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Kidney Tubuloids: A Fascinating New Member of the Organoid Family

Review of “Tubuloids derived from human adult kidney and urine for personalized disease modelling” from Nature Biotechnology by Stuart P. Atkinson

The adult stem cell-organoid system developed by the Hans Clevers laboratory at the Hubrecht Institute (Utrecht, the Netherlands) initially aimed to produce intestinal-like tissue [1]; however, their success soon led to the development of organoid protocols for other organs, and associated cancers [2, 3] and the application of this technology in the realms of personalized medicine [4, 5]. Now, the team returns with a Nature Biotechnology article in which Schutgens et al. further extend their organoid skills to the kidney in the hope of providing a quick a versatile means to model function and disease [6]. Let's welcome kidney tubuloids to the organoid family!

The authors report that tubuloid cultures derived from human and mouse kidney tissue or human urine via an adapted protocol employed for the expansion of adult intestinal Lgr5+ stem cells can be expanded over extended periods without the appearance of gross chromosomal abnormalities. Multifactorial analysis suggests that the human kidney tubuloids retained the characteristics of primary, functional renal epithelial cells, resembling proximal and distal nephron segments, and could be applied to generate personalized models of infectious, malignant, and hereditary kidney diseases.

Infection of kidney tubuloids with the BK virus, a tubule-specific circular DNA virus responsible for the loss of 5–10% of donor organs in kidney transplant recipients [7] for which no curative treatment exists, recapitulated the in vivo disease pathology and thus may represent a model system to test personalized treatment strategies. The generation of kidney tubuloids from Wilms´ tumors (tumoroids) may provide a more amenable means to study patient-derived tumors, given the problems associated with cell lines [8], which do not yield the histology of typical Wilms’ tumors,  and xenografts, which are expensive and difficult to culture in sufficient numbers to permit high-throughput studies. 

Additionally, the development of kidney tubuloids from the urine of a cystic fibrosis patient permitted the ex vivo assessment of treatment efficacy; a proof-of-principle for a single patient which requires further validation before possible widespread application in the place of other more invasive strategies involving rectal biopsies. Finally, the authors also proved that kidney tubuloid-derived cells could form leak-tight, polarized kidney tubules with trans-epithelial transporter activity in an organ-on-a-chip format, thereby enabling personalized transporter and drug-disposition studies.

While the authors provide a range of inspiring examples of the potential applications of their kidney tubuloid culture system, they also highlight the potential limitations; these include culture heterogeneity, the lack of glomerular cells, the general bias towards proximal tubule cell generation, and the overall lack of interstitial cells and vasculature.

For more on organoids, kidney tubuloids, tumoroids and more, stay tuned to the Stem Cells Portal!

References

  1. Sato T, Vries RG, Snippert HJ, et al., Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009;459:262-5.
  2. Clevers H, Modeling Development and Disease with Organoids. Cell 2016;165:1586-1597.
  3. Drost J and Clevers H, Organoids in cancer research. Nat Rev Cancer 2018;18:407-418.
  4. Dekkers JF, Wiegerinck CL, de Jonge HR, et al., A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med 2013;19:939-45.
  5. Dekkers JF, Berkers G, Kruisselbrink E, et al., Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med 2016;8:344ra84.
  6. Schutgens F, Rookmaaker MB, Margaritis T, et al., Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat Biotechnol 2019;37:303-313.
  7. Hirsch HH, Brennan DC, Drachenberg CB, et al., Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005;79:1277-86.
  8. Royer-Pokora B, Busch M, Beier M, et al., Wilms tumor cells with WT1 mutations have characteristic features of mesenchymal stem cells and express molecular markers of paraxial mesoderm. Hum Mol Genet 2010;19:1651-68.