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Stem Cells Transl Med. 2015 Sep;4(9):980-92. doi: 10.5966/sctm.2014-0219. Epub 2015 Jul 21.

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

Author information

1
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Clinical Research Center, Chiba University of Medicine, Chiba, Japan; Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
2
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Clinical Research Center, Chiba University of Medicine, Chiba, Japan; Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA osafu@cira.kyoto-u.ac.jp.

Abstract

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.

KEYWORDS:

Acute kidney injury; Cell- and tissue-based therapy; Induced pluripotent stem cells; Kidney; Nephrons; Renal progenitors; SIX2 protein

PMID:
26198166
PMCID:
PMC4542865
DOI:
10.5966/sctm.2014-0219
[Indexed for MEDLINE]
Free PMC Article

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