Activating Resident Neural Precursor Cells in the Spinal Cord to Promote Neural Repair
Bibliographic record
Abstract
Within the mammalian spinal cord there are two distinct populations of neural precursor cells: neural stem and progenitor cells (NSPCs) and oligodendrocyte progenitor cells (OPCs). NSPCs are located within the periventricular zone of the spinal cord and are relatively quiescent and non‐neurogenic under homeostatic conditions. OPCs are located throughout the grey and white matter of the spinal cord and give rise to new oligodendrocytes throughout life. Both of these populations are activated following injury, however, their response is not sufficient for functional recovery. We propose that enhancing resident precursor activation is a promising approach to improve structural and functional outcomes following SCI. The FDA‐approved drug metformin (MET) has demonstrated efficacy in promoting improved outcomes in the injured brain through pleiotropic effects including: decreased inflammation, enhanced precursor cell activation and increased neurogenesis and oligogenesis. Here, we seek to establish the influence of MET treatment on NSPC and OPC populations and explore whether MET can improve functional recovery following injury in the spinal cord. Our cellular data reveal that in uninjured animals, MET treatment significantly expands the NSPC pool in females, but not males; increases neurogenesis in males only and enhances oligogenesis across both sexes. Conversely, we observed no effect of MET treatment on the number of OPCs in uninjured mice, irrespective of sex. To test the efficacy of MET treatment following injury, we used two distinct models: (1) a dorsal column injury in the thoracic spinal cord (SCI), and (2), a model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). In both models, MET was delivered to mice immediately following injury and for 14 days. Following SCI, mice were tested on a skilled walking test on post‐injury days (PID) 7 and 14. While all mice showed a significant deficit on PID7, by PID14, MET treated animals were not significantly impaired relative to pre‐injury performance and naive controls. In the EAE model, we evaluated the efficacy of MET treatment through both clinical scoring (based on degree of paralysis) and gait analysis. EAE resulted in significant clinical deficits 14 days following induction, which were mitigated in mice that received MET. Additionally, our gait analysis revealed improved metrics in MET treated mice. Across both injury models we observed significantly reduced inflammation. Taken together, our results support MET as a viable therapeutic strategy to expand and enhance NSPCs, improve the response of OPCs and support functional recovery following spinal cord injury. Support or Funding Information Canadian Institute of Health Research Medicine by Design
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".