Intraparenchymal Injection of Bone Marrow Mesenchymal Stem Cells Reduces Kidney Fibrosis after Ischemia-Reperfusion in Cyclosporine-Immunosuppressed Rats

Abstract

Ischemia-reperfusion and immunosuppressive therapy are a major cause of progressive renal failure after kidney transplantation. Recent studies have shown that administration of bone marrow mesenchymal stem cells (MSCs) improves kidney functional recovery in the acute phase of post ischemia-reperfusion injury. In the present study, we used an original model of renal ischemia-reperfusion in immunosuppressed rats (NIRC) to investigate the effects of bone marrow MSCs on progression of chronic renal failure and the mechanisms potentially involved. Left renal ischemia-reperfusion (IR) was induced in unilateral nephrectomized Lewis rats. After IR, rats were treated daily with cyclosporine (10 mg/kg SC) for 28 days. MSCs were injected into the kidney at day 7 after IR. At day 28 after IR, kidneys were removed for histomorphological, biochemical, and gene expression analysis. The effect of conditioned media from MSCs on epithelial-mesenchymal transition was studied in vitro on HK2 cells. Our results show that, as compared to untreated NIRC rats, rats treated by intrarenal injection of MSCs 7 days after IR displayed improvement in renal function, reduction of interstitial fibrosis, and decrease in chronic tubule injury. These effects were associated with a decrease in interstitial a-SMA accumulation and MMP2 activity, markers of fibroblast/fibroblast-like cell activation, and renal remodeling, respectively. Finally, experiments in vitro showed that MSC-conditioned medium prevented epithelial-mesenchymal transition induced by TGF-b in HK2 cells. In conclusion, our results show that, in immunosuppressed animals, a single intrarenal administration of MSCs reduced renal fibrosis and promoted the recovery of renal function.

IGF-1 C Domain–Modified Hydrogel Enhances Cell Therapy for AKI

“…In rodent models, MSCs retard the progression of CKD by suppressing fibrosis. [37][38][39] Our study confirmed this effect and further demonstrated that MSC therapy with CS-IGF-1C hydrogel showed increased attenuation of fibrosis by substantially inhibiting expression of MMPs; this has been implicated in initiation and progression of renal fibrosis through epithelialmesenchymal transition as well as activation of fibroblasts. 40 Concordantly, cotransplantation of ADSCs and CS-IGF-1C hydrogel led to downregulated expression of a range of profibrotic genes, such as TGF-b, collagen type 1 a1, and fibronectin, in addition to increased expression of antifibrotic genes after AKI.…”

Effect of adipose tissue-derived stem cell injection in a rat model of urethral fibrosis

“…19 Furthermore, several animal studies determined that the administration of mesenchymal-derived stem cells significantly reduced fibrosis in the lung, kidney, and liver. [12][13][14] There are, however, no reports of stem cell-based therapy in the clinical management of urethral stricture disease. Our study is a proofof-concept study that demonstrates that local injection of ADSCs prevents fibrosis induced by TGF-β1 injection.…”

“…11 Furthermore, a number of animal studies have demonstrated that mesenchymal stem cells have antifibrotic properties that can reduce fibrosis in the lung, kidney, and liver. [12][13][14] We sought to evaluate the potential therapeutic benefits of adipose-derived stem cell (ADSCs) therapy in decreasing fibrotic tissue in a rat model of urethral fibrosis.…”

Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats

“…Direct parenchymal injection allows efficient local delivery of MSCs and promotes the recovery of renal fuction. 29 However, the locally delivered MSCs tend to be confined to the injection site without diffusion to the whole kidney. Furthermore, this invasive method may cause bleeding and tissue destruction leading to secondary kidney damage and adverse effect on renal function recovery.…”