Chih-Yu Yang1,2,3,4,5, Pu-Yuan Chang6, Jun-Yi Chen6, Bo-Sheng Wu7, An-Hang Yang6,7,8, Oscar Kuang-Sheng Lee6,7,9,10. 1. Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, 2F, Shou-Ren Bldg., No.155, Sec.2, Li-Nong St., Beitou Dist, Taipei, 11221, Taiwan. cyyang3@vghtpe.gov.tw. 2. Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan. cyyang3@vghtpe.gov.tw. 3. Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, 11217, Taiwan. cyyang3@vghtpe.gov.tw. 4. Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan. cyyang3@vghtpe.gov.tw. 5. Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), Hsinchu, 30010, Taiwan. cyyang3@vghtpe.gov.tw. 6. Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, 2F, Shou-Ren Bldg., No.155, Sec.2, Li-Nong St., Beitou Dist, Taipei, 11221, Taiwan. 7. Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan. 8. Department of Pathology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan. 9. Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan. 10. Department of Orthopedics, China Medical University Hospital, Taichung, 40447, Taiwan.
Abstract
BACKGROUND: Life-long peritoneal dialysis (PD) as a renal replacement therapy is limited by peritoneal fibrosis. Previous studies showed immunomodulatory and antifibrotic effects of adipose-derived mesenchymal stem cells (ADSCs) on peritoneal fibrosis. However, the role of the peritoneal macrophage in this process remains uninvestigated. METHODS: We examined the therapeutic effects of ADSC and bone marrow-derived mesenchymal stem cells (BM-MSC) in the rat model of dialysis-induced peritoneal fibrosis using methylglyoxal. In addition, treatment of macrophages with the conditioned medium of ADSC and BM-MSC was performed individually to identify the beneficial component of the stem cell secretome. RESULTS: In the in vivo experiments, we found dialysis-induced rat peritoneal fibrosis was attenuated by both ADSC and BM-MSC. Interestingly, ADSC possessed a more prominent therapeutic effect than BM-MSC in ameliorating peritoneal membrane thickening while also upregulating epithelial cell markers in rat peritoneal tissues. The therapeutic effects of ADSC were positively associated with M2 macrophage polarization. In the in vitro experiments, we confirmed that interleukin-6 (IL-6) secreted by MSCs upon transforming growth factor-β1 stimulation promotes M2 macrophage polarization. CONCLUSIONS: In dialysis-induced peritoneal fibrosis, MSCs are situated in an inflammatory environment of TGF-β1 and secrete IL-6 to polarize macrophages into the M2 phenotype. Our findings reveal a previously unidentified role of tissue macrophage in this antifibrotic process. ADSC has the advantage of abundance and accessibility, making the application values extremely promising. In dialysis-induced peritoneal fibrosis, peritoneal mesothelial cells secrete transforming growth factor-β1 (TGF-β1) when exposed to methylglyoxal (MGO)-containing peritoneal dialysate. When situated in TGF-β1, the inflammatory environment induces mesenchymal stem cells to secrete interleukin-6 (IL-6), IL-6 polarizes macrophages into the M2 phenotype. The dominant peritoneal tissue M2 macrophages, marked by upregulated Arg-1 expression, account for the attenuation of MGO-induced dedifferentiation of peritoneal mesothelial cells to maintain epithelial integrity.
BACKGROUND: Life-long peritoneal dialysis (PD) as a renal replacement therapy is limited by peritoneal fibrosis. Previous studies showed immunomodulatory and antifibrotic effects of adipose-derived mesenchymal stem cells (ADSCs) on peritoneal fibrosis. However, the role of the peritoneal macrophage in this process remains uninvestigated. METHODS: We examined the therapeutic effects of ADSC and bone marrow-derived mesenchymal stem cells (BM-MSC) in the rat model of dialysis-induced peritoneal fibrosis using methylglyoxal. In addition, treatment of macrophages with the conditioned medium of ADSC and BM-MSC was performed individually to identify the beneficial component of the stem cell secretome. RESULTS: In the in vivo experiments, we found dialysis-induced rat peritoneal fibrosis was attenuated by both ADSC and BM-MSC. Interestingly, ADSC possessed a more prominent therapeutic effect than BM-MSC in ameliorating peritoneal membrane thickening while also upregulating epithelial cell markers in rat peritoneal tissues. The therapeutic effects of ADSC were positively associated with M2 macrophage polarization. In the in vitro experiments, we confirmed that interleukin-6 (IL-6) secreted by MSCs upon transforming growth factor-β1 stimulation promotes M2 macrophage polarization. CONCLUSIONS: In dialysis-induced peritoneal fibrosis, MSCs are situated in an inflammatory environment of TGF-β1 and secrete IL-6 to polarize macrophages into the M2 phenotype. Our findings reveal a previously unidentified role of tissue macrophage in this antifibrotic process. ADSC has the advantage of abundance and accessibility, making the application values extremely promising. In dialysis-induced peritoneal fibrosis, peritoneal mesothelial cells secrete transforming growth factor-β1 (TGF-β1) when exposed to methylglyoxal (MGO)-containing peritoneal dialysate. When situated in TGF-β1, the inflammatory environment induces mesenchymal stem cells to secrete interleukin-6 (IL-6), IL-6 polarizes macrophages into the M2 phenotype. The dominant peritoneal tissue M2 macrophages, marked by upregulated Arg-1 expression, account for the attenuation of MGO-induced dedifferentiation of peritoneal mesothelial cells to maintain epithelial integrity.
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