R-spondin 3 regulates stem cell plasticity and recovery of damaged colon epithelium
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ABSTRACT:
PROVIDER: PRJNA475953 | ENA |
REPOSITORIES: ENA
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Project description:The gastrointestinal epithelial crypts are clonal units with a high cell turnover, driven by a small population of long-lived, Lgr5-expressing stem cells located in the crypt base. Despite this, depletion of Lgr5+ cells does not lead to severe pathology. Instead, other cell populations, such as secretory and enterocyte precursors are able to de-differentiate, replace Lgr5+ cells, and regenerate the crypt. However, the signals that regulate this epithelial plasticity are not well understood. Here we illuminate the hierarchical organization and regulation of stem cell plasticity in the colonic crypt. Using in vivo lineage tracing, we find that the classic Wnt target gene Axin2 is expressed in colonic Lgr5+ cells and adjacent Lgr5-negative cells that give rise to entire crypts upon Lgr5+ cell depletion. The identity of Lgr5+ cells is controlled by by R-spondin 3 (Rspo3) produced by myofibroblasts and the recovery of Lgr5+ cells upon depletion required functional Rspo3 signaling. In contrast, expression of Axin2 and the reserve stem cell function of Axin2+ cells is not dependent on Rspo3. Accordingly, upon knockout of Rspo3, Lgr5-negative Axin2+ cells are able to compensate the loss of the Lgr5+ cell compartment and maintain epithelial integrity. In contrast, Rspo3 is essential for maintaining epithelial integrity in the context of injury of the entire Axin2+ cell pool, as observed in the context of DSS colitis. We demonstrate that DSS induces a progressive loss of the Lgr5+ stem cells as well as Axin2+ Lgr5-negative reserve stem cell compartment. While Rspo3 deficient animals are unable to withstand this injury, in Rspo3 competent animals, crypt homeostasis and regeneration are fueled by the remaining Axin2-negative, differentiated cells. These cells can be reprogrammed by Rspo3 to proliferate and act as stem cells. Thus, we identity Rspo3 as a major regulator of the Lgr5 stem cell signature. While loss of this signature can be compensated by Rspo3-independent reserve stem cells under healthy conditions, it is essential for re-establishment of epithelial integrity upon crypt injury.
2019-06-01 | GSE115752 | GEO
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Project description:Intestinal ischemia induces mucosal damage while simultaneously activating intestinal stem cells (ISCs), which subsequently regenerate the damaged intestinal epithelium. However, whether angiocrine factors secreted from vascular endothelial cells (ECs) - blood and lymphatic ECs (BECs and LECs, respectively) – regulate ISC-mediated regeneration have yet to be elucidated. Here, we identify FOXC1 and FOXC2 as essential regulators of angiocrine signaling in regeneration of the small intestine after ischemia-reperfusion (I/R) injury. EC- and LEC-specific deletions of Foxc1, Foxc2, or both in mice augment I/R-induced intestinal damage by causing defects in vascular regrowth, expression of the chemokine CXCL12 and the Wnt activator R-spondin 3 in BECs and LECs, respectively, and activation of Wnt signaling in ISCs. Treatment with CXCL12 and R-spondin 3 rescues the I/R-induced intestinal damage in EC- and LEC-Foxc mutant mice, respectively. This study provides evidence that FOXC1 and FOXC2 are required for intestinal regeneration by stimulating angiocrine CXCL12 and Wnt signaling.
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Project description:Pioneering studies within the last few years have allowed the in vitro expansion of tissue-specific adult stem cells from a variety of endoderm-derived organs, including the stomach, small intestine and colon. Here we derived organoids from mouse gallbladder tissue (gallbladder organoids), from mouse liver (including the extrahepatic biliary ducts and gallbladder; liver organoids) and from mouse small intestine tissue (intestinal organoids). RNA was prepared from these organoids and used to assay expression of 21,258 genes using Affymetrix gene expression arrays. RNA was also prepared from mouse gallbladder, liver and small intestine tissues and used to assay gene expression in these tissues. Finally, gallbladder organoids were induced to differentiate by removing R-spondin 1 and noggin from the culture media and subjected to gene expression array analysis. RNA was extracted from mouse gallbladder organoids, differentiated gallbladder organoids, liver organoids, small intestine organoids, gallbladder tissue, liver tissue and small intestine tissue and then used for hybridization of Affymetrix gene expression microarrays.
2016-04-06 | E-GEOD-77461 | biostudies-arrayexpress
Project description:Pioneering studies within the last few years have allowed the in vitro expansion of tissue-specific adult stem cells from a variety of endoderm-derived organs, including the stomach, small intestine and colon. Here we derived organoids from mouse gallbladder tissue (gallbladder organoids), from mouse liver (including the extrahepatic biliary ducts and gallbladder; liver organoids) and from mouse small intestine tissue (intestinal organoids). RNA was prepared from these organoids and used to assay expression of 21,258 genes using Affymetrix gene expression arrays. RNA was also prepared from mouse gallbladder, liver and small intestine tissues and used to assay gene expression in these tissues. Finally, gallbladder organoids were induced to differentiate by removing R-spondin 1 and noggin from the culture media and subjected to gene expression array analysis.
2016-04-06 | GSE77461 | GEO
Project description:DGCR8 promotes intestinal regeneration of damaged epithelium in a p53 signaling dependent manner
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Project description:Transcriptional alterations in LSECs from healthy and damaged livers were determined using RNA Sequencing. Models include acute liver injury (1 ip injection of CCl4) with different timepoints during recovery. Illumina NextSeq 500 High was used for sequencing.
2021-10-08 | GSE180366 | GEO
Project description:Here, we used single cell RNA-sequencing (scRNA-seq) to profile 13-week post-conception distal human fetal lung explants cultured in an air liquid interface system and treated with an LGR5 ectodomain adenovirus that inhibits R-Spondin function or control adenovirus. A third, non-infected, condition was also sequenced. We also performed scRNA-seq on distal human fetal lung tissue from an 8.4-week post-conception biological specimen. Diverse cell lineages were captured in all data sets, and include epithelium, mesenchyme, immune, neurons, and endothelium.
2022-01-01 | E-MTAB-10662 | biostudies-arrayexpress
Project description:Gastric epithelial stem cells are responsible for constant epithelial self-renewal, which is accelerated by infection with the gastric pathogen Helicobacter pylori. However, the mechanism that regulates stem cell turnover in the stomach remains unknown. Here we show that signaling by R-spondin 3 and Wnt hierarchically organizes the stem cell compartment in the antrum, producing two Wnt-responsive populations, which are either Lgr5+ve or Axin2 +ve. The positional identity of the Axin2+ve population relies on R-spondin 3 produced by stromal myofibroblasts. Increased availability of R-spondin induces hyperproliferation through specific expansion of Axin2+ve but not Lgr5+ve cells. Similarly, infection with H. pylori induces an increase in stromal R-spondin 3 expression, resulting in hyperplasia as well as shedding of bacteria that have entered the gland. This identifies a role for stromal cells in environmental sensing to orchestrate epithelial homeostasis via Wnt signaling.
2017-06-30 | GSE79494 | GEO