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Nat Mater. 2017 Nov;16(11):1112-1119. doi: 10.1038/nmat4994. Epub 2017 Oct 2.

Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease.

Cruz NM1,2,3,4, Song X5,6, Czerniecki SM1,2,3,4, Gulieva RE1,2,3,4, Churchill AJ1,2,3,4, Kim YK1,2,3,4, Winston K1,2,3,4, Tran LM1,2,3,4, Diaz MA1,2,3,4, Fu H3,4,7,8, Finn LS9,10, Pei Y5,6, Himmelfarb J1,2,4, Freedman BS1,2,3,4.

Author information

1
Division of Nephrology, University of Washington School of Medicine, Seattle, Washington 98109, USA.
2
Kidney Research Institute, University of Washington School of Medicine, Seattle, Washington 98109, USA.
3
Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington 98109, USA.
4
Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109, USA.
5
Division of Nephrology, University Health Network, Toronto, Ontario M5G2N2, Canada.
6
University of Toronto, Toronto, Ontario M5G2N2, Canada.
7
Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109, USA.
8
Department of Bioengineering, University of Washington School of Medicine, Seattle, Washington 98109, USA.
9
Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98105, USA.
10
Department of Laboratories, Seattle Children's Hospital, Seattle, Washington 98105, USA.

Abstract

Polycystic kidney disease (PKD) is a life-threatening disorder, commonly caused by defects in polycystin-1 (PC1) or polycystin-2 (PC2), in which tubular epithelia form fluid-filled cysts. A major barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids. Here we show that systematic substitution of physical components can dramatically increase or decrease cyst formation, unveiling a critical role for microenvironment in PKD. Removal of adherent cues increases cystogenesis 10-fold, producing cysts phenotypically resembling PKD that expand massively to 1-centimetre diameters. Removal of stroma enables outgrowth of PKD cell lines, which exhibit defects in PC1 expression and collagen compaction. Cyclic adenosine monophosphate (cAMP), when added, induces cysts in both PKD organoids and controls. These biomaterials establish a highly efficient model of PKD cystogenesis that directly implicates the microenvironment at the earliest stages of the disease.

PMID:
28967916
PMCID:
PMC5936694
DOI:
10.1038/nmat4994
[Indexed for MEDLINE]
Free PMC Article

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