10-2: GENERATING AMYLOID RESISTANT STEM CELL-DERIVED BETA CELLS TO IMPROVE ISLET TRANSPLANT OUTCOMES IN TYPE 1 DIABETES
Bibliographic record
Abstract
Introduction: Insulin-producing human embryonic stem cell-derived β-cells (SC-β) are a promising alternative to islet transplantation for people with type 1 diabetes (T1D). SC-β cells may obviate need for organ donors, although long-term survival and function following transplantation remains a concern. Aggregation of islet amyloid polypeptide (IAPP), a hormone co-secreted with insulin from β-cells and the major component of cytotoxic islet amyloid in type 2 diabetes, has been implicated in islet transplant failure. Pramlintide is a non-aggregating, non-toxic human IAPP analogue used clinically as an adjunct therapy in T1D. We hypothesized that genetically engineered SC-β cells expressing pramlintide would have improved survival and function following transplantation. Methods: SCs were CRISPR-modified to produce a pramlintide analogue and differentiated to SC-β cells suitable for transplant. Diabetic immunodeficient mice (NSGs or SCID-Beige) were transplanted with 75-100 sorted wild-type (WT) or pramlintide SC-β cell clusters in the anterior chamber of the eye (ACE). Mice were fed a chow (n=6) or 45% high fat (HFD) diet (n=15) and blood glucose and C-peptide were assessed following fast-refeeding. Human-specific ELISAs were used to measure C-peptide and IAPP levels following glucose-stimulated secretion from SC-β cells and in transplanted animals. Results: Robust glucose-stimulated insulin secretion indicated maturation of both pramlintide and WT SC-β cells. Gene expression and ELISA confirmed production and secretion of pramlintide from mutant SC-β cells. Mice transplanted with WT or pramlintide SC-β cells secreted human C-peptide in response to fast-refeed at 5 and 10-weeks post-transplant. Immunostained graft sections harvested 90 days post-transplant revealed abundant SC-β cells co-expressing insulin and IAPP, suggesting in vivo maturation. WT SC-β cell graft-bearing mice fed HFD developed islet amyloid, while pramlintide SC-β cell grafts exhibited little or no amyloid. Conclusions: Pramlintide-expressing SC-β cells do not form amyloid following transplantation and have potential as an improved SC-β cell source for transplantation in T1D.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".