Acute kidney injury (AKI) is defined as a rapid loss of renal function resulting from various etiologies, with a mortality rate exceeding 60% among intensive care patients. Because conventional treatments have failed to alleviate this condition, the development of regenerative therapies using human induced pluripotent stem cells (hiPSCs) presents a promising new therapeutic option for AKI. We describe our methodology for generating renal progenitors from hiPSCs that show potential in ameliorating AKI. We established a multistep differentiation protocol for inducing hiPSCs into OSR1 + SIX2 + renal progenitors capable of reconstituting three-dimensional proximal renal tubule-like structures in vitro and in vivo. Moreover, we found that renal subcapsular transplantation of hiPSC-derived renal progenitors ameliorated the AKI in mice induced by ischemia/reperfusion injury, significantly suppressing the elevation of blood urea nitrogen and serum creatinine levels and attenuating histopathological changes, such as tubular necrosis, tubule dilatation with casts, and interstitial fibrosis. To our knowledge, few reports demonstrating the therapeutic efficacy of cell therapy with renal lineage cells generated from hiPSCs have been published. Our results suggest that regenerative medicine strategies for kidney diseases could be developed using hiPSC-derived renal cells. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:980-992
SIGNIFICANCEThis report is the first to demonstrate that the transplantation of renal progenitor cells differentiated from human induced pluripotent stem (iPS) cells has therapeutic effectiveness in mouse models of acute kidney injury induced by ischemia/reperfusion injury. In addition, this report clearly demonstrates that the therapeutic benefits come from trophic effects by the renal progenitor cells, and it identifies the renoprotective factors secreted by the progenitors. The results of this study indicate the feasibility of developing regenerative medicine strategy using iPS cells against renal diseases.
The electrochemical instability has been shown to appear in the transfer of cationic surfactant ions across the 1,2-dichloroethane/water interface. Cyclic voltammograms possess all fundamental characteristics that are predicted by the theory of electrochemical instability: the presence of the instability window, that is, the potential range where the interface becomes unstable, the location of the instability window around the standard ion transfer potential of surface-active ions, and the dependence of the width of the instability window on the concentration of the surfactant ions. Electrocapillary measurements clearly demonstrate that the interface becomes unstable, while the interfacial tension is positive, being higher than 20 mN m(-1). The electrocapillary curve exhibits the discontinuities at both ends of the instability window, indicating the similarity between the electrochemical instability and the phase transitions induced by the temperature, pressure, and chemical potential. The results from voltammetry and interfacial tension measurements for cationic surfactants support the idea that the electrochemical instability, so far reported in the transfer of anionic surfactants across the liquid/liquid interface, is one of intrinsic properties of the two-phase systems where the partition of surface-active ions takes place.
Irregular current spikes and other anomalies seen in voltammetry of the transfer of anionic surfactants, alkyl sulfonates, and alkyl sulfates across the 1,2-dichloroethane/water (DCE/W) interface are reproducible. The anomalies have a certain regularity that is predicted by a recently proposed concept, the electrochemical instability. Irregular current spikes follow after the augmentation of the current induced when the phase-boundary potential is brought close to the mid-point potential of the transferring surfactant ions. Potential-step chronoamperometry clearly demonstrates the presence of the instability window, that is, the potential region where the interface becomes unstable only in the limited range of the phase-boundary potential.
Recent studies using human pluripotent stem cells (hPSCs) have developed protocols to induce kidney-lineage cells and reconstruct kidney organoids. However, the separate generation of metanephric nephron progenitors (NPs), mesonephric NPs, and ureteric bud (UB) cells, which constitute embryonic kidneys, in in vitro differentiation culture systems has not been fully investigated. Here, we create a culture system in which these mesoderm-like cell types and paraxial and lateral plate mesoderm-like cells are separately generated from hPSCs. We recapitulate nephrogenic niches from separately induced metanephric NP-like and UB-like cells, which are subsequently differentiated into glomeruli, renal tubules, and collecting ducts in vitro and further vascularized in vivo. Our selective differentiation protocols should contribute to understanding the mechanisms underlying human kidney development and disease and also supply cell sources for regenerative therapies.
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