Kidney organoids: accurate models or fortunate accidents

Little, Melissa H.; Combes, Alexander N.

doi:10.1101/gad.329573.119

Cited by 115 publications

(110 citation statements)

References 157 publications

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“…In recent years, kidney organoids differentiated from human pluripotent stem cells (hPSC) have been established to study various types of kidney disorders (5,8). Kidney organoids were reported to be susceptible to proximal tubule injury caused by nephrotoxins, such as cisplatin (2,9,16,17).…”

Section: Introductionmentioning

confidence: 99%

Modeling acute kidney injury in kidney organoids with cisplatin

Digby

Przepiorski

Davidson

et al. 2019

Preprint

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Acute kidney injury (AKI) remains a major global healthcare problem and there is a need to develop human-based models to study AKI in vitro. Towards this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces HAVCR1 and CXCL8 expression, DNA damage (γH2AX) and cell death in the organoids in a dose-dependent manner but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial populations. This lack of specificity correlated with low expression of the proximal tubule-specific SLC22A2/OCT2 transporter for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4x 5 µM cisplatin over 7 days and found this causing less toxicity while still inducing a robust AKI response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of AKI in vitro, with the potential to identify new AKI biomarkers and develop better therapies.

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Section: Introductionmentioning

confidence: 99%

Modeling acute kidney injury in kidney organoids with cisplatin

Digby

Przepiorski

Davidson

et al. 2019

Preprint

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“…Several protocols have been developed for inducing the differentiation of iPSCs into kidney organoids 22,23 . Based on protocols described by Cruz et al 7 , we obtained structures with the characteristics of proximal tubules, including the expression of NHE3 and AQP1.…”

Section: Discussionmentioning

confidence: 99%

Kidney Organoids Generated from iPS Cells Obtained from the Erythroid Progenitors of Patients with Autosomal Dominant Polycystic Kidney Disease

Facioli

Lojudice

Anauate

et al. 2020

Preprint

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Background. Kidney organoids have been broadly obtained from commercially available induced pluripotent stem cells (iPSCs); however, it has been a great challenge to efficiently produce renal organoid models from patients with autosomal dominant polycystic kidney disease (ADPKD) that recapitulate both embryogenesis and the mechanisms of cystogenesis.Methods. Blood erythroid progenitors (EPs) from two ADPKD patients and one healthy control (HC) donor were reprogrammed by an episomal vector into iPSCs, which were differentiated into renal tubular organoids and then stimulated by forskolin to induce cysts formation. Results. iPSCs derived from EPs exhibited all characteristics of pluripotency and were able to differentiate into all three germ layers. 3D tubular organoids were generated from single cells after 28 days in Matrigel. HC and ADPKD organoids did not spontaneously form cysts, but upon forskolin stimulation, cysts-like structures were observed in the ADPKD organoids but not in the HC-derived organoids. Conclusion. The findings of this study showed that kidney organoids were successfully generated from the blood EP cells of ADPKD patients and a healthy control donor. This approach should contribute as a powerful tool for embryonic kidney developing model which is able to recapitulate the very early pathophysiological mechanisms involved in cytogenesis.

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“…Using optimised stepwise differentiation to separately generate nephron and ureteric bud progenitors before mixing in culture with embryo-derived stromal cells produced more refined kidney organoids [87]. In depth reviews of the protocols used for generation of kidney organoids and their uses are available [88][89][90][91]. Kidney organoids have yet to be leveraged for investigating diabetic nephropathy but there are several groups working in this area.…”

Section: Modelling Diabetic Complicationsmentioning

confidence: 99%

Diabetes through a 3D lens: organoid models

2020

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Diabetes is one of the most challenging health concerns facing society. Available drugs treat the symptoms but there is no cure. This presents an urgent need to better understand human diabetes in order to develop improved treatments or target remission. New disease models need to be developed that more accurately describe the pathology of diabetes. Organoid technology provides an opportunity to fill this knowledge gap. Organoids are 3D structures, established from pluripotent stem cells or adult stem/progenitor cells, that recapitulate key aspects of the in vivo tissues they mimic. In this review we briefly introduce organoids and their benefits; we focus on organoids generated from tissues important for glucose homeostasis and tissues associated with diabetic complications. We hope this review serves as a touchstone to demonstrate how organoid technology extends the research toolbox and can deliver a step change of discovery in the field of diabetes.

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Kidney organoids: accurate models or fortunate accidents

Cited by 115 publications

References 157 publications

Modeling acute kidney injury in kidney organoids with cisplatin

Modeling acute kidney injury in kidney organoids with cisplatin

Kidney Organoids Generated from iPS Cells Obtained from the Erythroid Progenitors of Patients with Autosomal Dominant Polycystic Kidney Disease

Diabetes through a 3D lens: organoid models

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