Pharmacological stimulation of murine and human hematopoetic stem cells
Notice bibliographique
Résumé
Hematopoietic stem cell (HSC) transplantation is a standard procedure in the treatment of hematological disorders and also applicable to support aggressive chemotherapy in cancer. In practice, the clinical outcome is often limited by inefficient bone marrow (BM) engraftment or by low numbers of available stem cells. It would therefore be desirable to enhance engraftment by pharmacological stimulation. HSC require several signals for successful migration into the bone marrow. One of these signals is provided by stimulation of Gα s [ 1 ]. Pretreatment with prostaglandin (PG) E 2 enhances engraftment via activation of Gα s -coupled EP 2 and EP 4 receptors [ 2 ]. Treprostinil is a stable analogue of prostacyclin/PGI 2 , which acts via IP, EP 2 and EP 4 receptors and is approved for treatment of pulmonary hypertension. Here we tested the hypothesis that treprostinil stimulates stem cell engraftment. Generation of murine bone marrow-derived HSCs: Undifferentiated HSC (lineage-negative, Lin− cells) were isolated from murine BM, separated by MACS (magnetic-assisted cell sorting) and characterized by fluorescence-activated cell sorting (FACS). BM transplantation: Lin− cells were pretreated in vitro in the absence and presence of 10 µM treprostinil alone or in combination with 30 µM FSK for 1 h at 37°C. The cellular threshold for successful transplantation was determined by titrating the number of HSCs required to allow for survival of lethally irradiated recipient mice. Engraftment and transplantation efficiency was determined by the analysis of white blood cell counts. Trepostinil triggered a concentration-dependent accumulation of cAMP in murine Lin− cells with an estimated EC 50 in the range of 0.3 µM. A treprostini-induced cAMP accumulation was also observed in human HSCs, which were also shown to express the mRNA encoding IP, EP 2 and EP 4 receptors. Treprostinil enhanced engraftment of HSCs; this conclusion is based on the following observations: (i) mice injected with treprostinil-pretreated Lin− cells had significantly higher levels of circulating white blood cells as compared to those receiving vehicle-treated Lin− cells (p < 0.05, unpaired t-test); (ii) when pretreated and untreated Lin− cells were mixed to compete for BM reconstitution, the pretreatment with treprostinil increased transplantation efficiency 1.5–3-fold; (iii) in vitro pretreatment of HSCs with trepostinil reduced the minimum number of cells required to rescue a mouse; (iv) engraftment of HSCs was further enhanced when treprostinil was also administered after injection of the pretreated HSCs. Treprostinil is suitable for improving haematopoetic stem cell transplantaion. The observations allow for designing a protocol to test the compound in a clinical trial.
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) | 0,001 | 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 ».