Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease

Sienna R. Li, Ramila E. Gulieva, Louisa Helms, Nelly M. Cruz, Thomas Vincent, Hongxia Fu, Jonathan Himmelfarb and Benjamin S. Freedman ()
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Sienna R. Li: University of Washington School of Medicine
Ramila E. Gulieva: University of Washington School of Medicine
Louisa Helms: University of Washington School of Medicine
Nelly M. Cruz: University of Washington School of Medicine
Thomas Vincent: University of Washington School of Medicine
Hongxia Fu: University of Washington School of Medicine
Jonathan Himmelfarb: University of Washington School of Medicine
Benjamin S. Freedman: University of Washington School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development.

Date: 2022
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DOI: 10.1038/s41467-022-35537-2

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