title: Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Toyohara
authors.affiliation: 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.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Mae
authors.affiliation: 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.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Sueta
authors.affiliation: 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.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Inoue
authors.affiliation: 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.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamagishi
authors.affiliation: 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.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: 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.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kasahara
authors.affiliation: 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.
authors.forename: Azusa
authors.initials: A
authors.lastname: Hoshina
authors.affiliation: 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.
authors.forename: Taro
authors.initials: T
authors.lastname: Toyoda
authors.affiliation: 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.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: 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.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Araoka
authors.affiliation: 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.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: 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.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: 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.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: 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.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamaji
authors.affiliation: 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.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: 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.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: 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.
authors.forename: Kenji
authors.initials: K
authors.lastname: Osafune
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001806:Blood Urea Nitrogen; D002454:Cell Differentiation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D005355:Fibrosis; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D007684:Kidney Tubules / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D019459:Urothelium / Q000166:cytology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C498490:OSR1 protein, human; C484762:SIX2 protein, human; D014157:Transcription Factors; D003404:Creatinine
keywords: Acute kidney injury; Cell- and tissue-based therapy; Induced pluripotent stem cells; Kidney; Nephrons; Renal progenitors; SIX2 protein