Dataset Information

Generation of Functioning Nephrons by Implanting Human Pluripotent Stem Cell-Derived Kidney Progenitors.

ABSTRACT: Human pluripotent stem cells (hPSCs) hold great promise for understanding kidney development and disease. We reproducibly differentiated three genetically distinct wild-type hPSC lines to kidney precursors that underwent rudimentary morphogenesis in vitro. They expressed nephron and collecting duct lineage marker genes, several of which are mutated in human kidney disease. Lentiviral-transduced hPSCs expressing reporter genes differentiated similarly to controls in vitro. Kidney progenitors were subcutaneously implanted into immunodeficient mice. By 12 weeks, they formed organ-like masses detectable by bioluminescence imaging. Implants included perfused glomeruli containing human capillaries, podocytes with regions of mature basement membrane, and mesangial cells. After intravenous injection of fluorescent low-molecular-weight dextran, signal was detected in tubules, demonstrating uptake from glomerular filtrate. Thus, we have developed methods to trace hPSC-derived kidney precursors that formed functioning nephrons in vivo. These advances beyond in vitro culture are critical steps toward using hPSCs to model and treat kidney diseases.

SUBMITTER: Bantounas I

PROVIDER: S-EPMC5918196 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

Generation of Functioning Nephrons by Implanting Human Pluripotent Stem Cell-Derived Kidney Progenitors.

Bantounas Ioannis I Ranjzad Parisa P Tengku Faris F Silajdžić Edina E Forster Duncan D Asselin Marie-Claude MC Lewis Philip P Lennon Rachel R Plagge Antonius A Wang Qi Q Woolf Adrian S AS Kimber Susan J SJ

Stem cell reports 20180208 3

Human pluripotent stem cells (hPSCs) hold great promise for understanding kidney development and disease. We reproducibly differentiated three genetically distinct wild-type hPSC lines to kidney precursors that underwent rudimentary morphogenesis in vitro. They expressed nephron and collecting duct lineage marker genes, several of which are mutated in human kidney disease. Lentiviral-transduced hPSCs expressing reporter genes differentiated similarly to controls in vitro. Kidney progenitors were ...[more]

PMID: 29429961

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Project description:UnlabelledAcute 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.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.

Dataset Information

Generation of Functioning Nephrons by Implanting Human Pluripotent Stem Cell-Derived Kidney Progenitors.

Publications

Generation of Functioning Nephrons by Implanting Human Pluripotent Stem Cell-Derived Kidney Progenitors.

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