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Single-cell RNA transcriptomic reveal the mechanism of MSC derived small extracellular vesicles against DKD fibrosis
Cheng Ji1,2, Jiahui Zhang2, Hui Shi2
1Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Chang Zhou, Jiangsu, 213004, China.
Abstract:
Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-β1+Arg1+ macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+ mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-β1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/β-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.
Insights
Mesenchymal stem cell-derived extracellular vesicles (MSC-sEVs) offer a novel treatment for diabetic kidney disease (DKD) fibrosis. They target profibrotic macrophages and mesangial cells, reducing renal fibrosis by modulating the YAP signaling pathway.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Diabetic kidney disease (DKD) is a chronic kidney disease marked by progressive fibrosis due to hyperglycemia, with limited treatment options.
- Fibrosis development significantly impacts patient prognosis in DKD.
Purpose of the Study:
- To investigate the therapeutic potential of mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) for DKD fibrosis.
- To elucidate the cellular and molecular mechanisms underlying MSC-sEVs' effects on the DKD fibrosis niche.
Main Methods:
- Single-cell RNA sequencing of 27,424 kidney cells to identify cell subpopulations and communication pathways.
- Transcriptome sequencing and LC-MS/MS analysis to assess molecular changes after MSC-sEV intervention.
- Analysis of ligand-receptor interactions and cell-communication networks.
Main Results:
- A novel profibrogenic macrophage subpopulation (TGF-β1+Arg1+) was identified and expanded in DKD kidneys.
- Actin+Col4a5+ mesangial cells differentiated into myofibroblasts, contributing to fibrosis.
- MSC-sEVs were found to restore kinase ubiquitin system levels and attenuate fibrosis by mediating YAP degradation via CK1δ/β-TRCP.
Conclusions:
- MSC-sEVs demonstrate a unique therapeutic strategy for DKD fibrosis at a single-cell level.
- The study reveals that MSC-sEVs target fibrosis-associated macrophages and mesangial cells, modulating the TGF-β1/Smad2/3/YAP axis.
- MSC-sEVs offer a promising novel therapeutic approach for renal fibrosis in DKD.
