Human iPS cell-derived cardiac tissue sheets for functional restoration of infarcted porcine hearts
Bibliographic record
Abstract
To realize human induced pluripotent stem cell (hiPSC)-based cardiac regenerative therapy, evidence of therapeutic advantages in human-sized diseased hearts are indispensable. In combination with an efficient and simultaneous differentiation of various cardiac lineages from hiPSCs and cell sheet technology, we aimed to generate clinical-sized large cardiac tissue sheets (L-CTSs) and to evaluate the therapeutic potential in porcine infarct heart. We simultaneously induced cardiomyocytes (CMs) and vascular cells [vascular endothelial cells (ECs) and vascular mural cells (MCs)] from hiPSCs. We generated L-CTSs using 10cm-sized temperature-responsive culture dishes. We induced myocardial infarction (MI) in micromini-pigs (15-25 kg) and transplanted the L-CTSs (Tx) 2 weeks after MI induction (4 sheets/recipient) under immunosuppression (Tx: n = 5, Sham: n = 5). Self-pulsating L-CTSs were approximately 3.5cm in diameter with 6.8×106±0.8 of cells containing cTnT+-CMs (45.6±13.2%), VE-cadherin+-ECs (5.3±4.4%) and PDGFRβ+-MCs (14.4±20.7%), respectively (n = 5). In Tx group, echocardiogram indicated a significantly higher systolic function of the left ventricle (LV) compared to that in sham control (Sham vs Tx: fractional shortening: 24.2±8.6 vs 40.5±9.7%; p<0.05). Ejection fraction evaluated by left ventriculogram was significantly higher in Tx group (25.3±6.2% vs 39.8±4.2%; p<0.01). Speckle tracking echocardiogram showed a significant increase of circumference strain in infarct and border regions after transplantation. Fibrotic area was significantly lower in Tx group (23.8±4.5 vs 15.9±3.8%; P<0.001). Capillary density in the border region was significantly higher in Tx group (75.9±42.6/mm2 vs 137.4±44.8/mm2, p<0.001). These data indicate that the L-CTS transplantation attenuated LV remodeling. L-CTSs potentially restore cardiac dysfunction of human-sized infarct heart.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".