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Abstract: TH-PO645

Hypoxia-Preconditioned Mesenchymal Stem Cells Attenuate Renal Fibrosis by Upregulating Renal M2 Macrophage Polarization

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

  • Tseng, Wei-Cheng, Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
  • Chen, Nien-Jung, National Yang-Ming University, Taipei, Taiwan
  • Hung, Shih-Chieh, China Medical University, Taichung, Taiwan
  • Tarng, Der-Cherng, Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital; Institute of Clinical Medicine, Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan
Background

Tubulointerstitial fibrosis is the final common pathway of all kidney diseases and also represents the major determinant of renal function decline. Infiltrating renal macrophages critically govern the homeostasis of renal fibrogenesis and the extent of renal interstitial fibrosis. M1 macrophages release pro-inflammatory cytokines and result in tissue destruction; conversely, M2 macrophages secrete anti-inflammatory cytokines and promote tissue repair. Mesenchymal stem cells (MSCs) are promising cell-based therapy and previously we have shown hypoxia-preconditioned MSCs (HMSCs) exhibited better anti-inflammatory and anti-apoptotic effects. Nonetheless, whether HMSCs attenuate renal interstitial fibrosis through modulating the phenotype of infiltrating macrophages remains unclear.

Methods

Male C57BL/6J mice undergoing unilateral ureteral obstruction (UUO) were administered either phosphate-buffered saline, normoxic MSCs or HMSCs. Histology, fibrosis content, inflammation markers and macrophage phenotypes were analyzed in the obstructed kidney tissue. In vitro, we also determined the phenotypic change and inflammatory gene expression in M1 macrophages after coculture either with normoxic MSCs or HMSCs.

Results

The extent of fibrosis in UUO-injured kidney was significantly decreased by HMSCs treatment as compared with normoxic MSCs or phosphate-buffered saline. Interestingly, HMSCs significantly decreased the number of inducible nitric oxide synthase (iNOS)-positive M1 macrophages and contributed to early expression of arginase (Arg)-1-positive M2 macrophages in obstructed kidney than normoxic MSCs, suggesting that HMSCs facilitated an M1-to-M2 phenotypic transition in obstructed kidneys. Flow cytometry, immunoblotting and real-time polymerase chain reaction analysis also demonstrated that HMSCs downregulated STAT-1, iNOS expression and upregulating mannose receptor and Arg-1 expression. Furthermore, HMSCs treatment resulted in more anti-inflammatory M2c macrophages and less pro-fibrotic M2a macrophages infiltration in obstructive kidneys.

Conclusion

HMSCs treatment reduced renal fibrosis and facilitated an early M1-to-M2 phenotypic change of renal macrophages in mice UUO, predominantly upregulating M2c macrophages. HMSCs can be a promising therapeutic approach for the inflammatory fibrotic kidney diseases.

Funding

  • Government Support - Non-U.S.