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Abstract: FR-OR11

Role of Biomechanics in the Regulation of Ureteric Bud Branching Morphogenesis

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Kuure, Satu, Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland
  • Iaroshenko, Vladislav, Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland
  • Kurtzeborn, Kristen, Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland

Group or Team Name

  • Kuure Lab.
Background

Branching morphogenesis is a fundamental developmental process driving the formation of several organs. Branching pattern in the developing kidney is stereotyped and involves geometrically distinct modes: tip bifurcation and trifurcation, and only very rarely lateral branching. The branching epithelium, known as ureteric bud (UB), undergoes a series of complex changes which first transform a single layered epithelial bud to an ampulla where then the terminal bifurcations take place. While the molecular mediators of tissue crosstalk during renal branching are rather well characterized, the mechanisms controlling exact branch-initiating cell identity in UB tips remain unknown. Moreover, the roles of cellular niche, extracellular matrix and biomechanics in branch point determination are poorly understood.

Methods

We utilize a combination of mouse genetics and a custom machine-learning based segmentation pipeline in MATLAB to quantify 3D UB epithelial cell shapes and sizes in wholemount kidneys to determine how cell shapes change and drive complex branching patterns. Live imaging of fluorescently labelled UB cells, traction force microscopy and primary UB cell cultures on matrices with varying stiffness are utilized to study how basic cellular features drive arborization of ureteric bud epithelium in normal and growth factor deficient kidneys.

Results

Cell shape characterization of 3D epithelium shows that individual cells in the bud stage are mostly elliptical but become significantly rounder as ureteric branching proceeds to the ampulla stage. In the next branch phase, the cells convert into elongated shape suggesting that the ampulla remodeling to bifurcated tips involves spatial constraints squeezing bud epithelial cells into tube-like organization. Accordingly, our results demonstrate not only remarkable differences in cell shapes in the MAPK/ERK-deficient UB epithelium incapable of complex branch formation but also clear fluctuations in adhesive forces exerted between epithelial cells themselves and towards their niche composed of nephron progenitors.

Conclusion

Our work describes the basic characteristics of ureteric bud epithelial cells during different branch formation phases. Together with our biomechanical studies, this provides a new cellular mechanism through which novel branch points are determined and how growth is regulated in developing kidney.

Funding

  • Government Support – Non-U.S.