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Determining lineage relationships in kidney development and disease

Nature Reviews Nephrology volume 18, pages 8–21 (2022)Cite this article

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Abstract

The lineage relationships of cells provide information about the origins of component cell types during development and repair as well as the source of aberrant cells during disease. Genetic approaches to lineage tracing applied in the mouse have revealed much about how the mammalian kidney forms, including the identification of key progenitors for the nephrons and stromal compartments. Inducible Cre systems have also facilitated lineage tracing studies in the postnatal animal that illustrate the changes in cellular fate that can occur during kidney injury. With the advent of single-cell transcriptional profiling and trajectory analyses, predictions of cellular relationships across development are now being made in model systems, such as the mouse, as well as in human fetal kidney. Importantly, these approaches provide predictions of lineage relationships rather than definitive evidence. Although genetic approaches to the study of lineage have not previously been possible in a human setting, the application of CRISPR–Cas9 gene editing of pluripotent stem cells is beginning to teach us about human lineage relationships.

Key points

  • Genetic lineage tracing in mouse has informed our understanding of mammalian kidney development; this approach has been particularly valuable in identifying the key progenitor cell types that give rise to the final organ.

  • Inducible lineage tracing has also led to improved understanding of responses to postnatal kidney injury; such studies can identify the normal and maladaptive responses of the tubular epithelium, potentially providing approaches for improving repair.

  • Pseudotime analyses of single-cell transcriptional data can predict likely lineage relationships but do not provide proof of lineage.

  • CRISPR–Cas9-based gene editing enables lineage tracing within pluripotent stem cell-derived organoid models of the human kidney; this approach provides a unique opportunity to investigate lineage during human development.

  • Advances in genetic scarring approaches combined with single-cell RNA sequencing will facilitate lineage tracing at the single-cell level, thereby providing a much higher resolution to analyses of lineage relationships across time.

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Fig. 1: The nephrogenic niche in the developing mammalian metanephros.
Fig. 2: Key lineage relationships in the developing kidney.
Fig. 3: New approaches for genomic barcoding or scar generation for the purposes of lineage tracing at the single-cell level.

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Acknowledgements

M.H.L. is a senior principal research fellow of the National Health and Medical Research Council, Australia (APP1136085). The authors were supported by the National Institutes of Health (UH3DK107344), Australian Research Council (DP190101705), NHMRC (GNT1156440), Medical Research Future Fund and the Stafford Fox Medical Research Foundation.

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Authors and Affiliations

  1. Murdoch Children’s Research Institute, Parkville, VIC, Australia

    Melissa H. Little, Sara E. Howden, Kynan T. Lawlor & Jessica M. Vanslambrouck

  2. Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia

    Melissa H. Little & Sara E. Howden

  3. Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, VIC, Australia

    Melissa H. Little

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Glossary

Metanephric kidney

The postnatal kidney. The metanephric kidneys arise from the metanephric mesenchyme during embryogenesis.

Transgenic mice

Mice into which foreign DNA has been delivered, usually via pronuclear injection. This term is also used more broadly to describe mice in which genetically modified pluripotent cells are introduced at the morula or blastocyst stage to generate chimeric animals.

Lineage relationships

The relationships between founder and progeny. In the context of tissues and organisms, the lineage of a cell describes which cell it has arisen from.

Morphogenesis

The development of morphological characteristics. In developmental biology, this term refers to the generation of form during organogenesis.

Nephron progenitor

A stem cell able to give rise to nephrons via a mesenchyme to epithelial transition.

Intermediate mesoderm

The region of the axial mesoderm between the paraxial and lateral plate mesoderm of the developing embryo. The intermediate mesoderm gives rise to the kidney and gonads.

Pronephric mesenchyme

The region of the intermediate mesoderm that gives rise to the pronephros.

Mesonephric mesenchyme

The nephrogenic region of the intermediate mesoderm that gives rise to the mesonephros.

Metanephric mesenchyme

The nephrogenic region of the intermediate mesoderm that gives rise to the metanephros, including the nephron progenitors, stroma and angioblasts.

Barcoding

A process of tagging with a molecular sequence for the purpose of identifying the origin of that sequence. Molecular barcodes can be introduced into individual cells via gene editing to facilitate lineage tracing or into transcripts during mRNA amplification or cDNA synthesis to facilitate multiplexing of samples in next-generation sequencing.

Human pluripotent stem cell

(hPSC). Cells that are able to give rise to all germ layers. HPSCs include human embryonic stem cells, which were initially isolated from the inner cell mass of a human blastocyst, and induced pluripotent stem cells, which are generated by reprogramming of any somatic cell to an equivalent pluripotent stem cell state.

Organoids

A group of cells that resemble a tissue or organ. This term has been applied to in vitro structures generated from postnatal epithelial progenitors and tissue organoids generated via the directed differentiation of pluripotent stem cells.

CRISPR–Cas9 gene editing

A gene editing system in which clustered regularly interspaced short palindromic repeats (CRISPR) sequences together with a CRIPSR-associated protein 9 (Cas9) facilitates the cutting of DNA in a targeted location. CRISPR–Cas9 gene editing is now readily used for targeted gene disruption or high-fidelity gene editing in transgenic animals and in cell lines, including pluripotent stem cell lines.

Transcriptional profiling

Evaluation of the global gene expression of a sample.

Nephric duct

Also referred to as the Wolffian duct or the mesonephric duct, this paired structure extends along the body axis within the intermediate mesoderm into which the pronephros and mesonephros drain and from which the ureteric bud arises.

Self-renewal

The process by which a dividing cell gives rise to more cells with identical cell identities. Stem cells are regarded as having a capacity to self-renew.

Mesenchymal-to-epithelial transition

The process whereby a mesenchymal cell type transitions to a polarized epithelial state.

Cre recombinase

A tyrosine recombinase enzyme derived from P1 bacteriophages that is able to carry out site-specific recombination events between two regions of DNA based upon recognition of a specific DNA sequence, the loxP site.

loxP sites

A DNA recognition sequence consisting of two 13-bp palindromic sequences with an asymmetric core spacer measuring 8 bp in length that gives the site directionality. loxP sites are recognized by Cre recombinase as a site for cutting and recombination.

Cap mesenchyme

A nephron progenitor population within the metanephros that is associated with the tips of the branching ureteric tree. Lineage tracing has identified this mesenchymal population as the progenitor for all regions of the nephron epithelium.

Renal vesicle

The earliest nephron structure that arises as the immediate result of nephron progenitor mesenchyme to epithelial transition.

Comma-shaped body

An early nephron stage between the renal vesicle and S-shaped body.

S-shaped body

A stage II nephron comprising proximal, distal and medial segments together with a distal connecting tubule marking the point at which the nephron joins the adjacent ureteric epithelium.

Rainbow reporter

A reporter system that applies the random combinatorial expression of multiple fluorescent reporters to enable colour-based lineage tracing. The reporters are flanked by Cre–loxP sites to enable stochastic labelling of each cell with the expression of three or more fluorophores in different ratios, which results in distinctive colours.

Ureteric epithelium

Epithelium that gives rise to the ureteric tree and ureter of the developing metanephric kidney. Cells of this lineage ultimately contribute to the collecting ducts and ureter of the final kidney.

Mosaic analysis with double markers

A genetic labelling method that enables simultaneous labelling and gene knockout within a subset of somatic cells. This method can be used to generate a small number of clonal cells that are homozygous for a deleterious gene mutation in the context of a functional heterozygous tissue.

Angiogenesis

The formation of new blood vessels via sprouting from existing endothelial vessels.

Vasculogenesis

A process of de novo blood vessel formation in which endothelial networks arise from endothelial progenitors known as angioblasts via coalescence

Plasticity

The ability of a cell type to change identity in response to changes in culture environment.

Transdifferentiation

The process by which cells of one identity adopt a distinct identity. Transdifferentiation is sometimes referred to as lineage reprogramming.

Label-retaining cells

(LRCs). Cells that retain a label, usually a uridine-based tag, inserted into the DNA. As such labels reduce with cell division, slow-dividing cells, such as quiescent stem cells, retain these labels in the long term.

Confetti lineage tracing

A lineage tracing approach in which a Brainbow construct is inserted into the Rosa26 locus and driven by a strong, ubiquitous promoter. This cassette yields the R26R-confetti allele, a general multicolour Cre recombinase-driven reporter.

Fluorescent ubiquitin-based cell cycle indicator

(FUCCI2). A derivative of fluorescent ubiquitin-based cell cycle indicator (FUCCI) that uses dual-colour imaging to identify live cells in G(1) and S/G(2)/M cellcycle phases. FUCCI2 provides improved colour contrast via mCherry and mVenus fluorescence.

FLP–FRT recombination

Flippase (FLP) is a sequence-targeted recombinase enzyme adapted from Saccharomyces cerevisiae that is able to cut DNA at flippase recognition target (FRT) sequences. FLP–FRT recombination can be combined with Cre recombinase to enable separable control of gene editing.

Renin lineage cells

Juxtaglomerular perivascular cells derived from renin-expressing progenitors.

Single-cell mRNA sequencing

(scRNA-seq). A method of transcriptional profiling that provides a global view of the mRNA present within each individual cell of a sample. This approach became available with the advent of next-generation sequencing technologies.

Pseudotime analyses

A mathematical evaluation of distance along a trajectory of cells within a population that is generally based upon relative similarity of transcriptional profiles. Pseudotime analyses can predict potential cell identity relationships, but they do not formally prove lineage.

Safe harbour locus

A site where genes or other genetic elements can be safely inserted and expressed with minimal negative impact on the host genome.

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Little, M.H., Howden, S.E., Lawlor, K.T. et al. Determining lineage relationships in kidney development and disease. Nat Rev Nephrol 18, 8–21 (2022). https://doi.org/10.1038/s41581-021-00485-5

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