Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice.

UNLABELLED: 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. SIGNIFICANCE: This 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.

Transgenic mouse expressing human CCR5 as a model for in vivo assessments of human selective CCR5 antagonists.

The species selectivity of receptor antagonists often hinders their preclinical assessment in vivo. In order to evaluate human selective CC chemokine receptor type 5 (CCR5) antagonists in vivo, we generated human CCR5 transgenic mice that expressed the transgene on both peripheral blood leukocytes as well as thymocytes. The selective CCR5 ligand CC chemokine ligand 4 (CCL4)/macrophage inflammatory protein (MIP)-1beta induced the chemotaxis of thymocytes that had been derived from the transgenic mice, but not from littermate mice, suggesting that the human CCR5 expressed in the transgenic mice were functional. The binding of the human CCR5 specific antibody 45531 to peripheral blood granulocytes from the transgenic mice was inhibited by human selective CCR5 antagonist SCH-351125. Using this antibody, we developed an ex vivo assay system that is suitable for the evaluation of a test compound's ability to occupy the human CCR5 receptor on mouse peripheral blood leukocytes. This transgenic mouse model is useful for estimating the pharmacodynamics of human selective CCR5 antagonists in vivo.