673. Threshold of Normal Stem Cells for Successful Correction of Murine β-Thalassemia
Notice bibliographique
Résumé
To achieve a permanent correction of the β-thalassemia phenotype, it is necessary to establish basic criteria to serve as reference. Using the hemi-βthal mouse deleted from the two adult genes in the β-globin locus on a homogenous genetic background, we have shown that not only red blood cells (RBCs) have a shortened half-life but also that the late erythroid precursors have cellular and structural anomalies resulting in severe ineffective erythropoiesis. Based on this characterization, we hypothesized that bone marrow transplantation of normal donor cells into a thalassemic recipient would have a strong selective advantage and predominate upon erythroid differentiation and maturation. Our aim was to determine the minimal percent of normal bone marrow cells that is necessary to engraft for a future curative gene therapy approach. We have used a Competitive Repopulating Assay by transplanting lethally irradiated recipient mice with a fixed number of bone marrow cells containing reciprocal proportions of normal and hemi-βthal cells ranging from 5 to 100%. The assays were designed to generate 11 chimeric groups of hemi-βthal mice with at least 5 mice per group transplanted with normal and hemi-βthal bone marrow cells. Analysis of 95 hemi-βthal recipient mice followed for short and long-term post-transplantation (2 months to >1 year) were carried out by various cellular, molecular and physio-pathologic evaluation. These analyses showed that a chimerism of 19–24 % normal engrafted cells, determined by the Gpi1a marker, produced 40–50% of normal RBCs in the peripheral blood. Interestingly, the osmotic fragility of the RBCs from the chimeric hemi-βthal groups displayed a two-step lysis corresponding to the chimerism of the two RBC populations. The hematological parameters of the 19–24% chimeric hemi-βthal mice were significantly improved with increase hemoglobin of 3–4 g/dl and mean cell volume (MCV) reaching normal range. With 19% chimerism, RBC half-life was increased by at least 60% relative to control and their morphology was significantly ameliorated. Similarly, bone marrow and splenic erythropoiesis was improved with increasing chimerism. Consequent to the normalization of RBC half-life and splenic erythropoiesis, the pathology of chimeric mice showed a significant decrease in splenomegaly and in extramedullary splenic hematopoiesis/erythropoiesis. Furthermore, the lifespan of the chimeric mice was increased to normal life expectancy even with 24% chimerism, suggesting a general improvement of the mice physiology. Hence these results determined a two-fold selective advantage of normal RBC relative to thalassemic cells. Altogether, these results established a therapeutic range of 19–24% of engrafted normal/modified bone marrow cells for a physiologic impact and for a significant long-term correction of hemi-βthal mouse condition in vivo.
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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 ».