S1P Receptor Modulation by Fingolimod Promotes Human Oligodendrocyte Progenitor Cell Differentiation through Cell-Autonomous and Non-Cell Autonomous Mechanisms via ERK1/2 and p38MAPK Activation (I7-1.001)
Bibliographic record
Abstract
OBJECTIVE:To elucidate the molecular signaling mechanisms mediating FTY720p effects on human fetal oligodendrocyte progenitor cells (OPCs) differentiation and axonal ensheathment. BACKGROUND:FTY720 (Fingolimod) is a clinically approved sphingosine-1-phosphate receptor (S1PR) modulator which readily enters the CNS. FTY720 phosphate (FTY720p), the active moiety of FTY720 which undergoes phosphorylation in vivo, modulates initial process outgrowth in human progenitor and mature oligodendrocyte cultures and enhances differentiation and axonal ensheathment of OPCs when co-cultured with rat dorsal root ganglia neurons (DRGNs). Although repeated daily application of FTY720p inhibits cell signaling and/or functional responses mediated by the natural ligand S1P in human astrocytes and oligodendrocytes, FTY720p can continue to induce persistent receptor-mediated activation of signaling pathways. DESIGN/METHODS:OPCs were selected from 15-18 gestational week human brain samples using PDGFRα- or A2B5- antibody-coated immuno-magnetic beads. FTY720p or S1P (both at 50 nM) were added either daily or every 2 days. Phosphorylation of ERK1/2, p38MAPK or CREB was determined by Western blotting or immuno-staining together with cell type-specific markers. RESULTS:At an early time point (day 2), FTY720-p activated ERK1/2, p38MAPK and CREB in O4 positive cells, as well as in beta-III Tubulin positive neurons and GFAP positive astrocytes. In later cultures (day 6), FTY720-p activated p38MAPK in O4 positive cells, p38MAPK and ERK1/2 in neurons, and p38MAPK, ERK1/2 and CREB in astrocytes. O4 cells in later cultures (day 6) are morphologically more differentiated compared to early time point cultures. A MEK inhibitor (U0126) prevented the differentiation of OPCs into O4 positive cells, while a p38MAPK inhibitor (PD169316) blocked progression into O4 positive and into galactocerebroside (GC) positive stages of differentiation. CONCLUSIONS:Our results demonstrate that FTY720p, under conditions that model clinical use, can act directly on OPCs to impact differentiation, and also indirectly via neurons and astrocytes by activating ERK1/2 and p38MAPK. Study Supported by:MS Society of Canada; CIHR (Industry partnership program); Novartis.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".