TY - JOUR
T1 - Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease
AU - Cruz, Nelly M.
AU - Song, Xuewen
AU - Czerniecki, Stefan M.
AU - Gulieva, Ramila E.
AU - Churchill, Angela J.
AU - Kim, Yong Kyun
AU - Winston, Kosuke
AU - Tran, Linh M.
AU - Diaz, Marco A.
AU - Fu, Hongxia
AU - Finn, Laura S.
AU - Pei, York
AU - Himmelfarb, Jonathan
AU - Freedman, Benjamin S.
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/10/2
Y1 - 2017/10/2
N2 - 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 cysts1,2.Amajor barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis3,4. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids5,6. Herewe showthat 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.
AB - 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 cysts1,2.Amajor barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis3,4. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids5,6. Herewe showthat 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.
UR - http://www.scopus.com/inward/record.url?scp=85037734904&partnerID=8YFLogxK
U2 - 10.1038/NMAT4994
DO - 10.1038/NMAT4994
M3 - Letter
C2 - 28967916
AN - SCOPUS:85037734904
SN - 1476-1122
VL - 16
SP - 1112
EP - 1119
JO - Nature Materials
JF - Nature Materials
IS - 11
ER -
