Generation and validation of an aryl hydrocarbon receptor knockout human embryonic stem cell line
Bibliographic record
Abstract
ABSTRACT Glucose homeostasis is tightly controlled by hormones secreted from pancreatic islets. The most abundant cell type in islets is the β-cell, which secretes insulin in response to nutritional stimuli. We previously reported that the adverse metabolic effects of high-dose dioxin exposure in mice are regulated by the aryl hydrocarbon receptor (AHR) specifically in β-cells. Additionally, fetal exposure to low-dose dioxin reduced β-cell area in female mice at birth; however, the role of AHR in β-cell development has not been explored. To characterize the AHR pathway in developing human β-cells, we differentiated human embryonic stem cells (hESCs) into “islet-like” cell clusters (SC-islets) in vitro and treated cells with vehicle or dioxin for 24-hours at key stages of differentiation. Dioxin exposure robustly upregulated AHR gene targets ( CYP1A1, AHRR ) at all stages of differentiation but only had modest effects on markers of islet development and maturity. We next generated an AHR knock-out (KO) hESC line and found that basal CYP1A1 expression was profoundly suppressed in AHR-KO cells compared to parental cells at all stages of differentiation. Key markers of developing and mature pancreatic islets were largely unaffected by AHR deletion; however, G6PC2 was consistently downregulated in SC-islets from AHR-KO cells compared to parental cells. Interestingly, AHR-KO SC-islets also showed modestly increased insulin secretion relative to the parental line, suggesting a role for AHR in islet development. This novel AHR-KO cell line will allow for deeper investigation into the impact of AHR on development of human islets and other cell lineages.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.003 |
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".