Biomechanical regulation of cell shapes promotes branching morphogenesis of the ureteric bud epithelium
Bibliographic record
Abstract
Abstract Background Branching morphogenesis orchestrates organogenesis in many tissues including kidney, where ureteric bud branching determines kidney size and nephron number. Defects in branching morphogenesis result in congenital renal anomalies which manifest as deviations in size, function, and nephron number thus critically compromising the lifelong renal functional capacity established during development. Advances in the genetic and molecular understanding of ureteric bud branching regulation have proved insufficient to improve prognosis of congenital renal defects. Thus, we addressed mechanisms regulating three-dimensional (3D) ureteric bud epithelial cell morphology and cell shape changes during novel branch initiation to uncover the contributions of cellular mechanics on cellular functions and tissue organization in normal and branching-compromised bud tips. Methods We explored epithelial cell behavior at all scales by utilizing a combination of mouse genetics and a custom machine-learning segmentation pipeline in MATLAB. Ureteric bud epithelial cell shapes and sizes were quantified in 3D wholemount kidneys. A combination with live imaging of fluorescently labelled UB cells, traction force microscopy, and primary UB cells were used to determine how basic cellular features and niche biomechanics contribute to complex novel branch point determination in the process that aims at gaining optimal growth and epithelial density in a limited space. Results Machine learning-based segmentation of tip epithelia identified geometrical round-to-elliptical transformation as a key cell shape change facilitating shifts in growth direction that enable propitious branching complexity. Cell shape and molecular analyses in branching-compromised epithelia demonstrated a failure to condense cell size and conformation. Analysis of branching-compromised ureteric bud derived epithelial cells demonstrated disrupted E-CADHERIN and PAXILLIN mediated adhesive forces and defective cytoskeletal dynamics as detected by fluorescent labelling of actin in primary ureteric bud epithelial cells. Branching-compromised ureteric bud epithelial cells showed wrinkled nuclear shapes and alterations in MYH9-based microtubule organization, which suggest a stiff cellular niche with disturbed sensing of and response to biomechanical cues. Conclusions Our results indicate that the adhesive forces within the epithelium and towards the niche composed of nephron progenitors must dynamically fluctuate to allow complexity in arborization during new branch formation. The data collectively propose a model where epithelial cell crowding in tandem with stretching transforms individual cells into elliptical and elongated shapes. This creates local curvatures that drive new branch formation during the ampulla-to-asymmetric ampulla transition of ureteric bud.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".