62: Importance of the Timing Between the Induction of Muscle Regeneration and the Transplantation of Muscle Precursor Cells in the Outcome of the Graft: A Study in Nonhuman Primates
Notice bibliographique
Résumé
Introduction Transplantation of muscle precursor cells (MPCs) is a major strategy for a potential future treatment of genetic myopathies such as muscular dystrophies. The MPC transplantation protocol that we developed in non-human primates allowed the restoration of the genetically missing protein (dystrophin) with better efficacy than previously in muscle fibers of patients with Duchenne muscular dystrophy, but needs improvements to obtain a broader cell engraftment and dystrophin restoration. Of the factors analyzed so far in non-human primates to increase the cell engraftment, the only one that favored a broader integration of the grafted cells in the muscle fibers of the recipient was the induction of profuse muscle regeneration in parallel to the cell graft. Since muscle regeneration is a dynamic process, it is necessary to investigate the moment in which the grafted cells are more likely to integrate profusely into the recipient muscle fibers. To elucidate that, we carried out a study in non-human primates. Methods We transplanted allogeneic MPCs labeled with ß-galactosidase (ß-Gal) in muscle regions of 1 cm3 of cynomolgus monkeys, using arrays of 25 parallel equidistant perpendicular injections. The sites were treated or not with intramuscular electroporation (3 pulses of 400 V/cm and 5 ms with a delay of 200 ms) to trigger massive muscle regeneration. MPC transplantations were performed immediately after electroporation, as well as on days 1 to 7 after electroporation and days 1, 2, 3, 6 and 7 before electroporation. Tacrolimus was administered daily to control acute rejection. Cell grafted regions were sampled one month after transplantation, snap frozen in liquid nitrogen and sectioned in a cryostat. Muscle cross-sections were stained with hematoxylin and eosin and for histochemical demonstration of ß-Gal. The amount of ß-Gal+ myofibers was quantified in the cross-sections as an indication of engraftment success. Results The amount of ß-Gal+ muscle fibers was significantly increased by a factor of 3.2 ± 1.2 in the muscles in which cell transplantation was done immediately after electroporation, with respect to regions grafted similarly but without electroporation (p < 0.0001 in a paired t test).The set of values from days +3 to +7 (cell transplantation post-electroporation) implied a significant reduction in the number of ß-Gal+ muscle fibers (p < 0.05 in a paired t test). There were no significant differences in the other timings, having in some cases a large variation of values. Conclusion According to these data, MPC transplantation must be concomitant with the induction of muscle regeneration to ensure an increase in the cell engraftment. If MPC transplantation is performed between days 3 and 7 after the induction of muscle regeneration, this can jeopardize the cell engraftment, while in the rest of the timings studied the results can be very variable. This work was supported by a grant of the Jesse’s Journey Foundation for Gene and Cell Therapy of Canada to D.S. and a grant of the Canadian Institutes of Health Research to J.P.T.
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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) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».