Relevance of kidney organoids

Kidney organoids are relevant from several perspectives, including modelling of kidney disease and injury. Commonly-used in vitro two-dimensional cell (2D) models are limited because cells behave differently in a 2D configuration and cannot constitute in vivo-relevant cell-cell interactions.[1

Besides, contemporary in vivo animal models often fail to represent human diseases due to species-species differences.[2] Modelling diseases using organoids surpasses these problems. Stem cells from patients with a certain disease can be grown to organoids, which can experimentally be manipulated in each disease context. Gut organoids are currently the best-established organoid disease model and are already used in practice to model cystic fibrosis. In most cystic fibrosis patients, a dysfunctional CFTR gene causes improper fluid transport along the gut epithelium, which expresses in abnormally thick and sticky mucus.[3] CFTR is therefore important in fluid transport in the gut, which could be observed by patient gut organoids swelling less than control gut organoids,[4] an observation in parallel with the disease phenotype. Kidney organoids have also been shown to be relevant in modelling acute kidney disease, because in vivo-relevant biomarkers of kidney and DNA damage show expression in organoids after injury infliction. It has been shown that, after treatment of kidney organoids with antibiotic gentamicin or anti-cancer drug cisplatin, organoid cells showed expression of kidney injury marker 1.[5]

Modeling kidney diseases

Organoids can also be used to screen for efficacy and safety of potentially disease-curing drugs. Drug development currently experiences that 66% and 30% of all preclinically validated drugs fail to enter the next developmental stage from phase II and phase III, respectively.[6] This phenomenon illustrates the huge gap between preclinical drug validation and success of these drugs in the clinic, which exists because the simple two-dimensional in vitro cell models often do not resemble the much more complex in vivo pathologies.[2] Large-scale use of organoid systems in drug screening might bridge the gap between pre-clinical validation and use of the drug in the clinic, as they are considered to more closely resemble the in vivo situation than two-dimensional cell cultures.[11, 7] Drug screens employing organoid systems have already proven successful. For example, Huang et al. performed screening of candidate drugs to treat pancreatic cancer on organoids derived from patient stem cells, and found that the organoids responded better than other candidate drugs to UNC1999, an inhibitor of epigenetic regulator H3K27me3.[8] Also from the perspective of safety, kidney organoids would be a useful tool in drug nephrotoxicity screenings. Compared to all other cell types, kidney cells are especially sensitive to toxins, xenobiotics, metabolic waste products and other potentially harmful compounds,[5, 9] mainly because these compounds become highly concentrated in renal cells due to extensive water resorption.[12] Nephrotoxicity in kidney cells and subsequent kidney dysfunction is therefore a common complication of drug administration.[9, 10]

Author: Daan Smits

References

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