Bone mesenchymal stem cells pretreated with erythropoietin enhance the effect to ameliorate cyclosporine A‐induced nephrotoxicity in rats

et al. 2020

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Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI).The main drawbacks of MSC therapy including the lack of specific homing following systemic infusion and early death of the cells in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning promotes the therapeutic effect of the MSCs, although the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO on bone marrow mesenchymal stem cells (BMSCs) for the treatment of AKI. ResultsWe found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in the BMSCs, which was decreased following EPO pretreatment indicating that EPO protected the cells from apoptosis. Further, we found that EPO upregulated SIRT1 and Bcl-2 expression, and downregulated p53 expression. The EPO-mediated antiapoptotic mechanism in pretreated BMSCs may be mediated though the SIRT1 pathway. In a rat AKI model, our data showed that 24 h following intravenous infusion, GFP-BMSCs were predominantly in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs, and increased the distribution of the BMSCs to the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-a and significantly higher level of IL-10 compared to rats infused with BMSCs. The administration of EPO-BMSCs after reperfusion was more effective in reducing serum creatinine, blood urea nitrogen, and pathological scores in the I/R-AKI rats than BMSCs.Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs in improving renal function and pathological presentation in I/R-AKI rats. BackgroundAcute kidney injury (AKI) is one of the most clinically impactful diseases with high morbidity and mortality [1,2]. Multiple injuries such as those resulting from sepsis, ischemia/reperfusion (I/R), and drug administration may induce AKI. I/R injury is a major cause of human AKI, which is associated with tubular necrosis, cast formation, tubular dilation, loss of brush border, and inflammation [3]. AKI remains a worldwide public health concern due to the increased risk for subsequent development of 4 chronic kidney disease (CKD) [4]. The annual medical expenses associated with AKI treatment places a heavy burden on the public health care system, and yet AKI lacks an established treatment strategy. Therefore, there is an urgent need to find innovative and effective therapeutic strategies for AKI. The application of mesenchymal stem cells (MSCs) has been suggested as a potentially promising treatment strategy for AKI [5,6].In the recent years, MSCs have become an area of intense research in the field of stem cell therapy.MSCs are adherent, fibroblast-like cells, derived from different tissues and organs including bone marrow, umbilical cord blood, adipose tissue, and solid organs that have the potential for multidirectional diff...

Section: Discussionmentioning

confidence: 94%

“…These BMSCs significantly inhibited the apoptosis of HK2 cells from the toxicity of cyclosporin A (CsA). Moreover, the one-time infusion treatment with EPO-BMSCs significantly improved the renal function of CsA-induced chronic toxic renal injury, and promoted the repair of renal fibrosis in rats [18].…”

mentioning

confidence: 90%

Bone mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

et al. 2020

Preprint

Self Cite

“…After incubation with EPO, most of the cells exhibited parallelly-oriented laments organized along the cell axis. We observed that C-X-C chemokine receptor type 4 (CXCR4), a pivotal mediator of migration and engraftment in MSCs, was up-regulated following EPO treatment, enhancing the migration ability of BMSCs [20].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the single infusion treatment with EPO-BMSCs signi cantly improved the renal function in CsAinduced chronic toxic renal injury, and promoted the repair of renal brosis in rats [20].…”

Section: Introductionmentioning

confidence: 94%

Bone marrow derived mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

et al. 2020

Preprint

Self Cite

Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect; however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow derived mesenchymal stem cells (BMSCs) for AKI treatment. Results We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated SIRT1 and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did. Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.

“…These BMSCs signi cantly inhibited the apoptosis induced by cyclosporine A (CsA) toxicity in HK2 cells. Moreover, the single infusion treatment with EPO-BMSCs signi cantly improved the renal function in CsA-induced chronic toxic renal injury, and promoted the repair of renal brosis in rats [18].…”

Section: Introductionmentioning

confidence: 95%

Bone mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

et al. 2020

Preprint

Self Cite

Background: Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect; however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow mesenchymal stem cells (BMSCs) for AKI treatment.Results: We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated SIRT1 and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did.Conclusions: Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.