Stem cell-derived kidney organoids: engineering the vasculature

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Abstract

Kidney organoids can be generated from human pluripotent stem cells (PSCs) using protocols that resemble the embryonic development of the kidney. The renal structures thus generated offer great potential for disease modeling, drug screening, and possibly future therapeutic application. At the same time, use of these PSC-derived organoids is hampered by lack of maturation and off-target differentiation. Here, we review the main protocols for the generation of kidney organoids from human-induced PSCs, discussing their advantages and limitations. In particular, we will focus on the vascularization of the kidney organoids, which appears to be one of the critical factors to achieve maturation and functionality of the organoids.

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Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

Minoru Takasato, Pei X Er, Han S Chiu … (2015)

The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.

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Nephron organoids derived from human pluripotent stem cells model kidney development and injury

Ryuji Morizane, Albert Lam, Benjamin S Freedman … (2015)

Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) would enable organ regeneration, disease modeling, and drug screening in vitro. We established an efficient, chemically defined protocol for differentiating hPSCs into multipotent nephron progenitor cells (NPCs) that can form nephron-like structures. By recapitulating metanephric kidney development in vitro, we generate SIX2+SALL1+WT1+PAX2+ NPCs with 90% efficiency within 9 days of differentiation. The NPCs possess the developmental potential of their in vivo counterparts and form PAX8+LHX1+ renal vesicles that self-pattern into nephron structures. In both 2D and 3D culture, NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle, and distal tubules in an organized, continuous arrangement that resembles the nephron in vivo. We also show that this organoid culture system can be used to study mechanisms of human kidney development and toxicity.

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Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells.

Atsuhiro Taguchi, Yusuke Kaku, Tomoko Ohmori … (2014)

Recapitulating three-dimensional (3D) structures of complex organs, such as the kidney, from pluripotent stem cells (PSCs) is a major challenge. Here, we define the developmental origins of the metanephric mesenchyme (MM), which generates most kidney components. Unexpectedly, we find that posteriorly located T(+) MM precursors are developmentally distinct from Osr1(+) ureteric bud progenitors during the postgastrulation stage, and we identify phasic Wnt stimulation and stage-specific growth factor addition as molecular cues that promote their development into the MM. We then use this information to derive MM from PSCs. These progenitors reconstitute the 3D structures of the kidney in vitro, including glomeruli with podocytes and renal tubules with proximal and distal regions and clear lumina. Furthermore, the glomeruli are efficiently vascularized upon transplantation. Thus, by reevaluating the developmental origins of metanephric progenitors, we have provided key insights into kidney specification in vivo and taken important steps toward kidney organogenesis in vitro. Copyright © 2014 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Marije Koning:

ORCID: http://orcid.org/0000-0001-9094-1004

m.koning@lumc.nl

Journal

Journal ID (nlm-ta): Cell Mol Life Sci

Journal ID (iso-abbrev): Cell. Mol. Life Sci

Title: Cellular and Molecular Life Sciences

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1420-682X

ISSN (Electronic): 1420-9071

Publication date (Electronic): 5 December 2019

Publication date PMC-release: 5 December 2019

Publication date (Print): 2020

Volume: 77

Issue: 12

Pages: 2257-2273

Affiliations

[1 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Internal Medicine-Nephrology, , Leiden University Medical Center, ; Leiden, The Netherlands

[2 ]GRID grid.10419.3d, ISNI 0000000089452978, Einthoven Laboratory of Vascular and Regenerative Medicine, , Leiden University Medical Center, ; Leiden, The Netherlands

Author information

Marije Koning http://orcid.org/0000-0001-9094-1004

Article

Publisher ID: 3401

DOI: 10.1007/s00018-019-03401-0

PMC ID: 7275011

PubMed ID: 31807815

SO-VID: 2aa953bf-dd2b-4851-b274-06d25f004e6d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 8 March 2019

Date revision received : 16 October 2019

Date accepted : 26 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002997, Nierstichting;

Award ID: RECORD KID 15RN02

Funded by: Regenerative Medicine Crossing Borders

Funded by: Health~Holland

Funded by: FundRef http://dx.doi.org/10.13039/501100005040, Bontius Stichting;

Award ID: Wiyadharma fellowship

Award Recipient : Cathelijne W. van den Berg

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ScienceOpen disciplines: Molecular biology

Keywords: transplantation,angiogenesis,vasculogenesis,endothelial cells,nephrons

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ScienceOpen disciplines: Molecular biology

Keywords: transplantation, angiogenesis, vasculogenesis, endothelial cells, nephrons

Stem cell-derived kidney organoids: engineering the vasculature

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Abstract

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Stress signalling in stem cells

Most cited references 68

Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

Nephron organoids derived from human pluripotent stem cells model kidney development and injury

Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells.

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