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Generation of Human PSC-Derived Kidney Organoids with Patterned Nephron Segments and a De Novo Vascular Network.

Cell stem cell (2019-07-16)
Jian Hui Low, Pin Li, Elaine Guo Yan Chew, Bingrui Zhou, Keiichiro Suzuki, Tian Zhang, Michelle Mulan Lian, Meng Liu, Emi Aizawa, Concepcion Rodriguez Esteban, Kylie Su Mei Yong, Qingfeng Chen, Josep M Campistol, Mingliang Fang, Chiea Chuen Khor, Jia Nee Foo, Juan Carlos Izpisua Belmonte, Yun Xia
ABSTRACT

Human pluripotent stem cell-derived kidney organoids recapitulate developmental processes and tissue architecture, but intrinsic limitations, such as lack of vasculature and functionality, have greatly hampered their application. Here we establish a versatile protocol for generating vascularized three-dimensional (3D) kidney organoids. We employ dynamic modulation of WNT signaling to control the relative proportion of proximal versus distal nephron segments, producing a correlative level of vascular endothelial growth factor A (VEGFA) to define a resident vascular network. Single-cell RNA sequencing identifies a subset of nephron progenitor cells as a potential source of renal vasculature. These kidney organoids undergo further structural and functional maturation upon implantation. Using this kidney organoid platform, we establish an in vitro model of autosomal recessive polycystic kidney disease (ARPKD), the cystic phenotype of which can be effectively prevented by gene correction or drug treatment. Our studies provide new avenues for studying human kidney development, modeling disease pathogenesis, and performing patient-specific drug validation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
CHIR99021, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal Anti-Calbindin-D-28K antibody produced in mouse, clone CB-955, ascites fluid
Sigma-Aldrich
Anti-Sox2 Antibody, Chemicon®, from rabbit