Poster Session 1: Stem Cell Biology; Therapeutics: New Agents (not approved, phase 2–3)
Bibliographic record
Abstract
Background: To recapitulate key stages of organ development, we engineered liver organoids using human induced pluripotent stem cells (iPSC), human mesenchymal stem cells (MSC), and human umbilical vein endothelial cells (HUVEC) as described previously.Because regulatory mechanisms of organoid maturation are not well defined, we investigated the differentiation patterns of liver organoids and tested if differentiation of iPSC requires direct contact with MSC and HUVEC.Methods: iPSC were differentiated to hepatic endoderm (iPS-HE) by Act,Wn-t3a,DMSO,and Knock-Out Serum Replacement then co-cultured with MSC and HUVEC to generate 3D organoids (liver buds).Following implantation under kidney capsules of mice, plasma levels of human albumin (ALB) and alpha1-antitrypsin (A1AT) were monitored by ELISA.To investigate whether cellcell contact is a key mechanism by which MSC and HUVEC induce bud formation and maturation of iPS-hepatocytes, we cultured iPS-HE in the upper well of a transwell system, where MSC or HUVEC resided in the lower well individually or in co-culture.The expression of alphafetoprotein (AFP), HNF4a,ALB,A1AT,CPS1,BSEP,and CD31 was determined by immunostaining or by ELISA.Results: Temporal-spatial analysis by time-lapse microscopy revealed self assembly of iPS-HE, MSC, and HUVEC into a 3D tissue in 24 hr following a condensation and folding pattern to form a concave hemisphere.Hepatocytic differentiation in the buds was demonstrated by the AFP+/HNF4+ cells by whole-mount staining, in proximity to CD31+ endothelial cells.After implantation of the buds, human ALB (140-260ng/ml) and A1AT (62-174ng/ml) were detected in mouse plasma.Explanted organoids showed hepatocyte-like morphology organized in cellular clusters surrounded by vascular networks.Using the transwell culture to determine the role of paracrine effect, we found that ALB concentration in culture supernatants achieved 1587±233ng/ml/day in iPS-HE with MSC in the lower well (iPS/MSC) and 1881±162ng/ml/day in iPS-HE/HUVEC, which were higher than iPS-HE cultured with MSC+HUVEC in the lower (455±110ng/ml/day) or iPS-HE alone (81±21ng/ml/day, P<0.01);A1AT was similarly higher in iPS-HE/MSC and iPS-HE/HUVEC (P<0.01).By immunostaining, the expression of ALB,A1AT,CPS1,and BSEP was more reproducible and uniform in the iPS-HE/MSC, followed by iPS-HE/HUVEC; the expression pattern for these proteins was limited or absent if iPS-HE were cultured alone or in iPS-HE/ MSC+HUVEC.Conclusions: iPS-HE interacts with MSC and HUVEC to assemble liver organoids, which supports hepatic differentiation.MSC derived soluble factors can promote functional maturation of iPS-HE in vitro monolayer culture.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.003 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.004 | 0.003 |
| Insufficient payload (model declined to judge) | 0.172 | 0.077 |
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".