Abstract 473: Genetic Fate Mapping Identifies Second Heart Field Epicardial Progenitor Cells as a Source of Adipocytes in Arrhythmogenic Right Ventricular Cardiomyopathy
Bibliographic record
Abstract
The pathological hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), a genetic disease of desmosomal proteins, is fibro-adipocytic replacement of cardiac myocytes. The cellular origin of adipocytes in ARVC is an enigma. In desmosomal ARVC the impetus has to instigate from cells that express the mutant protein. Cardiac myocytes are the only cells in the heart known to express the desmosomal proteins. Adult myocytes are terminally differentiated, and hence, an unlikely source. In contrast, cardiac progenitor cells can differentiate to different lineages. Thus, we conditionally deleted Dsp, encoding desmoplakin, and concomitantly expressed enhanced yellow fluorescent protein (EYFP) using the Cre-LoxP technique, regulated by Nkx2.5, an early cardiac lineage promoter. We also screened the human hearts with ARVC for co-expression of markers of cardiac cell lineages and adipocytes. We generated Nkx-2.5-Cre:Dsp W/F and Nkx-2.5-Cre:Dsp W/F :R26-EYFP F/F mice, which showed enlarged hearts, depressed cardiac systolic function and patchy areas of fibro-adiposis, particularly at the epicardium. We detected expression of EYFP by immunoblotting (IB) and immunofluorescence (IF) and expression of cardiac progenitor cells and adipocytes markers by IF. A subset of epicardial cells in the Nkx-2.5-Cre:Dsp W/F :R26-EYFP F/F mice co-expressed adipogenic transcription factors C/EBP-α and PPAR-γ along with EYFP and the second heart field markers IsI1 and Mef2c. Likewise, we detected co-expression of C/EBP-α and IsI1 or Mef2C in the fibro-adipocytic regions in human hearts with ARVC. To determine the specific cardiac cell lineage that differentiates to adipocytes, we co-stained sections of human and lineage trace mouse hearts and detected co-expression of SM actin, a marker of smooth muscle cells (SMCs) and C/EBP-α as well as co-expression of cardiac α-actin, a marker of cardiac myocytes, and C/EBP-α but not co-expression of PECAM1, a marker of endothelial cells and C/EBP-α. We conclude excess adipocytes in desmosomal ARVC originate from second heart field epicardial SMCs/myocyte progenitor cells.
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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 | 0.001 |
| 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".