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Cell Stem Cell. 2019 Sep 5;25(3):373-387.e9. doi: 10.1016/j.stem.2019.06.009. Epub 2019 Jul 11.

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

Author information

1
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
2
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; Human Genetics, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore.
3
Institute for Advanced Co-Creation Studies, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan; Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
4
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore.
5
Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
6
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
7
Humanized Mouse Unit, Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
8
Humanized Mouse Unit, Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119288, Singapore.
9
Hospital Clinic, University of Barcelona, IDIBAPS, 08036 Barcelona, Spain.
10
School of Civil and Environmental Engineering, Nanyang Technological University Singapore, 50 Nanyang Avenue, Singapore 639798, Singapore; Nanyang Environment and Water Research Institute, Nanyang Technological University Singapore, Singapore 637141, Singapore.
11
Human Genetics, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore; Singapore Eye Research Institute, 20 College Road Discovery Tower, Level 6 The Academia, Singapore 169856, Singapore.
12
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; Human Genetics, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore. Electronic address: jianee.foo@ntu.edu.sg.
13
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: belmonte@salk.edu.
14
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore. Electronic address: yunxia@ntu.edu.sg.

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.

KEYWORDS:

ARPKD; developmental modeling; disease modeling; implantation; kidney organoid; nephron patterning; patient-specific iPSC; pluripotent stem cells; single-cell RNA-seq; vascular progenitors

PMID:
31303547
PMCID:
PMC6731150
[Available on 2020-09-05]
DOI:
10.1016/j.stem.2019.06.009

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