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Lgr4 maintains Lgr5+ crypt base columnar cell identity required for intestinal homeostasis and regeneration [scRNA-seq]

ABSTRACT: The intestinal epithelium is amongst the most rapidly self-renewing epithelia in mammals. Wnt signalling is known to be essential for intestinal homeostasis and regeneration. However, the underlying cellular hierarchy remains debated. Recent models have challenged dogma with a LGR4/FGBFBP1+ isthmus cell being upstream of the Lgr5⁺ crypt base columnar (CBC) cells. Importantly the precise functional roles of Lgr4 and Lgr5 not fully understood. Here we show that Lgr4 is broadly expressed within the intestinal epithelial cells (including in Lgr5+ CBCs) and is required directly for Lgr5+ CBCs, Paneth cells, long term crypt survival and regeneration. Lgr5 loss expands CBC markers and Paneth cells at the expense of Goblet cells. Loss of Lgr4 function can be rescued by loss of the E3 ubiquitin ligases ZNFR3/RNF43. Together, these findings establish LGR4 as the principal Wnt-potentiating Lgr receptor and an indispensable, regulator of Lgr5+ CBC cell identity in intestinal homeostasis and regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE343665 | GEO | 2026/08/20

REPOSITORIES: GEO

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Lgr4 maintains Lgr5+ crypt base columnar cell identity required for intestinal homeostasis and regeneration [RNA-Seq]

Project description:The intestinal epithelium is amongst the most rapidly self-renewing epithelia in mammals. Wnt signalling is known to be essential for intestinal homeostasis and regeneration. However, the underlying cellular hierarchy remains debated. Recent models have challenged dogma with a LGR4/FGBFBP1+ isthmus cell being upstream of the Lgr5⁺ crypt base columnar (CBC) cells. Importantly the precise functional roles of Lgr4 and Lgr5 not fully understood. Here we show that Lgr4 is broadly expressed within the intestinal epithelial cells (including in Lgr5+ CBCs) and is required directly for Lgr5+ CBCs, Paneth cells, long term crypt survival and regeneration. Lgr5 loss expands CBC markers and Paneth cells at the expense of Goblet cells. Loss of Lgr4 function can be rescued by loss of the E3 ubiquitin ligases ZNFR3/RNF43. Together, these findings establish LGR4 as the principal Wnt-potentiating Lgr receptor and an indispensable, regulator of Lgr5+ CBC cell identity in intestinal homeostasis and regeneration.

2026-08-20 | GSE343667 | GEO

Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells

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Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells

Project description:Gene inactivation of the orphan G protein-coupled receptor Lgr4, a paralog of the epithelial stem cell marker Lgr5, results in 50% decrease of epithelial cell proliferation and 80% reduction in terminal differentiation of Paneth cells in postnatal mouse intestinal crypts. When cultured ex vivo, Lgr4-deficient crypts or progenitors, but not Lgr5-deficient progenitors, die rapidly with dramatic downregulation of stem cell markers and Wnt target genes, including Lgr5. Partial rescue of this phenotype is achieved by LiCl addition to the culture medium, but not by Wnt agonists. Our results identify Lgr4 as a permissive factor of the Wnt pathway in the intestine and, as such, as a potential target for intestinal cancer therapy. Microarray hybridization was performed on LGR4 KO intestinal crypts at day 0, day 0.5 and day 1 versus wild-type crypts. The effects of LiCl treatment on LGR4 KO crypts at day1 versus control cells were investigated. After amplification and labelling, sample pairs were hybridized onto Mouse Exonic Evidence Based Oligonucleotide (MEEBO) arrays containing on average 38784 mouse 70mer oligonucleotide probes (Stanford University, US). Hybridizations were replicated with dye swap.

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Expression data from FACS-purified Lgr5-EGFP+ intestinal cells from Ubc9+/+ and Ubc9+/- mice

Project description:The Lgr5+ intestinal stem cell, Paneth and transit-amplifying cell compartment constitute the intestinal crypt which is the constant source of differentiated epithelial cells that replenish the intestinal villi ensuring organ maintenance and regeneration. The Lgr5+ crypt-based columnar (CBC) cells have been identified as the intestinal stem cells (ISCs) and, importantly, as cells-of-origin of intestinal cancer. We used microarrays to detail the global program of gene expression in normal ISCs describing a mild downregulation of the sumoylation (post-translational modification (PTM) of proteins by SUMO) imposed by the loss of one allele of the unique E2-conjugating enzyme (Ubc9) of the pathway.

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An Lgr5-independent developmental lineage is involved in mouse intestinal regeneration (ATAC seq)

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An Lgr5-independent developmental lineage is involved in mouse intestinal regeneration II

Project description:Collagenase/dispase (CD fraction) treatment of intestinal tissue from adult mice generates cells growing in matrigel as immortal cystic spheroids in addition to differentiated organoids. Contrary to classical EDTA-derived organoids, these spheroids display poor intestinal differentiation and are independent of Rspondin/Noggin/EGF for growth. Their transcriptome resembles strikingly that of fetal intestinal spheroids, with downregulation of crypt base columnar cell (CBC) markers (Lgr5, Ascl2, Smoc2, Olfm4). In addition, they display upregulation of inflammatory and mesenchymal genetic programs, together with robust expression of YAP target genes. Lineage tracing, cell-sorting and single cell RNA sequencing experiments demonstrate that adult spheroid-generating cells belong to a hitherto undescribed developmental lineage, independent of Lgr5+ve CBCs, and are involved in regeneration of the epithelium following CBC ablation

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An Lgr5-independent developmental lineage is involved in mouse intestinal regeneration [scRNA-Seq]

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Single-Cell Transcriptomes of the Regenerating Intestine Reveal a Revival Stem Cell [part 2]

Project description:The weekly turnover of the intestinal epithelium is driven by multipotent, Lgr5+, crypt base columnar cells (CBCs). In response to injury, however, Lgr5+ cells are lost but then re-emerge and are required for successful recovery. How these resurgent Lgr5+ stem cells arise is unclear. We transcriptionally profiled single cells from regenerating intestinal epithelia and identified a unique cell type we term the revival stem cell (rSC). rSCs are mutually exclusive to CBCs and are distinguished by elevated expression of cell survival and DNA repair genes. In homeostasis, rSCs are extremely rare, but nevertheless give rise to all the major cell types of the intestine including crypt-villus axes. After damage rSCs display a 20-fold, Yap-dependent, transient expansion, reconstitute the Lgr5+ CBC compartment and are required to regenerate a functional intestine. These studies define a unique stem cell phenotype that is mobilized by damage to reconstitute the intestinal epithelium.

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