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
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".