Transforming growth factor-β1-overexpressing mesenchymal stromal cells induced local tolerance in rat renal ischemia/reperfusion injury.

Abstract

Regulatory T cells (Tregs) suppress excessive immune responses and play a crucial protective role in acute kidney injury (AKI). The aim of this study was to examine the therapeutic potential of transforming growth factor (TGF)-β1-overexpressing mesenchymal stromal cells (MSCs) in inducing local generation of Tregs in the kidney after ischemia/reperfusion (I/R) injury. MSCs were transduced with a lentiviral vector expressing the TGF-β1 gene; TGF-β1-overexpressing MSCs (designated TGF-β1/MSCs) were then transfused into the I/R-injured kidney via the renal artery. MSCs genetically modified with TGF-β1 achieved overexpression of TGF-β1. Compared with green fluorescent protein (GFP)/MSCs, TGF-β1/MSCs markedly improved renal function after I/R injury and reduced epithelial apoptosis and subsequent inflammation. The enhanced immunosuppressive and therapeutic abilities of TGF-β1/MSCs were associated with increased generation of induced Tregs and improved intrarenal migration of the injected cells. Futhermore, the mechanism of TGF-β1/MSCs in attenuating renal I/R injury was not through a direct canonical TGF-β1/Smad pathway. TGF-β1/MSCs can induce a local immunosuppressive effect in the I/R-injured kidney. The immunomodulatory activity of TGF-β1-modified MSCs appears to be a gateway to new therapeutic approaches to prevent renal I/R injury.