Human kidney organoids: progress and remaining challenges

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Abstract

Kidney organoids are regarded as important tools with which to study the development of the normal and diseased human kidney. Since the first reports of human pluripotent stem cell-derived kidney organoids 5 years ago, kidney organoids have been successfully used to model glomerular and tubular diseases. In parallel, advances in single-cell RNA sequencing have led to identification of a variety of cell types in the organoids, and have shown these to be similar to, but more immature than, human kidney cells in vivo. Protocols for the in vitro expansion of stem cell-derived nephron progenitor cells (NPCs), as well as those for the selective induction of specific lineages, especially glomerular podocytes, have also been reported. Although most current organoids are based on the induction of NPCs, an induction protocol for ureteric buds (collecting duct precursors) has also been developed, and approaches to generate more complex kidney structures may soon be possible. Maturation of organoids is a major challenge, and more detailed analysis of the developing kidney at a single cell level is needed. Eventually, organotypic kidney structures equipped with nephrons, collecting ducts, ureters, stroma and vascular flow are required to generate transplantable kidneys; such attempts are in progress.

Key points

  • Kidney organoids are useful for modelling early onset diseases that affect glomeruli and renal tubules.

  • A better understanding of the gene expression changes that occur at a single-cell level during development of the human embryonic kidney is necessary to guide further maturation of kidney organoids; technologies such as single-cell RNA-sequencing represent powerful tools for this purpose.

  • The induction of branching ureteric buds can be achieved using a protocol that differs from that used for the induction of nephron progenitor cells.

  • Notable challenges to the use of organoids for regenerative medicine remain, including approaches to the generation of higher-order structures, organoid maturation, vascularization and single-ureter formation.

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Fig. 1: Interactions between the nephron progenitor, ureteric bud and stromal lineages during kidney development.
Fig. 2: Distinct developmental paths of nephron progenitor cells and the ureteric bud during mouse kidney development in vivo and in vitro.
Fig. 3: Disease modelling using human induced pluripotent stem cells.
Fig. 4: An approach to generate higher-order structure of the kidney in vitro.
Fig. 5: Strategies for the reconstruction of kidneys in large animals.

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Acknowledgements

I thank A. Taguchi, S. Tanigawa and all the other members of the Nishinakamura laboratory for their contributions to the establishment of kidney organoid protocols and for helpful discussions.

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Correspondence to Ryuichi Nishinakamura.

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Nature Reviews Nephrology thanks M. Little, R. Morizane and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Induced pluripotent stem cells

(iPSCs). Generated by the forced expression of several transcription factors in somatic cells and can differentiate into a variety of cell types.

Nephron progenitor cell

A population in the embryonic kidney that can differentiate into glomerular podocyte, Bowman’s capsule, renal tubule and loop of Henle.

Metanephric mesenchyme

A population of cells accumulated around the ureteric bud tips. It contains nephron progenitors and stromal progenitors.

Ureteric bud

A population of cells in the embryonic kidney that undergoes extensive branching and differentiates into collecting ducts and ureters.

Bowman’s capsule

An epithelial sac surrounding the glomerulus. A structure consisting of Bowman’s capsule and a glomerulus is referred to as a renal corpuscle.

Mesonephros

The embryonic kidney that develops earlier and more anteriorly than the metanephros. After forming Wolffian ducts, most parts of the mesonephros degenerate during development.

Metanephros

The embryonic kidney that appears last and develops into the permanent kidney.

Wolffian duct

Also known as the mesonephric duct. The epithelial duct of the mesonephros that elongates in an anterior-to-posterior direction. A portion close to the posterior end sprouts to form the ureteric bud.

Primitive streak

An elongated furrow formed along the axis of gastrulation-stage embryos. Mesodermal and endodermal cells are generated from the primitive streak.

Renal coloboma syndrome

A condition that manifests as kidney and eye abnormalities. It is mainly caused by PAX2 mutations.

Angiogenesis

The branching of existing vessels.

Vasculogenesis

The de novo formation of vessels from mesodermal precursors.

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Nishinakamura, R. Human kidney organoids: progress and remaining challenges. Nat Rev Nephrol 15, 613–624 (2019) doi:10.1038/s41581-019-0176-x

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