Differential Effects of HOXB4 Overexpression on Short and Long-Term Repopulating Cells in Nonhuman Primates.
Notice bibliographique
Résumé
Abstract The inability to expand hematopoietic stem cells (HSCs) has been a significant limitation for clinical transplantation and gene therapy applications. Here we examined in a clinically relevant nonhuman primate model the ability of HOXB4 to expand HSCs and thus potentially overcome this limitation. Using a competitive repopulation assay we directly compared engraftment of HOXB4-transduced and control-transduced CD34+ cells. In 3 animals, cells were infused after a 3-day transduction and in 2 animals after an additional 6 to 9 days ex vivo expansion. Follow-up for these animals is up to 15-months. In the 3 animals that received HOXB4GFP-transduced cells without additional ex vivo culture, gene transfer efficiencies in CD34+ cells were similar between HOXB4GFP and YFP transduced cells: 45% (range 36–55%) vs. 38% (range 36– 40%). We observed a dramatic increase in HOXB4GFP marked cells from 20–30% to 52–62% during the early engraftment period, resulting in an up to 10-fold difference in granulocyte marking between HOXB4GFP and YFP marked cells at 5 weeks post-transplantation. Although gene-marking levels declined over time, HOXB4 marking was still about 2 to 3-fold higher than marking in control cells even at 15 months post-transplantation. A more pronounced effect was observed in the 2 animals that received HOXB4-overexpressing cells after an additional 6 to 9 days of ex vivo culture. Again, no difference in transduction efficiency was observed between YFP (range 34–49%) and HOXB4GFP (range 39–43%) marked cells before transplantation. However, HOXB4 marking was higher than YFP marking 1 week after transplantation, with up to a 34-fold difference in granulocyte marking at 2 weeks post-transplantation. Although the difference was decreased thereafter, a 4 to 10-fold difference was maintained in granulocyte marking after 3 months post-transplantation, suggesting a potential effect on the expansion of long-term repopulating cells. Subset analysis by flow cytometry and Taqman PCR showed HOXB4GFP and YFP marking in all subsets. Marking in CD13+ granulocytes and CD14+ monocytes was higher with HOXB4GFP-transduced cells and marking in CD3+ T cells was higher with YFP-transduced cells, suggesting that HOXB4 overexpression may have a more pronounced effect on engraftment and differentiation of myeloid than T-lymphoid precursors. LAM-PCR analysis demonstrated multiple clones of HOXB4GFP+ cells and control YFP+ cells. Our results demonstrate that HOXB4 overexpression in CD34+ cells has a very dramatic effect on expansion and engraftment of short-term repopulating cells with a less pronounced effect on long-term repopulating cells. These data should have important implications for the expansion and transplantation of HSCs, in particular for cord blood transplantations.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».