomics
Background:
- Renal fibrosis (RF) is a significant complication of chronic kidney disease (CKD) with limited treatment options.
- Understanding the cellular and molecular mechanisms driving RF is crucial for developing effective therapies.
Purpose of the Study:
- To identify key cell subtypes and molecular biomarkers involved in the pathogenesis of renal fibrosis.
- To elucidate the functional pathways regulated by these biomarkers in RF.
Main Methods:
- Integration of single-cell and bulk transcriptomic data.
- Cell subtype identification using Scissor analysis and CIBERSORTx.
- Biomarker discovery via gene expression analysis and WGCNA.
- Functional enrichment analysis and qPCR validation in mouse models.
Main Results:
- Thick ascending limb (TAL) cells, specifically cortical TAL (CTAL) and adaptive TAL (aTAL) subtypes, were identified as predominant and heterogeneous cell populations in RF.
- STAT1 and PARP8 were found to be upregulated, while HS6ST2, PTGER3, and TMEM207 were downregulated in RF.
- Functional enrichment analysis revealed associations with metabolic reprogramming and immune perturbation pathways.
Conclusions:
- CTAL and aTAL cells are central players in the development of renal fibrosis.
- Experimentally validated biomarkers offer potential therapeutic targets and drug repurposing opportunities for RF intervention.
