Microparticles derived from human erythropoietin mRNA-transfected mesenchymal stem cells inhibit epithelial-to-mesenchymal transition and ameliorate renal interstitial fibrosis

Stem Cell Research & Therapy

Hyung Jong Kim¹  Jong Hyun Jhee²  Tae Yeon Kim²  Seok-hyung Kim³  Hoon Young Choi⁴  Mirae Lee⁵  Hyeong Cheon Park⁶ 

[1] Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Korea;Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea;Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea;Division of Nephrology, Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Gangwon-do, Korea;Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea;Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea;Graduate Program of Nano Science and Technology, Yonsei University, Seoul, Korea;Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea;Graduate Program of Nano Science and Technology, Yonsei University, Seoul, Korea;Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea;Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea;

关键词: Microparticles;    Transforming growth factor-β1;    Renal fibrosis;    Epithelial-to-mesenchymal transition;    Erythropoietin;   

DOI  :  10.1186/s13287-020-01932-z

来源: Springer

【 摘 要 】

BackgroundRenal tubulointerstitial fibrosis (TIF) plays an important role in the progression of chronic kidney disease (CKD) and its pathogenesis involves epithelial-to-mesenchymal transition (EMT) upon renal injury. Recombinant human erythropoietin (rhEPO) has been shown to display novel cytoprotective effects, in part by inhibiting transforming growth factor (TGF)-β1-induced EMT. Here, we evaluated the inhibitory effects of microparticles (MPs) derived from human EPO gene-transfected kidney mesenchymal stem cells (hEPO-KMSCs) against TGF-β1-induced EMT in Madin-Darby canine kidney (MDCK) cells and against TIF in mouse kidneys with unilateral ureteral obstruction (UUO).MethodsEMT was induced in MDCK cells by treatment with TGF-β1 (5 ng/mL) for 48 h and then inhibited by co-treatment with rhEPO (100 IU/mL), mock gene-transfected KMSC-derived MPs (MOCK-MPs), or hEPO-KMSC-derived MPs (hEPO-MPs) for a further 48 h. UUO was induced in FVB/N mice, which were then treated with rhEPO (1000 IU/kg, intraperitoneally, every other day for 1 week), MOCK-MPs, or hEPO-MPs (80 μg, intravenously). Alpha-smooth muscle actin (α-SMA), fibronectin, and E-cadherin expression were evaluated in MDCK cells and kidney tissues, and the extent of TIF in UUO kidneys was assessed by immunohistochemical staining.ResultsTGF-β1 treatment significantly increased α-SMA and fibronectin expression in MDCK cells and decreased that of E-cadherin, while co-treatment with rhEPO, MOCK-MPs, or hEPO-MPs markedly attenuated these changes. In addition, rhEPO and hEPO-MP treatment effectively decreased phosphorylated Smad2 and Smad3, as well as phosphorylated p38 mitogen-activated protein kinase (MAPK) expression, suggesting that rhEPO and rhEPO-MPs can inhibit TGF-β1-induced EMT via both Smad and non-Smad pathways. rhEPO and hEPO-MP treatment also significantly attenuated the extent of renal TIF after 1 week of UUO compared to MOCK-MPs, with hEPO-MPs significantly reducing myofibroblast and F4/80+ macrophage infiltration as well as EMT marker expression in UUO renal tissues in a similar manner to rhEPO.ConclusionsOur results demonstrate that hEPO-MPs modulate TGF-β1-induced EMT in MDCK cells via the Smad2, Smad3, and p38 MAPK pathways and significantly attenuated renal TIF in UUO kidneys.

【 授权许可】

CC BY