Nestin+ Cells Isolated From The Peritoneum Attenuate Peritoneal Fibrosis Via Suppressing IL-33 /ST2 Signaling

Abstract

Background The intermediate filament protein Nestin, a specific marker for multifunctional, multilineage progenitor cells, is regulated during the progression of reparative and reactive fibrosis in the liver, heart and kidney. However, whether Nestin regulates peritoneal fibrosis via suppressing IL-33/ST-2 signaling is unclear. Methods High-glucose peritoneal dialysis solution (PDS) or TGF-β1 was administered to a mouse peritoneal dialysis (PD) model to induce peritoneal fibrosis (PF) in vivo and to human peritoneal mesothelial cells (HPMCs) in vitro to stimulate accumulation of extracellular matrix (ECM). Nestin+ cells isolated from the peritoneum of Nestin-green fluorescent protein (GFP) transgenic mice were transplanted in vivo, and adeno-associated virus (AAV)-RNAi was used to silence IL-33 in vitro. Results Notably, Nestin was found in both the mouse peritoneum and HPMCs derived from PD effluent (PDE) and HMrSV5. These Nestin+ PMCs showed extensive proliferation for more than 20 passages. The mice that received chronic PDS infusions showed typical features of PF, including substantially increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and increased expression levels of α-smooth muscle actin (α-SMA) and collagen I (Col I). Nestin+ cells isolated from the peritoneum could significantly ameliorate these pathological changes. A parallel decrease in interleukin-33 (IL-33) and ST-2 accumulation in the peritoneum of Nestin+ cell-transplanted mice was observed. In addition, downregulation of IL-33 expression increased TGF-β1-induced ECM in the HPMCs. Conclusion Nestin+ cells isolated from the peritoneum had a clear protective effect on high-glucose PDS-induced PF by suppressing IL-33/ST-2 signaling.