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Transcriptional evaluation of the developmental accuracy, reproducibility and robustness of kidney organoids derived from human pluripotent stem cells

Belinda Phipson, Pei Xuan Er, Lorna Hale, David Yen, Kynan Lawlor, Minoru Takasato, Jane Sun, Ernst Wolvetang, Alicia Oshlack, Melissa Little
doi: https://doi.org/10.1101/238428
Belinda Phipson
Murdoch Childrens Research Institute;
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Pei Xuan Er
Murdoch Childrens Research Institute;
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Lorna Hale
Murdoch Childrens Research Institute;
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David Yen
Murdoch Childrens Research Institute;
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Kynan Lawlor
Murdoch Childrens Research Institute;
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Minoru Takasato
RIKEN Center for Developmental Biology;
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Jane Sun
University of Queensland
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Ernst Wolvetang
University of Queensland
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Alicia Oshlack
Murdoch Childrens Research Institute;
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Melissa Little
Murdoch Childrens Research Institute;
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  • For correspondence: melissa.little@mcri.edu.au
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Abstract

We have previously reported a protocol for the directed differentiation of human induced pluripotent stem cells to kidney organoids comprised of nephrons, proximal and distal epithelium, vasculature and surrounding interstitial elements. The utility of this protocol for applications such as disease modelling will rely implicitly on the developmental accuracy of the model, technical robustness of the protocol and transferability between iPSC lines. Here we report extensive transcriptional analyses of the sources of variation across the timecourse of differentiation from pluripotency to complete kidney organoid, focussing on repeated differentiations to day 18 organoid. Individual organoids generated within the same differentiation experiment show Spearmans correlation coefficients of >0.99. The greatest source of variation was seen between experimental batch, with the enrichment for genes that also varied temporally between day 10 and day 25 organoids implicating nephron maturation as contributing to transcriptional variance between individual differentiation experiments. A morphological analysis revealed a transition from renal vesicle to capillary loop stage nephrons across the same time period. Distinct iPSC clones were also shown to display congruent transcriptional programs with inter-experimental and inter-clonal variation most strongly associated with nephron patterning. Even epithelial cells isolated from organoids showed transcriptional alignment with total organoids of the same day of differentiation. This data provides a framework for managing experimental variation, thereby increasing the utility of this approach for personalised medicine and functional genomics.

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The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-NC 4.0 International license.
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  • Posted December 22, 2017.

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Transcriptional evaluation of the developmental accuracy, reproducibility and robustness of kidney organoids derived from human pluripotent stem cells
Belinda Phipson, Pei Xuan Er, Lorna Hale, David Yen, Kynan Lawlor, Minoru Takasato, Jane Sun, Ernst Wolvetang, Alicia Oshlack, Melissa Little
bioRxiv 238428; doi: https://doi.org/10.1101/238428
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Transcriptional evaluation of the developmental accuracy, reproducibility and robustness of kidney organoids derived from human pluripotent stem cells
Belinda Phipson, Pei Xuan Er, Lorna Hale, David Yen, Kynan Lawlor, Minoru Takasato, Jane Sun, Ernst Wolvetang, Alicia Oshlack, Melissa Little
bioRxiv 238428; doi: https://doi.org/10.1101/238428

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