The Regulation of Intestinal Smooth Muscle Cell Proliferation in Crohn’s Disease – Is NR4A1 a Novel Target to Treat Fibrostenosis?
Notice bibliographique
Résumé
Intestinal fibrosis and stricture formation are common complications of Crohn’s disease (CD). Recently, the stricturing phenotype has been recognized to be primarily attributable to hypertrophy/hyperplasia of smooth muscle, rather than an increase in fibrosis alone. Despite advances in treatment of CD, current therapies do little to prevent or reverse strictures. NR4A1 is an orphan nuclear receptor that has been reported as anti‐fibrotic in non‐intestinal systems and exhibits anti‐proliferative effects in smooth muscle cells (SMCs). NR4A1 gene variants have been associated with increased risk of inflammatory bowel disease, however, the mechanisms regulating NR4A1 expression and its role in intestinal SMC function have not been investigated. We sought to characterize and understand the role of NR4A1 activation in the regulation of mitogen‐induced proliferation of intestinal SMCs. We hypothesized that the activation of NR4A1 negatively regulates proliferative signaling and cell survival in intestinal SMCs. To test the hypothesis, primary intestinal SMCs were isolated from Nr4a1 +/+ and Nr4a1 −/− mice. Furthermore, a commercially sourced human primary intestinal SMC line was used. To assess the response of SMCs to culture and identify growth differences, proliferation was measured via trypan blue exclusion and EdU incorporation. In mouse and human SMCs, proliferation was induced by platelet‐derived growth factor‐BB (PDGF‐BB) and NR4A1 activation was assessed by pretreating with selective agonists, cytosporone‐B (Csn‐B) and 6‐mercaptopurine (6‐MP), at various concentrations. Mass spectrometry was used to characterize proteomic differences between Nr4a1 +/+ and Nr4a1 −/− SMCs. Expression levels of NR4A1 were assessed by qPCR and western blot after mitogen exposure and Csn‐B treatment. Nr4a1 −/− cells exhibited a significantly higher rate of proliferation compared to Nr4a1 +/+ cells, under both basal and mitogen‐exposed conditions. Proteomic analysis showed that Nr4a1 −/− SMCs exhibited increased expression of proteins related to the cell cycle and metabolism, compared to Nr4a1 +/+ SMCs. Pretreating human intestinal SMCs with Csn‐B and 6‐MP significantly attenuated proliferation induced by PDGF‐BB. Similar effects were observed in Nr4a1 +/+ SMCs, however, the anti‐proliferative effect of Csn‐B was absent in Nr4a1 −/− cells. Furthermore, NR4A1 expression was rapidly induced by Csn‐B and PDGF‐BB, the latter response suggesting the existence of a potential negative feedback mechanism to control mitogen‐induced SMC proliferation. Our results suggest that NR4A1 is a critical regulator of intestinal SMC proliferation and its induction by mitogens may contribute to a negative feedback loop to control smooth muscle growth. These data support targeting NR4A1 to treat excessive smooth muscle hypertrophy/hyperplasia that contributes to tissue remodelling observed in fibrostenotic CD. Support or Funding Information Canadian Institutes of Health Research
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».