Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors

Hiratsuka, Ken; Monkawa, Toshiaki; Akiyama, Tasuku; Nakatake, Yuhki; Oda, Mayumi; Goparaju, Sravan K.; Kimura, Hiromi; Chikazawa-Nohtomi, Nana; Sato, Saeko; Ishiguro, Kei‐ichiro; Yamaguchi, Shintaro; Suzuki, Shingo; Morizane, Ryuji; Ko, Shigeru B. H.; Itoh, Hiroshi; Ko, Minoru S.H.

doi:10.1038/s41598-018-37485-8

Cited by 51 publications

(46 citation statements)

References 68 publications

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“…Among various candidates, iPSCs have shown promising therapeutic potential for kidney disorders 40–42 . This is supported by several studies demonstrating the differentiation of iPSCs into renal lineage 20,34,43,44 and organoids 45,46 as well as their capabilities for in-vivo transplantation 47,48 and generating complex kidney structures 49,50 .…”

Section: Discussionmentioning

confidence: 70%

RETRACTED ARTICLE: Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

Ahmadi

Moghadasali

Ezzatizadeh

et al. 2019

Sci Rep

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Injury to podocytes is a principle cause of initiation and progression of both immune and non-immune mediated glomerular diseases that result in proteinuria and decreased function of the kidney. Current advances in regenerative medicine shed light on the therapeutic potential of cell-based strategies for treatment of such disorders. Thus, there is hope that generation and transplantation of podocytes from induced pluripotent stem cells (iPSCs), could potentially be used as a curative treatment for glomerulonephritis caused by podocytes injury and loss. Despite several reports on the generation of iPSC-derived podocytes, there are rare reports about successful use of these cells in animal models. In this study, we first generated a model of anti-podocyte antibody-induced heavy proteinuria that resembled human membranous nephropathy and was characterized by the presence of sub-epithelial immune deposits and podocytes loss. Thereafter, we showed that transplantation of functional iPSC-derived podocytes following podocytes depletion results in recruitment of iPSC-derived podocytes within the damaged glomerulus, and leads to attenuation of proteinuria and histological alterations. These results provided evidence that application of iPSCs-derived renal cells could be a possible therapeutic strategy to favorably influence glomerular diseases outcomes.

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Section: Discussionmentioning

confidence: 70%

RETRACTED ARTICLE: Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

Ahmadi

Moghadasali

Ezzatizadeh

et al. 2019

Sci Rep

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“…It is thought to closely recapitulate human in vivo environment because it consists of several cell types and contains multicellular organ structures, displaying architectures and functionalities similar to in vivo organs [11]. So far, organoids of various organs [12][13][14][15][16] have been generated including different renal-like cell types and self-organizing renal organoids [17][18][19][20][21][22][23]. They have been verified to be excellent high-throughput drug screening models [6].…”

Section: Introductionmentioning

confidence: 99%

Formation and optimization of three-dimensional organoids generated from urine-derived stem cells for renal function in vitro

et al. 2020

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Background: Organoids play an important role in basic research, drug screening, and regenerative medicine. Here, we aimed to develop a novel kind of three-dimensional (3D) organoids generated from urine-derived stem cells (USCs) and to explore whether kidney-specific extracellular matrix (kECM) could enable such organoids for renal function in vitro. Methods: USCs were isolated from human urine samples and cultured with kECM extraction to generate 3D organoids in vitro. Eight densities from 1000 to 8000 cells per organoids were prepared, and both ATP assay and Live/Dead staining were used to determine the optimal USC density in forming organoids and kECM additive concentration. The morphology and histology of as-made organoids were evaluated by hematoxylin and eosin (H.E.) staining, immunofluorescence staining and whole mount staining. Additionally, RT-qPCR was implemented to detect renal-related gene expression. Drug toxicity test was conducted to evaluate the potential application for drug screening. The renal organoids generated from whole adult kidney cells were used as a positive control in multiple assessments. Results: The optimized cell density to generate ideal USC-derived organoids (USC-organoids) was 5000 cells/well, which was set as applying density in the following experiments. Besides, the optimal concentration of kECM was revealed to be 10%. On this condition, Live/Dead staining showed that USC-organoids were well self-organized without significant cell death. Moreover, H.E. staining showed that compact and viable organoids were generated without obvious necrosis inside organoids, which were very close to renal organoids morphologically. Furthermore, specific proximal tubule marker Aquaporin-1 (AQP1), kidney endocrine product erythropoietin (EPO), kidney glomerular markers Podocin and Synaptopodin were detected positively in USC-organoids with kECM. Nephrotoxicity testing showed that aspirin, penicillin G, and cisplatin could exert drug-induced toxicity on USCorganoids with kECM.

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“…7D). In a similar way, all three ClC-5 mutants increased cell-to-substrate adhesion ( (Kruppel Like Factor 4; logFC -0.99) which has been identified as a renal linage master regulatory transcription factor [35]. Taken together, these results suggest that lack of ClC-5 widely affects the phenotype of RPEC/TERT1 cells, but it remains to be known whether lack of ClC-5 impacts on these processes through its effect on endosomal acidification, altered chloride transport, protein endocytosis, or its participation in macromolecular complexes.…”

Section: Clc-5 Silencing and Mutations V523del E527d And I524k Impaimentioning

confidence: 76%

Global gene-expression analysis reveals the molecular processes underlying ClC-5 loss-of-function in novel Dent Disease 1 cellular models

Durán

Burballa

Cantero-Recasens

et al. 2020

Preprint

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Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria (LMWP) and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis with progression to chronic kidney disease (CKD). Although loss-of-function mutations in the geneCLCN5encoding the electrogenic Cl−/H+antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype-phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. Here, in order to discover the mechanisms leading to proximal tubule dysfunction due to ClC-5 loss-of-function, we have generated and characterized new human cellular models of DD1 by silencingCLCN5and introducing the ClC-5 pathogenic mutants V523del, E527D and I524K into the human proximal tubule-derived cell line RPTEC/TERT1. Depletion ofCLCN5or expression of mutant ClC-5 impairs albumin endocytosis, increases substrate adhesion and decreases collective migration, which correlates with a less differentiated epithelial phenotype. Interestingly, although all conditions compromised the endocytic capacity in a similar way, their impact on gene expression profiles was different. Our DNA microarray studies show that ClC-5 silencing or mutant re-introduction alter pathways related to nephron development, anion homeostasis, organic acid transport, extracellular matrix organization and cell migration, compared to control cells. Cells carrying the V523del ClC-5 mutation show the largest differences in gene expression vs WT cells, which is in agreement with the more aggressive clinical phenotype observed in some DD1 patients. Overall, this work emphasizes the use of human proximal tubule derived cell models to identify the molecular processes underlying ClC-5 deficiency.

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Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors

Cited by 51 publications

References 68 publications

RETRACTED ARTICLE: Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

RETRACTED ARTICLE: Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

Formation and optimization of three-dimensional organoids generated from urine-derived stem cells for renal function in vitro

Global gene-expression analysis reveals the molecular processes underlying ClC-5 loss-of-function in novel Dent Disease 1 cellular models

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