Mechanisms and therapeutic effects of CX3CR1-engineered adipose-derived mesenchymal stem cell sheets in attenuating renal ischemia-reperfusion injury

Renal ischemia–reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) in a variety of clinical settings. Current therapeutic interventions are significantly constrained by limitations include low drug specificity, requisite repeated administration, and a paucity of effective treatments. Although mesenchymal stem cells (MSCs) based therapies exhibit treatment prospects for mitigating renal IRI, low retention and translational efficacy still hinder clinical application. To address these pivotal limitations, this study employed an innovative combinatorial approach integrating genetic engineering with cell sheet technology. Specifically, we generated genetically engineered CX3CR1 overexpressing MSCs sheets to investigate their therapeutic effects and mechanism in attenuating renal IRI in a rat model. Results showed that CX3CR1-MSCs cell sheets were positive for CD31, CD34, α-SMA and Fibronectin. In vivo, these sheets amplified MSCs paracrine effects, promoted the recruitment and polarization of M2 macrophage phenotype, stimulated renal vascularization, and inhibited fibrosis and inflammation. In vivo imaging in animals revealed genetically engineered cell sheets markedly improved the retention of MSCs in the kidney, enhancing both cell engraftment and paracrine therapeutic action. Our results indicate that CX3CR1-engineered MSCs sheets offer superior prevention against renal IRI.