Single-cell analysis reveals congruence between kidney organoids and human fetal kidney

Alexander N Combes,Alicia Oshlack,Pei Xuan Er,Luke Zappia,Melissa H Little

doi:10.1186/s13073-019-0615-0

Alexander N Combes, Alicia Oshlack + Show 3 more

Open Access

https://doi.org/10.1186/s13073-019-0615-0

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Abstract

BackgroundHuman kidney organoids hold promise for studying development, disease modelling and drug screening. However, the utility of stem cell-derived kidney tissues will depend on how faithfully these replicate normal fetal development at the level of cellular identity and complexity.MethodsHere, we present an integrated analysis of single cell datasets from human kidney organoids and human fetal kidney to assess similarities and differences between the component cell types.ResultsClusters in the combined dataset contained cells from both organoid and fetal kidney with transcriptional congruence for key stromal, endothelial and nephron cell type-specific markers. Organoid enriched neural, glial and muscle progenitor populations were also evident. Major transcriptional differences between organoid and human tissue were likely related to technical artefacts. Cell type-specific comparisons revealed differences in stromal, endothelial and nephron progenitor cell types including expression of WNT2B in the human fetal kidney stroma.ConclusionsThis study supports the fidelity of kidney organoids as models of the developing kidney and affirms their potential in disease modelling and drug screening.

Highlights

Human kidney organoids hold promise for studying development, disease modelling and drug screening
Segmented epithelial nephrons, stroma and endothelial cells have been identified within human kidney organoids by correlating tissue morphology with established markers of equivalent cell types in mouse
It is unclear how closely kidney organoid cell types align with cells specified in an in vivo environment and characterising cell types derived from pluripotent cells in vitro must rely on combinations of markers unique to the cell type of interest

Summary

Introduction

Human kidney organoids hold promise for studying development, disease modelling and drug screening. Knowledge of developmental programs can be used to direct the differentiation of human-induced pluripotent stem cells towards a desired cell fate Such approaches have successfully generated models of human intestinal epithelium, brain and ear, in each instance forming multicellular self-organising structures termed organoids by mimicking conditions that regulate development of the same tissues during embryogenesis [1]. The value of Component cell types present within kidney organoids have primarily been defined by detecting established markers of murine renal cell types by immunofluorescence. This has identified cell types with similarity to endothelial cells (CD31+), stroma (MEIS1+), nephron progenitor cells (SIX2+, HOXD11+, WT1+, PAX2+), and epithelial structures with markers of the ureteric epithelium (PAX2+, GATA3+, CDH1+), renal vesicle (JAG1+), distal tubule (CDH1+, GATA3−), loop of Henle (UMOD+, CDH1+), proximal tubule (LTL+CDH1−, CUBN+) and podocytes (NPHS1+) [2, 3]. As these markers were selected based on an understanding of mouse kidney development, they are not definitive evidence of an appropriate human cell type

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