Mapping disease-specific vascular cell populations responsible for obliterative arterial remodelling during the development of pulmonary arterial hypertension
Bibliographic record
Abstract
AIMS: Pulmonary arterial hypertension (PAH) is a lethal pulmonary vascular disease characterized by arteriolar pruning and occlusive vascular remodelling leading to increased pulmonary vascular resistance and eventually right heart failure. While endothelial cell (EC) injury and apoptosis are known triggers for this disease, the mechanisms by which they lead to complex arterial remodelling remain obscure. We employed multiplexed single-cell RNA sequencing at multiple timepoints during the onset and progression of disease in a model of severe PAH to identify mechanisms involved in the development of occlusive arterial lesions. METHODS AND RESULTS: Single-cell transcriptional analysis resolved 44 global lung cell populations, with widespread early transcriptomic changes at 1 week affecting endothelial, stromal, and immune cell populations. In particular, two EC clusters were greatly expanded during PAH development and were identified as being disease specific: a relatively de-differentiated (dD) EC population that was enriched for Cd74 expression while exhibiting a loss of endothelial identity; and an activated arterial EC (aAEC) population that uniquely exhibited persistent differential gene expression throughout PAH development consistent with a growth regulated state. dDECs were primed to undergo endothelial-mesenchymal transition as evidenced by reduced activity of master EC transcription factors, Erg and Fli1, and further supported by RNA velocity analysis showing vectors leading to fibroblast clusters. Of note, aAECs exhibited high expression of Tm4sf1, a gene implicated in cancer cell growth, that was also expressed by a smooth muscle (SM)-like pericyte cluster, and were highly localized to regions of arterial remodelling in both the rat model and PAH patients, contributing to intimal occlusive lesions and SM-like pericytes forming bands of medial muscularization. CONCLUSION: Together these findings implicate disease-specific vascular cells in PAH progression and suggest that TM4SF1 may be a novel therapeutic target for arterial remodelling.
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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 | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 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".