<i>Ex vivo</i> expansion of skeletal muscle stem cells with a novel small compound inhibitor of eIF2α dephosphorylation
Bibliographic record
Abstract
Abstract BACKGROUND Regeneration of adult tissues requires the activity of rare, mitotically quiescent somatic stem cells. These features are illustrated by the muscle stem cell (MuSC), also known as the satellite cell for its satellite position underneath the basal lamina of the myofiber. Isolation of MuSCs results in their rapid activation of the myogenic program and their subsequent culture ex vivo leads to loss of stem cell regenerative capacity. These shortcomings make MuSCs difficult to study, manipulate and prevent cell based therapies. We have previously shown that muscle stem cells (MuSCs) require tightly regulated protein synthesis through the phosphorylation of eIF2α. Sal003, an analog of salubrinal that blocks eIF2α dephosphorylation, promotes ex vivo expansion of MuSCs retaining regenerative capacity after engraftment into the Dmd mdx mouse model of Duchenne muscular dystrophy. METHODS Since micromolar concentrations of sal003 (10μM) are required to expand MuSCs ex vivo , we undertook a structure relations study to identify novel sal003 analogs with efficacy at lower concentrations. We demonstrate ex vivo expansion of MuSCs isolated from wild-type and mdx mice using new compounds, and use CRISPR/Cas9 genome editing tools to restore dystrophin expression in cultured MuSCs. RESULTS Here, we have synthesized and screened chemical analogs of sal003 to identify a novel compound promoting the ex vivo expansion of MuSCs. The novel compound expands wild-type and mdx MuSCs more efficiently than sal003 and also prolongs culture of primary myoblasts from isolated MuSCs. CONCLUSIONS We identify a novel sal003 analog, C10, with increased potency at lower concentrations. Culture conditions including sal003 or C10 can extend culture of primary myoblasts from isolated MuSCs, which we predict will enable their further study, genetic manipulation and cell based therapies.
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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".