Induced pluripotent stem cell-derived endothelial progenitor cells attenuate ischemic acute kidney injury and cardiac dysfunction

Abstract

BackgroundRenal ischemia–reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), which is associated with high morbidity and mortality. AKI is a serious and costly medical condition. Effective therapy for AKI is an unmet clinical need, and molecular mechanisms underlying the interactions between an injured kidney and distant organs remain unclear. Therefore, novel therapeutic strategies should be developed.MethodsWe directed the differentiation of human induced pluripotent stem (iPS) cells into endothelial progenitor cells (iEPCs), which were then applied for treating mouse AKI. The mouse model of AKI was induced by I/R injury.ResultsWe discovered that intravenously infused iEPCs were recruited to the injured kidney, expressed the mature endothelial cell marker CD31, and replaced injured endothelial cells. Moreover, infused iEPCs produced abundant proangiogenic proteins, which entered into circulation. In AKI mice, blood urea nitrogen and plasma creatinine levels increased 2 days after I/R injury and reduced after the infusion of iEPCs. Tubular injury, cell apoptosis, and peritubular capillary rarefaction in injured kidneys were attenuated accordingly. In the AKI mice, iEPC therapy also ameliorated apoptosis of cardiomyocytes and cardiac dysfunction, as indicated by echocardiography. The therapy also ameliorated an increase in serum brain natriuretic peptide. Regarding the relevant mechanisms, indoxyl sulfate and interleukin-1β synergistically induced apoptosis of cardiomyocytes. Systemic iEPC therapy downregulated the proapoptotic protein caspase-3 and upregulated the anti-apoptotic protein Bcl-2 in the hearts of the AKI mice, possibly through the reduction of indoxyl sulfate and interleukin-1β.ConclusionsTherapy using human iPS cell-derived iEPCs provided a protective effect against ischemic AKI and remote cardiac dysfunction through the repair of endothelial cells and the attenuation of cardiomyocyte apoptosis.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1092-x) contains supplementary material, which is available to authorized users.

Stem cells: a potential treatment option for kidney diseases

“…Interestingly, iEPC therapy also ameliorated apoptosis of cardiomyocytes and cardiac dysfunction and no GFP-iEPCs in mouse hearts were observed. It was speculated that the protective effect of iEPC therapy on the heart may have resulted from the reduction of uremic toxin IS and proinflammatory IL-1β in circulation [205]. In addition, the injection of kidney SP cells into the AKI model demonstrated the recovery of renal function [198,199].…”

Human urine-derived stem cells protect against renal ischemia/reperfusion injury in a rat model via exosomal miR-146a-5p which targets IRAK1

“…Stem cell therapy represents a promising new frontier in the treatment of renal diseases 8 . Many types of stem cells, including mesenchymal stem cells (MSCs), spermatogonial stem cells, induced pluripotent stem cells (iPSCs) and the cells derived from iPSCs have been found to either attenuate kidney dysfunction or stabilize morphological changes in renal IRI 9 , 10 . Treatments with MSCs specifically have entered clinical trials 11 .…”

Therapeutic Potential of Human Induced Pluripotent Stem Cells and Renal Progenitor Cells in Experimental Chronic Kidney Disease

“…Some mechanisms have been proposed to explain the bene cial effect of cell therapy on improving renal injury, especially with the use of iPSCs and RPCs [2,17,18,22,[33][34][35][36][37][38][39]. RPCs can differentiate in vivo by forming renal tubules and acting through pro-proliferative, anti-apoptotic and anti-in ammatory effects [22], as well as by integrating into the kidney [17], decreasing the level of vascular rarefaction and preventing endothelial mesenchymal transition [18].…”