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Abstract

During early kidney organogenesis, nephron progenitor cells move from the tip to the branch of the ureteral bud to form the so-called pretubular aggregate, the precursor structure of the later nephron. It is assumed that cell pattern formation during this critical phase of organogenesis is primarily controlled by chemotactic mechanisms and differential cell-cell adhesion. The spatial-temporal organization of this process is not yet fully understood. In recent studies, a nonlinear swarm-like pattern of cell movement has been observed.

In order to gain a better understanding of these processes, I elaborated a three-dimensional mathematical Cellular Potts model, and carried out, validated and applied corresponding model simulations. The model parameters were estimated from experimental data obtained in ex vivo kidney explant and dissociation-reaggregation organoid culture studies.

The simulations showed that an optimal enrichment and aggregation of nephron progenitor cells in the corner niche of the ureteral bud branch depends on three factors: the secretion of chemoattractant molecules by a) the epithelial cells of the ureteral bud and b) the nephron progenitor cells themselves, and c) by different adhesion energies between the different cell types. Furthermore, it was observed both experimentally and in the model simulation that nephron progenitor cells move at a higher speed in the corner region of the ureteral bud branches than in their region of origin at the tip of the bud from which they originate. The existence of different cell velocity domains along the ureteral bud was also evaluated with the self-organizing map technique.

In summary, I was able to confirm in the present work the suitability of the Cellular Potts model approach for simulating cell movements and pattern formation during early nephrogenesis. A further refinement of the model should allow the effects of developmental changes the cell phenotypes and the molecular interactions during organ development.