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Abstract: FR-PO395

Hypoxic Mesenchymal Stem Cells-Derived Extracellular Vesicles Suppress Renal Fibrosis by Downregulating Rheb/mTOR Signaling

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Tseng, Wei-Cheng, Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
  • Tarng, Der-Cherng, Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Background

Renal interstitial fibrosis, characterized by overactivated myofibroblasts and excessive deposition of extracellular matrix, is the final common pathway of all kinds of renal diseases. Recent evidence suggests that Rheb/mTOR signaling may activate renal fibroblasts and promote renal fibrosis. Till now, specific treatment targeting the pathophysiology of renal fibrosis remains an unmet medical need. Hypoxic mesenchymal stem cells (HMSC) represent novel frontiers in treating organ fibrosis. HMSCs can confer their paracrine therapeutic effects through the secreted extracellular vesicles (EVs), which are small membrane vesicles as a novel form of intercellular communication. Nevertheless, the detailed mechanisms that underlie the therapeutic effect of HMSC-EVs remain to be investigated.

Methods

HMSC-EVs were first isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis, immunoblotting, and flow cytometry. After subjected to unilateral ureteral obstruction (UUO), 6-week-old male C57BL/6 mice were administered HMSC-EVs intravenously. In vitro, renal proximal NRK-52E epithelial cells were treated with transforming growth factor-beta 1 in the presence or absence of HMSC-EVs. The extent of renal fibrosis and the relevant pathomechanism of Rheb/mTOR signaling were investigated by histology, immunoblotting, and immunohistochemistry.

Results

We found the injured renal tubular cells can incorporate the HMSC-EVs, which further reduced renal fibrosis both in vivo and in vitro. HMSC-EVs not only effectively reduced UUO-induced renal interstitial fibrosis but also suppressed the expression of alpha-smooth muscle actin and fibronectin expression in vitro. Notably, HMSC-EVs decreased the expression of profibrotic Rheb in the UUO-injured renal tubular epithelial cells. Moreover, HMSC-EVs also inhibited mTOR and p70S6K expression in the obstructed kidneys.

Conclusion

The present study was the first to uncover the anti-fibrotic role of HMSC-EVs by suppressing Rheb-mTOR-p70S6K signaling in renal fibrosis. Our findings shed new light on the therapeutic effect of HMSC-EVs, and provide the bench evidence for applying the HMSC-EVs to treat patients with fibrotic kidney diseases.