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Abstract: FR-PO351

Trajectory Analysis of the Kidney Organoid Proteome Extends Its Modelling Potential of Disease

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Lassé, Moritz, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Demir, Fatih, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • El Saghir, Jamal, University of Michigan, Ann Arbor, Michigan, United States
  • Fischer, Matthew, University of Michigan, Ann Arbor, Michigan, United States
  • Bonin, Léna Lydie, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Hutzfeldt, Arvid D., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Dumoulin, Bernhard, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Reinhard, Linda, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Hoxha, Elion, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Beck, Bodo B., Uniklinik Koln, Cologne, Nordrhein-Westfalen, Germany
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Harder, Jennifer L., University of Michigan, Ann Arbor, Michigan, United States
  • Rinschen, Markus M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

Kidney organoids are a valuable and innovative model to understand genetic diseases, kidney development and transcriptomic dynamics. However, details of proteome organization during organoid development are insufficiently characterized. It is unclear how the organoid proteome changes during differentiation, and if more complex disease processes such as inflammatory tissue responses could be modelled using organoids.

Methods

Here, we used proteomics to compare organoids with existing model systems such as native glomeruli and cultured podocytes. We characterize the trajectory of organoid differentiation and delineate innate immune responses in organoids to expand its scope as a model system in nephrology. We also compared our proteomics with bulk and single cell transcriptomic data.

Results

Genes involved in Focal segmental glomerulosclerosis (FSGS) and cystic kidney disease were abundantly expressed on protein level, distinguishing organoids from almost every available cell culture model. On their pathway to terminal differentiation, organoids developed increased deposition of extracellular matrix. Single cell transcriptomic analysis suggests that most changes locate to podocytes and early podocyte progenitors. This matrix deposition of organoids during maturation was similar to the matrix deposits found in human FSGS but differed markedly from other in vitro and in vivo animal disease models. A novel signaling system discovered was the TNFα system, a system also available in podocytes. Incubation of organoids with high concentrations of TNFα led to an activation of NF-kB signaling, and secretion of cytokines and complement components, alongside with extracellular matrix components.

Conclusion

We provide a repository of human kidney organoid proteins and show their potential to model pathophysiological pathways beyond genetic diseases. Signaling systems in these organoids link inflammatory signaling, production of cytokines and complement, and production of extracellular matrix.