Implantation of dedifferentiated fat cells ameliorated antineutrophil cytoplasmic antibody glomerulonephritis by immunosuppression and increases in tumor necrosis factor-stimulated gene-6

Abstract

Introduction The implantation of dedifferentiated fat (DFAT) cells has been shown to exert immunosuppressive effects. To develop DFAT cell therapy for antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis, the effects of the implantation of DFAT cells on ANCA glomerulonephritis were investigated in mice. Methods PKH26-labeled DFAT cells (105) were infused through the posterior orbital venous plexus to investigate delivery of DFAT cells in ICR mice. DFAT cells (105) were also implanted in SCG mice as a model for ANCA glomerulonephritis. Expression of tumor necrosis factor-stimulated gene-6 (TSG-6) mRNA and protein in kidney was evaluated, and the expression of microRNAs associated with TSG-6 in plasma, lung and kidney was analyzed. Expressions of CD44, prostaglandin (PG) E2, interleukin (IL)-10, IL-1β, tumor necrosis factor (TNF)-α mRNAs, C–C motif chemokine ligand 17 (CCL-17) and monocyte chemoattractant protein (MCP)-1 proteins were measured in kidney from SCG mice implanted with DFAT cells. Results After their intravenous infusion, almost all DFAT cells were trapped in the lung and not delivered into the kidney. Implantation of DFAT cells in SCG mice suppressed glomerular crescent formation, decreased urinary protein excretions and increased expression of TSG-6 mRNA, protein and immunostaining in kidney from these mice. Increased expression of microRNA 23b-3p in plasma, kidney and lung; decreased expression of CD44 mRNA; and increased expression of PGE2 and IL-10 mRNAs were also observed in kidney from these mice. Implantation of DFAT cells also decreased the expression of TNF-α and MCP-1 proteins and increased that of CCL-17 protein in kidney from the SCG mice. Survival rates were higher in SCG mice implanted with DFAT cells than in SCG mice without implantation. Conclusion Mechanisms underlying the effects of improvement of ANCA glomerulonephritis are associated with immunosuppressive effects by TSG-6 and the transition of M1–M2 macrophages, suggesting that implantation of DFAT cells may become a cell therapy for ANCA glomerulonephritis.

TSG-6 (Tumor Necrosis Factor-α-Stimulated Gene/Protein-6): An Emerging Remedy for Renal Inflammation

“…These observations indirectly imply that DFAT cells, and by extension TSG-6, improve renal degeneration in monoclonal antibody-induced glomerulonephritis predominately secondary to immunosuppressive mechanisms. Furthermore, in antineutrophil cytoplasmic antibody glomerulonephritis, 57 DFAT cells suppressed glomerular crescent formation, decreased urinary protein excretion, and markedly upregulated kidney expression of TSG-6 mRNA and protein level, whereas CD44 mRNA declined. Therefore, DFAT cells may modulate immunoactivity by suppressing the activity and infiltration of immune cells via TSG-6.…”

Therapeutic potential of dedifferentiated fat cells in a rat model of osteoarthritis of the knee

“…Experimental evidence has shown the therapeutic potential of DFATs in animal models of various diseases, including osteochondral injuries [ [11] , [12] , [13] ]. In addition, in vitro and in vivo investigations have established the immunosuppressive effects of DFATs through TNF-α stimulated gene/protein 6 (TSG-6) [ 14 , 15 ]. DFATs can be prepared not only from subcutaneous adipose tissue (SC) but also from the infrapatellar fat pad (IFP) extracted during TKA.…”