Lgr5+ Stem Cells Maintain Apex Position in Cell Hierarchy of the Intestinal Epithelium During Homeostasis and Injury
Bibliographic record
Abstract
SUMMARY The cellular origin of intestinal epithelial homeostasis and regeneration has been a subject of continued debate, with recent models challenging the primacy of WNT-dependent Lgr5⁺ crypt base columnar (CBC) cells as the central intestinal stem cell population. Here, we revisit this question through quantitative integration of single-cell transcriptomic, chromatin accessibility, spatial, and lineage-tracing analyses across the proximal-to-distal axis of the small intestinal epithelium. Our data show that under homeostatic conditions, Lgr5⁺ cells exclusively sustain epithelial self-renewal in nearly all crypt–villus units along the entire length of the small intestine, a process for which R-spondin is indispensable. Following irradiation or chemotoxic injury, surviving Lgr5⁺ cells and their progeny reprogram into transient fetal-like cell states that initiate epithelial repair. Crucially, successful regeneration depends on the reactivation of canonical WNT/β-catenin signaling, as evidenced by increased TCF motif accessibility and upregulation of WNT target genes in newly forming Lgr5 + stem cells. Accordingly, pharmacological inhibition of WNT signaling blocks the reconstitution of Lgr5⁺ cells and crypt regeneration, leading to epithelial collapse. These findings reconcile prior controversies by demonstrating the central role of Lgr5⁺ CBC cells in epithelial self-renewal and regeneration following injury.
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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) | 0.001 | 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".