A27 MSH2 CONTRIBUTES TO SELF-RENEWAL OF ESOPHAGEAL ORGANOIDS
Bibliographic record
Abstract
Abstract Background The esophagus is lined by a stratified epithelium in which basal cells can proliferate and undergo differentiation while migrating towards the lumen. In the basal layer, we also find Krt15+ stem cells that are multipotent, self-renewing and that have regenerative capacity. However, mechanisms that specifically control their functions remain unknown. Interestingly, RNA sequencing and gene set enrichment analysis (GSEA) revealed an enrichment of a gene set associated with DNA repair in Krt15+ cells in comparison to Krt15- cells. We also observed that Msh2 (MutS homolog 2), a gene associated with the DNA mismatch repair (MMR) mechanism, is the most significantly upregulated gene in Krt15+ stem cells. Aims To determine the impact of Msh2 loss on self-renewal of esophageal organoids under normal and stress conditions. Methods Esophageal epithelial cells were isolated from a wild type mouse and grown as organoids, a 3D culture model that supports stem cell growth and morphologically reproduces the tissue of origin. To determine Msh2 role in esophageal epithelium, this gene was deleted through a CRISPR/Cas9 approach in mouse esophageal organoids. Invalidation was confirmed by Western Blot and immunofluorescence. Impact of Msh2 loss on self-renewal was measured under normal condition and following radiation. Results At baseline, loss of Msh2 decreases the organoid formation rate of esophageal organoids. Furthermore, following high-dose radiation, Msh2 deficient cells form less organoids than control cells. These results suggest that self-renewal capacity is reduced when Msh2 is depleted. Interestingly, following radiation, organoids depleted for Msh2 show higher residual levels of p-H2AX, a DNA damage marker, and p-ATM, a key kinase in DNA damage response, suggesting that their capacity to cope with DNA damages is reduced. Conclusions Our results suggest that Msh2 contributes to maintaining genomic integrity in esophageal cells and that contributes to maintaining self-renewal capacity of basal cells and possibly esophageal stem cells. Funding Agencies Canada Research Chair.
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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) | 0.002 | 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".