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. 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.

Novel regenerative therapy for acute kidney injury

“…Our results demonstrate that the transplantation of renal progenitors derived from human iPSCs has therapeutic benefits against AKI, mainly by producing trophic effects [41].…”

“…Our group has reported methods for inducing renal progenitor cells from human iPSCs/ESCs using stepwise differentiation and chemical biology strategies [41,45,46]. By screening growth factors and chemical compounds that can induce renal progenitor cells from human iPSCs, we could induce OSR1 + IM cells and OSR1 + SIX2 + renal progenitors.…”

“…Recently, two reports including one from our group have shown the therapeutic effects of renal progenitor cells differentiated from human iPSCs against AKI [41,42]. Because of the potential to infinitely proliferate and bypass immunorejection issues, iPSCs are considered a more stable and suitable cell source for renal stem/progenitor cells.…”

“…CHIR99021 an inhibitor of glycogen synthase kinase 3 (GSK3), TTNPB an analog of retinoic acid, DMH1 a selective BMP antagonist, FBS fetal bovine serum, P/SM penicillin streptomycin, KSR knockout serum replacement, 2ME 2-mercaptoethanol, NEAA non-essential amino acid, BMP bone morphogenetic protein, TGF transforming growth factor. Adapted from Toyohara et al [41] model. While the differentiation protocol and the type of AKI mouse model were different from our report, the transplantation of renal progenitors in their study also improved AKI.…”

“…+ renal progenitors, we derived OSR1-GFP/SIX2-tdTomato double knockin human iPSC lines [41]. We differentiated the human iPSC line into OSR1 + IM cells using our robust differentiation protocol and then screened for growth factors and compounds that can further differentiate OSR1 + IM cells into OSR1 + SIX2…”