Kidney Week

Abstract: FR-OR040

Nephron Progenitor Commitment Is a Stochastic Process Influenced by Cell Migration

Session Information

• Defining Cellular Composition and Mechanisms of Kidney Formation
  October 26, 2018 | Location: 4, San Diego Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

• Lawlor, Kynan T., Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

Kynan T. Lawlor, PhD

• Zappia, Luke, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

Luke Zappia,

• Lefevre, James, Institute for Molecular Bioscience, The University of Queensland, Highgate Hill, Queensland, Australia

James Lefevre,

• Park, Joo-Seop, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

Joo-Seop Park,

• Hamilton, Nicholas A., Institute for Molecular Bioscience, The University of Queensland, Highgate Hill, Queensland, Australia

Nicholas A. Hamilton,

• Oshlack, Alicia, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

Alicia Oshlack,

• Little, Melissa H., Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

Melissa H. Little,

• Combes, Alexander N., University of Melbourne, Parkville, Victoria, Australia

Alexander N. Combes,

Background

Nephrons in the mouse kidney are formed from self-renewing mesenchymal progenitors that reside within a niche defined by the cap mesenchyme and ureteric epithelial tip. As the kidney develops, progenitor cells differentiate in response to inductive cues and exit the niche to form nephrons. We previously showed that the cap mesenchyme population is highly dynamic, migrating both within and between domains in response to niche cues. In this study we examine how migrating progenitors initiate nephrogenesis in a precise, spatially regulated manner.

Methods

We used lineage tracing, live timelapse imaging, single cell RNA-seq and computational modelling to characterise the fate of commiting mouse nephron progenitors.

Results

Using a tamoxifen inducible Wnt4-CreERT2 activated reporter we show that committing cells give rise to both the nephrons and a proportion of the progenitor pool. Timelapse imaging reveals a population of cells that are labelled at sites of nephrogenesis but escape commitment and re-enter the progenitor niche. Re-entry occurs continually during kidney development, leading to an accumulation of ‘escapers’ over time. Single cell RNA-seq reveals that these ‘escapers’ exist in the same range of transcriptional states as the unlabelled progenitor pool, suggesting that progenitors may traverse the transcriptional hierarchy between self-renewal and commitment in both directions. Consistent with this plasticity, live imaging analysis of individual cell fate suggests that some cells do not commit immediately but remain within the pre-tubular aggregate through branching iterations and contribute to subsequent nephrons.

Conclusion

We propose that nephron progenitor commitment is a stochastic process where the duration of exposure to spatially defined inductive cues is dependant on migration events. Progenitor plasticity may enable robust regulation of nephrogenesis as niches grow and are remodelled during organogenesis.

Funding

• Government Support - Non-U.S.