Directed Differentiation of Mouse and Human Pluripotent Stem Cells to Renal Progenitors and Kidney Organoids
Bibliographic record
Abstract
Pluripotent stem cells (PSC) hold great promise in regenerative medicine. In order to harness their potential, we need to understand how to differentiate PSC to the cell types of interest. Here, we differentiated mouse embryonic stem cells (ESC) to renal progenitors and kidney organoids in a controlled and step-wise manner. We used microarray to explore whole genome transcriptional changes that occurred at each stage of differentiation and found that as the cells differentiated, genes associated with metanephros, ureteric bud and blood vessel development, and cell-matrix adhesion were significantly upregulated. Over-expression of Pax2, Six1, Eya1 and Hox11 paralogues during differentiation did not improve differentiation efficiency. We were able to aggregate the renal progenitors to form kidney organoids consisting of LTL+/E cadherin+ mature proximal tubules and extracellular matrix proteins secreted by the cells themselves. We showed how we can use ESC-derived organoids to study cisplatin-induced kidney injury and as a platform for nephrotoxicity screening. Next, we used a mouse secondary reprogramming system to generate induced pluripotent stem cells (iPSC) from proximal tubule cells (PTC) and tail tip fibroblasts (TTF). We showed that there were no significant differences in the expression of pluripotency-associated markers and renal progenitor markers between the undifferentiated PTC iPSC and TTF iPSC, but after differentiation to renal progenitors, the expression of renal progenitor markers was significantly higher in PTC iPSC-derived progenitors compared to TTF iPSC-derived progenitors. Lastly, we adapted our mouse ESC differentiation protocol to human iPSC and found that the protocol could yield approximately 40% SIX2+ cells. In summary, we demonstrated a novel method of differentiating mouse ESC to renal progenitors and kidney organoids, showed how we can modify this system to investigate the influence of gene dosage and epigenetic memory on renal differentiation, and lastly, showed how we can use this organoid system as a semi-high throughput platform for nephrotoxicity screening.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".