(F1204) TONSIL-DERIVED MESENCHYMAL STEM CELLS AMELIORATED PERITONEAL EPITHELIAL-TO-MESENCHYMAL TRANSITION AND FIBROSIS VIA A MITIGATION OF OXIDATIVE STRESS
Abstract: Mesenchymal stem cells (MSCs) are multipotent adult stem cells with regenerative capabilities and exert paracrine actions on damaged tissues. The epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs) is an early mechanism of peritoneal dysfunction in peritoneal dialysis (PD). MSCs have recently attracted attention for their ability to prevent organ fibrosis by inhibiting EMT. This study investigates the role of T-MSCs in TGFβ-induced EMT of human peritoneal mesothelial cells (HPMCs) and its underlying mechanism. An animal model of PD was established in Sprague-Dawley rats by daily infusion of glucose-based dialysate with methylglyoxal for three weeks. T-MSCs (5 x 10^6) were administered intraperitoneally on day 14. Expression of markers of EMT and oxidative stress were evaluated in peritoneal membrane with the peritoneal equilibrium test (PET) and histologic analysis. HPMCs were co-cultured with MSCs or MSC-conditioned medium (CM) using a transwell co-culture system to evaluate EMT, reactive oxygen species (ROS) generation, and the expression of antioxidant enzymes and anti-fibrotic proteins. Comparative analyses were performed using T-MSC, adipose-derived MSCs (AD-MSC) or bone marrow-derived MSCs (BM-MSC). PD+T-MSCs rats had improved D2/D0 glucose and D/P creatinine ratios compared to PD rats. Anti-human nuclei staining revealed scattered positive signals along the peritoneal mesothelial layer in PD +T-MSCs rats. In PD+T-MSCs, EMT and peritoneal fibrosis were alleviated with the restoration of oxidant-antioxidant balance as evidenced by decreased expression of 8-OHdG, NT, and 4-HNE, along with increased GSH and SOD2 in peritoneal membrane. Co-culture of HPMCs with T-MSCs or T-MSC-CM inhibited TGFβ-induced EMT and ROS generation. T-MSCs expressed higher levels of antioxidant enzymes (catalase, GPx, and SOD) and anti-fibrotic proteins (HGF and BMP-7) compared to AD-MSCs and BM-MSCs. TGF-β-induced reduction in expressions of antioxidant enzyme and antifibrotic peptides in HPMCs were restored by T-MSC-CM. These findings highlight the anti-fibrotic and antioxidant effects of T-MSCs, suggesting their therapeutic potential in preventing peritoneal dysfunction and fibrosis in PD patients.
Funding Source: This work was supported by the Korean Fund for Regenerative Medicine (KFRM, 23A0201L1) grant funded by the Korea government (MIST).
