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Peer-reviewedCC BY-NC-NDGenome biology

Stochasticity in response to rostrocaudal and mediolateral determinants influences inaccurate specification within kidney organoids.

  • Sean B Wilson1,2
  • Jessica M Vanslambrouck1,3
  • Pei Xuan Er1
  • Mian Xie1
  • Hannah Baric1
  • Berta Vidal Pitarch2
  • Alisa Agafonova4
  • Himanshi Arora5
  • Walter Muskovic5
  • Drew Neavin5
  • Angela Murphy5
  • Ala Trusina4
5 more authors
  • Sara E Howden1,3
  • Allara K Zylberberg1,3
  • Kynan T Lawlor1,3
  • Joseph E Powell5,6
  • Melissa H Little7,8,9
9 affiliations
  1. 1Novo Nordisk Foundation Centre for Stem Cell Medicine, Murdoch Children's Research Institute, Parkville, Melbourne, 3052, Australia.
  2. 2Novo Nordisk Foundation Centre for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
  3. 3Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
  4. 4Neils Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
  5. 5Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.
  6. 6UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW, 2052, Australia.
  7. 7Novo Nordisk Foundation Centre for Stem Cell Medicine, Murdoch Children's Research Institute, Parkville, Melbourne, 3052, Australia. [email protected].
  8. 8Novo Nordisk Foundation Centre for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark. [email protected].
  9. 9Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia. [email protected].
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Abstract

Background

The differentiation of human pluripotent stem cells to kidney requires the accurate recapitulation of complex morphogenetic patterning events within an in vitro environment. Current protocols are assumed to accurately pattern through intermediate mesoderm to kidney with outcomes described based on formation of recognized renal structures. However, these protocols show significant technical variability and the presence of 'off target' cell types. We hypothesise that such 'off-target' cells represent heterogeneity in commitment along predictable rostrocaudal or mediolateral axes with respect to intermediate mesoderm.Results

To test this hypothesis, we perform a temporal (4 stages across 27 days) factorial (21 growth factor conditions) screen evaluating the impact of perturbation to a commonly used kidney organoid protocol and evaluate the relative cellular composition at a single cell level. We test growth factor variation during early mesodermal patterning via variation in FGF, BMP and RA signalling. While the prevalence of 'off-target' endpoints shifts predictably along rostrocaudal and mediolateral axes, patterning to neural/glial, paraxial and intermediate mesoderm endpoints is evident in all conditions. Heterogeneity of specification is observed using different cell lines in the same protocol and in a distinct differentiation protocol designed to generate neuromesodermal progenitors.Conclusions

We suggest a stochasticity in early mesodermal patterning in vitro with heterogeneous trajectories arising early in the protocol and leading to indeterminate mesodermal states with considerable resulting in plasticity.

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Cite

BibTeXRIS
BibTeX
@article{wilson2026stochasticity,
  title = {{Stochasticity in response to rostrocaudal and mediolateral determinants influences inaccurate specification within kidney organoids.}},
  author = {Sean B Wilson and Jessica M Vanslambrouck and Pei Xuan Er and Mian Xie and Hannah Baric and Berta Vidal Pitarch and Alisa Agafonova and Himanshi Arora and Walter Muskovic and Drew Neavin and Angela Murphy and Ala Trusina and Sara E Howden and Allara K Zylberberg and Kynan T Lawlor and Joseph E Powell and Melissa H Little},
  journal = {Genome biology},
  year = {2026},
  month = aug,
  doi = {10.1186/s13059-026-04221-9},
  url = {https://europepmc.org/article/MED/42963553},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Stochasticity in response to rostrocaudal and mediolateral determinants influences inaccurate specification within kidney organoids.
AU  - Sean B Wilson
AU  - Jessica M Vanslambrouck
AU  - Pei Xuan Er
AU  - Mian Xie
AU  - Hannah Baric
AU  - Berta Vidal Pitarch
AU  - Alisa Agafonova
AU  - Himanshi Arora
AU  - Walter Muskovic
AU  - Drew Neavin
AU  - Angela Murphy
AU  - Ala Trusina
AU  - Sara E Howden
AU  - Allara K Zylberberg
AU  - Kynan T Lawlor
AU  - Joseph E Powell
AU  - Melissa H Little
PY  - 2026
DA  - 2026/08/03
JO  - Genome biology
DO  - 10.1186/s13059-026-04221-9
UR  - https://europepmc.org/article/MED/42963553
AB  - Background  The differentiation of human pluripotent stem cells to kidney requires the accurate recapitulation of complex morphogenetic patterning events within an in vitro environment. Current protocols are assumed to accurately pattern through intermediate mesoderm to kidney with outcomes described based on formation of recognized renal structures. However, these protocols show significant technical variability and the presence of 'off target' cell types. We hypothesise that such 'off-target' cells represent heterogeneity in commitment along predictable rostrocaudal or mediolateral axes with respect to intermediate mesoderm.Results  To test this hypothesis, we perform a temporal (4 stages across 27 days) factorial (21 growth factor conditions) screen evaluating the impact of perturbation to a commonly used kidney organoid protocol and evaluate the relative cellular composition at a single cell level. We test growth factor variation during early mesodermal patterning via variation in FGF, BMP and RA signalling. While the prevalence of 'off-target' endpoints shifts predictably along rostrocaudal and mediolateral axes, patterning to neural/glial, paraxial and intermediate mesoderm endpoints is evident in all conditions. Heterogeneity of specification is observed using different cell lines in the same protocol and in a distinct differentiation protocol designed to generate neuromesodermal progenitors.Conclusions  We suggest a stochasticity in early mesodermal patterning in vitro with heterogeneous trajectories arising early in the protocol and leading to indeterminate mesodermal states with considerable resulting in plasticity.
SN  - 1474-7596
SN  - 1474-760X
ER  -