A65 HNF4A IS A KEY REGULATOR OF THE EPITHELIAL STEM CELL NICHE.
Notice bibliographique
Résumé
HNF4α is a transcriptional factor downregulated in intestinal bowel diseases (IBD). Epithelial deletion of HNF4α in the mouse intestine leads to spontaneous intestinal inflammation. Those observations suggest that HNF4α could play an important role in epithelial homeostasis. The intestinal crypt is the functional compartment responsible for the maintenance of this homeostasis. Proliferation of stem cells is essential for the mucosa healing following injuries, while Paneth cells are important regulators of this process through the secretion of stem cell niche factors including WNT3, a key activator of the canonical WNT/β-catenin pathway. We aimed to investigate if HNF4α could play an intrinsic role in stem and Paneth cells for the maintenance of the epithelial niche in intestinal crypts. Villin-Cre/HNF4αloxp/loxp and the hydroxytamoxifen (4OHT) inducible Villin-Cre ERT2/HNF4αloxp/loxp mouse models were used in this study. Isolated crypts were processed for protein and RNA isolation. Enteroids were derived from these models and used for RNAseq and qPCR experiments. Enteroids were derived from jejunal crypts of inducible Villin-Cre ERT2/HNF4αloxp/loxp mice. Induction of HNF4α deletion with 4OHT led to degeneration of these enteroids starting 5 days after the deletion, an observation reminiscent of enteroids derived from the Villin-Cre/HNF4αloxp/loxp mouse model. EdU incorporation assays showed a decrease in the proliferative rate of enteroids 4 days following HNF4α deletion. RNAseq was next performed on RNA isolated from enteroids induced for HNF4α deletion after 2 and 4 days in culture. Transcriptomic analysis identified more than a thousand of genes differentially expressed following the deletion of HNF4α under these conditions. A significant reduction of WNT3 was predicted, an observation that was further confirmed by qPCR and Western in jejunal crypts of HNF4α mutant mice. To measure the functional relevance of WNT3 reduction during enteroids degeneration, a rescue experiment was performed. WNT3A supplementation was able to maintain HNF4α deleted enteroids in culture. Transcriptomic analysis of WNT3A-treated enteroids showed rescue for 85% of the genes identified to be modulated in enteroids deleted for HNF4α. To further verify if HNF4α may contribute to Paneth cell differentiation, enteroids committed to differentiate into the Paneth lineage were deleted for HNF4α. Gene transcript expression of Paneth cell markers (Defa3, Defa5, Defa20, Defa21-22, Lyz and WNT3) were all downregulated in the absence of HNF4α as opposed to EpHB3, which was not significantly modulated. This study identifies HNF4α as a key regulator of Paneth cell function for maintenance of the epithelial stem cell niche. These observations provide a novel mechanistic loop for which the intestinal epithelial healing process could be dependent following stress-related injuries. CIHRCCC-Vertex
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 | 0,001 | 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 ».