Regenerative potential of induced pluripotent stem cells derived from patients undergoing haemodialysis in kidney regeneration

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Abstract

Kidney regeneration from pluripotent stem cells is receiving a lot of attention because limited treatments are currently available for chronic kidney disease (CKD). It has been shown that uremic state in CKD is toxic to somatic stem/progenitor cells, such as endothelial progenitor and mesenchymal stem cells, affecting their differentiation and angiogenic potential. Recent studies reported that specific abnormalities caused by the non-inherited disease are often retained in induced pluripotent stem cell (iPSC)-derived products obtained from patients. Thus, it is indispensable to first assess whether iPSCs derived from patients with CKD due to non-inherited disease (CKD-iPSCs) have the ability to generate kidneys. In this study, we generated iPSCs from patients undergoing haemodialysis due to diabetes nephropathy and glomerulonephritis (HD-iPSCs) as representatives of CKD-iPSCs or from healthy controls (HC-iPSCs). HD-iPSCs differentiated into nephron progenitor cells (NPCs) with similar efficiency to HC-iPSCs. Additionally, HD-iPSC-derived NPCs expressed comparable levels of NPC markers and differentiated into vascularised glomeruli upon transplantation into mice, as HC-iPSC-derived NPCs. Our results indicate the potential of HD-iPSCs as a feasible cell source for kidney regeneration. This is the first study paving the way for CKD patient-stem cell-derived kidney regeneration, emphasising the potential of CKD-iPSCs.

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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

Takashi Yokoo:

ORCID: http://orcid.org/0000-0003-1838-7998

tyokoo@jikei.ac.jp

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 8 October 2018

Publication date PMC-release: 8 October 2018

Publication date Collection: 2018

Volume: 8

Electronic Location Identifier: 14919

Affiliations

[1 ]ISNI 0000 0001 0661 2073, GRID grid.411898.d, Division of Nephrology and Hypertension, Department of Internal Medicine, , The Jikei University School of Medicine, ; 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461 Japan

[2 ]ISNI 0000 0001 0660 6749, GRID grid.274841.c, Department of Kidney Development, Institute of Molecular Embryology and Genetics, , Kumamoto University, ; 2-2-1, Honjo, Chuo-ku, Kumamoto, 860-0811 Japan

[3 ]ISNI 0000 0000 9071 0620, GRID grid.419538.2, Department of Genome Regulation, , Max Planck Institute for Molecular Genetics, ; Ihnestraße 63-73, 14195 Berlin, Germany

[4 ]ISNI 0000 0001 0661 2073, GRID grid.411898.d, Division of Regenerative Medicine, , The Jikei University School of Medicine, ; 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461 Japan

Author information

Takashi Yokoo http://orcid.org/0000-0003-1838-7998

Article

Publisher ID: 33256

DOI: 10.1038/s41598-018-33256-7

PMC ID: 6175865

PubMed ID: 30297790

SO-VID: c4fe7bb6-41a9-40d1-823b-4df03536c3c1

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Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 May 2018

Date accepted : 26 September 2018

Funding

Funded by: FundRef https://doi.org/10.13039/501100007638, Kidney Foundation, Japan (Kidney Foundation Japan);

Award ID: JKFB15-1

Award Recipient : Takashi Yokoo

Funded by: FundRef https://doi.org/10.13039/501100001691, Japan Society for the Promotion of Science (JSPS);

Award ID: 16H03175

Award Recipient : Takashi Yokoo

Funded by: FundRef https://doi.org/10.13039/100009619, Japan Agency for Medical Research and Development (AMED);

Award ID: 17ek0310006h0002

Award Recipient : Takashi Yokoo

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Regenerative potential of induced pluripotent stem cells derived from patients undergoing haemodialysis in kidney regeneration

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Most cited references 36

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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Cited by 12

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