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Abstract: FR-OR038

Human Nephron Segmentation: Opportunities to Replicate Cellular Programs In Vitro

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

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

Author

  • Lindstrom, Nils, The University of Southern California, Los Angeles, California, United States

Group or Team Name

  • Andrew McMahon laboratory
Background

Advances in renal bioengineering have shown how pluripotent stem cells can be differentiated into composite cell-structures called ‘kidney organoids’. These technologies can, if harnessed properly, hold potential for human kidney disease modeling, nephrotoxicity screens, and renal replacement therapies. However, the intense interest into the kidney organoids have highlighted our current insufficient understanding of normal human kidney development and raised the question of whether the blueprint for nephrogenesis established in the mouse, frog, and fish, is actually applicable to the human system and the organoid.

Methods

To establish a cellular and molecular understanding of human development we have carefully scrutinized and contrasted it with mouse kidney development using a broad range of technologies including bulk RNA-sequencing (conventional and MARIS-based), single-cell RNA sequencing, in situ hybridization, immunofluorescent stains (three dimensional and two dimensional), and confocal live fate-mapping.

Results

We demonstrate significant conservation between human and mouse patterning programs alongside distinct divergences in anatomies and expression patterns (JASN 2018 PMIDs: 29449453, 29449451, 29449449). Further, our examination of the human system resulted in the proposition of a new model for how nephrons form and pattern. Mesenchymal nephron progenitors are recruited into the forming nephron over a protracted period of time and it is the order of recruitment that dictates the spatial identities and eventual fates of each cell. We demonstrate this model by high-resolution image analyses and 3D reconstructions of human nephrogenesis and confirmed it through direct visualization and cell fate analysis in the mouse kidney organ cultures. Single-cell RNA sequencing of the human nephrogenic niche revealed the molecular events occurring during these early patterning processes and predicted developmental trajectories adopted by nephron progenitor cells in forming segment-specific domains of the human nephron.

Conclusion

The temporal-recruitment model for nephron polarity and patterning provides a framework for how integrated signaling pathways drive mammalian nephrogenesis. Collectively, these studies benchmark human nephrogenesis and predicts why current organoids fall short of replicating the in vivo nephron.

Funding

  • NIDDK Support