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Abstract: PO1724

The Mesenchymal Stem Cell Marker Meflin Defines a Novel Subset of Renal Fibroblasts and Counteracts the Action of TGF-β

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Minatoguchi, Shun, Nagoya university graduate school of Medicine, Department of Nepgrology, Nagoya, Aichi, Japan
  • Saito, Shoji, Nagoya university graduate school of Medicine, Department of Nepgrology, Nagoya, Aichi, Japan
  • Maruyama, Shoichi, Nagoya university graduate school of Medicine, Department of Nepgrology, Nagoya, Aichi, Japan
Background

Fibroblasts proliferation is the hallmark of renal fibrosis and is important for the progression of CKD. Recently developed single-cell sequencing technology has revealed the substantial heterogeneity of cells that constitute the kidney in health and disease. The heterogeneity of renal fibroblasts, however, has not been completely understood. We recently reported that a fibroblast subset marked by Meflin, a marker of undifferentiated mesenchymal stem cells, has a role to suppress fibrosis in cardiac disease conditions and pancreatic cancer. In the present study, we examined the role of Meflin and the distribution of Meflin-positive fibroblasts in kidney by using cultured fibroblasts and mouse models.

Methods

We evaluated the expression of Meflin in normal and fibrotic kidney by in situ hybridization(ISH). To assess the expression of Meflin at a cellular level, we used the rat renal fibroblast cell line NRK49f.

Results

ISH revealed that Meflin was expressed by some rare stromal cells found in the interstitial and peri-glomerular areas in the normal kidney. Meflin-positive cells were also detected in the wall of middle-sized vessels in the medulla of the kidney. Induction of renal fibrosis by obstructive nephropathy(UUO model) led to a significant proliferation of Meflin-positive cells, which seemed to be distinct from αSMA positive myofibroblasts. Consistent with this, the analysis of single-cell transcriptomic databases showed Meflin and αSMA are expressed in distinct subsets of fibroblasts in the kidney. The expression pattern of Meflin was also confirmed by lineage tracing assay. In the UUO model, some of Meflin-lineage cells were positive for αSMA, suggesting that they give rise to myofibroblasts in the progression of fibrosis.
Finally, we assessed the function of Meflin using NRK49f. Meflin expression was significantly downregulated by TGFβ stimulation, and exogenous Meflin overexpression led to the suppression of TGFβ induced αSMA and vimentin expression.

Conclusion

Our present study identified a new subset of renal fibroblasts, which is positive for Meflin but negative or weakly positive for α-SMA. Consistent with our previous studies, Meflin has a role to counteract the action of TGF-β, implying that Meflin-positive fibroblasts have a role to suppress or alleviate renal fibrosis.

Funding

  • Private Foundation Support