Nicotinamide promotes differentiation of pancreatic endocrine progenitors from human pluripotent stem cells through poly (ADP-ribose) polymerase inhibition
Bibliographic record
Abstract
Abstract The generation of pancreatic endocrine progenitor cells is an important step in the differentiation of beta cells from human pluripotent stem cells (hPSC). This stage is marked by the expression of Nkx6.1, a transcription factor with well understood downstream targets but with unclear upstream regulators. In hPSC differentiation, Nkx6.1 is strongly induced by nicotinamide, a derivative of vitamin B3, which has three known functions within a cell. Nicotinamide inhibits two classes of enzymes known as poly-ADP-ribose polymerases (PARPs) and sirtuins. It also contributes to the cellular pool of nicotinamide adenosine deoxynucleotide (NAD + ) after conversion in the nicotinamide salvage pathway. Induction of Nkx6.1 expression in pancreatic endocrine progenitors by nicotinamide was mimicked by 3 PARP inhibitors (PJ34, olaparib, NU1025). Small molecule inhibition of the nicotinamide salvage pathway reduced Nkx6.1 expression but not Pdx1 expression and caused alteration in NAD + /NADH ratio. Nkx6.1 expression was not affected by sirtuin inhibition. Metabolic profiling of differentiating pancreatic and endocrine progenitors showed that oxygen consumption increases as differentiation progresses, and that nicotinamide reduces oxygen consumption rate. Expression of Nkx6.1 and other beta cell related genes, including Ins2 and Pdx1 increased in mouse islets after exposure to nicotinamide. In summary, nicotinamide induced Nkx6.1 expression in differentiating human pancreatic endocrine progenitors through inhibition of the PARP family of enzymes. Nicotinamide administration was also associated with increased NAD+/NADH ratio, without affecting Nkx6.1 expression. Similarly, the association between nicotinamide and Nkx6.1 expression was also seen in isolated mouse islets. These observations show a link between the regulation of beta cell identity and the effectors of NAD + metabolism, suggesting possible therapeutic targets in the field of diabetes.
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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".