Interpreting Geometric Rules of Early Kidney Formation for Synthetic Morphogenesis
- Development, Organoids, and Genetic Models of Kidney Diseases
November 03, 2023 | Location: Room 105, Pennsylvania Convention Center
Abstract Time: 04:48 PM - 04:57 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 600 Development, Stem Cells, and Regenerative Medicine
- Hughes, Alex, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Group or Team Name
- Hughes Lab, Penn Bioengineering.
The kidney develops through coordinated growth of ureteric epithelial tubules (the future urinary collecting ducts), stroma, and nephron progenitors in the cap mesenchyme that surrounds each ureteric tip as they branch. Dynamic interactions between these tissues set nephron numbers for life, impacting the probability of adult disease. How then are the rates of nephron formation and ureteric tubule duplication balanced?
Here we study the geometric and mechanical consequences of tubule tip packing at the embryonic kidney surface for tip organization and nephron formation. We study whole-mount mouse embryonic kidneys and human iPSC-derived nephron progenitor organoids using confocal immunofluorescence, mechanical microindentation, Brillouin microscopy, laser microdissection, and spatial RNA sequencing.
We find that over developmental time, kidney curvature reduces and ‘tip domains’ pack more closely, which together create a semi-crystalline tip geometry at the kidney surface. We apply a geometric parameter of tip domains called the shape index to predict a rigidity transition to more solid-like tissue properties at later developmental stages and confirm by micromechanical measurements. At the level of individual tips we use the shape index to define a tip ‘life-cycle’ between branching events, and find that nephrogenesis rate varies over this life-cycle. Applying force inference techniques adapted from a cell vertex model and validating with laser ablation shows that tip domains experience a cyclical mechanical transient over each life-cycle. We then hypothesized that tip duplication periodically creates a mechanical microenvironment permissive to nephrogenesis. Indeed, mimicking a mechanical transient in human iPSC-derived nephron progenitor organoids increased Wnt-driven commitment to early nephron cell aggregates.
The data suggest that temporal waves of mechanical stress within nephron progenitor populations could constitute a clock that synchronizes nephron formation and ureteric tubule duplication. Ongoing work to understand the spatial and temporal regulation of nephron induction will clarify variation in nephron endowment between kidneys and advance engineered replacement kidney tissues for regenerative medicine.
- NIDDK Support