Regionally defined stem cell growth directs cell fate during intestinal nutrient adaptation
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE222254 | GEO | 2024/02/14
REPOSITORIES: GEO
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Project description:Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance causing obesity and increased risk for type 2 diabetes (T2D) and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). But, how an obesogenic diet affects ISC identity and fate decisions is not well understood. Here, we study the intestinal responses to an obesogenic diet in mice by combining single-cell profiling of more than 27,000 small intestinal crypt cells with genetic lineage labelling and tracing of ISC fate decisions and in situ metabolomics. We find that an obesogenic diet induces ISC and progenitor hyperproliferation, but also enhances ISC differentiation and cell turnover. Furthermore, the regional identity of ISCs and enterocytes is reprogrammed from a distal to a proximal phenotype and enterocyte zonation is altered to adapt cell function to nutrient availability. Single-cell resolution of the enteroendocrine lineage shows an increase in endocrine progenitors and peptidergic enteroendocrine cell (EEC) types and a decrease in serotonergic EEC types. Mechanistically, we can link increased fatty acid synthesis, Ppar signalling and the Insr/Igf1r/Akt pathway to ISC dysfunction, hyperproliferation and impaired endocrine differentiation. In summary, our work describes key molecular mechanisms of diet-induced intestinal maladaptation in mice that promote obesity, and, thus, underlie the pathogenesis of the metabolic syndrome and associated complications.
2021-07-15 | GSE148227 | GEO
Project description:Shavenbaby (Svb) transcription factor is involved in the homeostasis of intestinal stem cells (ISCs), and the differentiation of their enteroblast progeny (EB) into enterocytes (EC). Svb is produced as a long repressor protein called SvbRepressor (SvbREP). In presence of Pri peptides SvbREP is processed into a shorter activator form (SvbACT) through partial proteasomal degradation of the REP domain. In ISCs/EBs, Pri triggers SvbREP to ACT maturation, while SvbREP form accumulates in differentiated enterocytes. The absence of Svb promote the apoptosis of the intestinal stem cells. In ISCs/EBs, the ectopic expression of SvbREP form promotes the differentiation and the overexpression of SvbACT promotes hyperplasia. (Al Hayek, et al 2020) Based on these functional analyses, Svb appears to control ISC/EB survival and behavior, balancing proliferation and differentiation through a molecular switch between its 2 antagonistic isoforms. In this study, we determine the Svb target genes in different cell types along the intestinal cell lineage. This particular metadata sheet refers to enteroblast (EB) transcriptomic data (RNAseq) in control condition and upon modulation of Svb function.
2023-12-14 | GSE220323 | GEO
Project description:Intestinal stem cell (ISC) differentiation is regulated precisely by a niche in the crypt, where lymphocytes may interact with stem and transient amplifying (TA) cells. However, whether and how lymphocyte-stem/TA cell contact affects ISC differentiation is largely unknown. Here, we uncover a novel role of T cell-stem/TA cell contact in ISC fate decisions. We show that intestinal lymphocyte depletion results in skewed ISC differentiation in mice, which can be rescued by T cell transfer. Mechanistically, integrin αEβ7 expressed on T cells binds to E-cadherin on ISCs and TA cells, triggering E-cadherin endocytosis and the consequent Wnt and Notch signaling alterations. Blocking αEβ7—E-cadherin adhesion suppresses Wnt signaling and promotes Notch signaling in ISCs and TA cells, leading to defective ISC differentiation. Thus, αEβ7+ T cells regulate ISC differentiation at single-cell level through cell-cell contact-mediated αEβ7—E-cadherin adhesion signaling, highlighting a critical role of the T cell-stem/TA cell contact in maintaining intestinal homeostasis.
2021-09-14 | GSE133691 | GEO
Project description:Intestinal stem cells (ISCs) maintain gut homeostasis by differentiating into different epithelial cell types, which is precisely regulated by a niche of accessory cell types. In the niche, lymphocytes may interact with stem and transient amplifying (TA) cells in the intestinal crypts. However, it is unknown whether and how the lymphocyte- stem/TA cell contacts affect ISC differentiation. Here we discover and mechanistically dissect the role of T cell-stem/TA cell contacts in ISC fate decision. We found T cells are often seen in contact with ISCs and TA cells in the small intestinal crypts, whereas B cell-stem/TA cell interaction was hardly observed. Using single-cell RNA sequencing and immunostaining, we showed that depletion of intestinal lymphocytes resulted in aberrant ISC differentiation in mice, with decreased Paneth and goblet cells, increased enteroendocrine cells and impaired enterocyte maturation. Transferring T cells but not B cells into those mice efficiently restored normal ISC differentiation. Mechanistically, integrin αEβ7 on T cells binds to E-cadherin on ISCs and TA cells. Blocking this adhesion suppressed Wnt signaling in ISCs and TA cells and promoted Notch signaling in TA cells, leading to defective ISC differentiation. In vitro study using purified αEβ7 protein showed consistent effects on the intestinal organoid differentiation. Taken together, our study reveals that the gut-resident integrin αEb7+ T cells regulate the ISC differentiation through adhesion between αEβ7 on T cells and E-cadherin on ISCs and TA cells. The αEβ7-E-cadherin adhesive signaling is critical for the fate decision of ISCs and the maintenance of intestinal homeostasis.
2022-08-02 | GSE135316 | GEO
Project description:Background & Aims: Intestinal stem cells (ISCs) are sensitive to dietary alterations and nutrient availability. Neurotensin (NT), a gut peptide localized predominantly to the small bowel and released by fat ingestion, stimulates the growth of intestinal mucosa under basal conditions and during periods of nutrient deprivation, suggesting a possible role for NT on ISC function. Methods: Lgr5-EGFP, NT wild type (Nt+/+) and Lgr5-EGFP, NT knockout (Nt-/-) mice were fed ad libitum (AL) or fasted for 48 h. Small intestine crypts were examined by RNAseq analysis. Results: Loss of NT impaired crypt cell proliferation and ISC function in a manner dependent on nutrient status. Under nutrient-rich conditions, NT stimulated the expression of genes that promote cell cycle progression, leading to crypt cell proliferation. Under conditions of nutrient depletion, NT stimulated WNT/β-catenin signaling and promoted an ISC gene signature, leading to enhanced ISC function. NT was required for the induction of WNT/β-catenin signaling and ISC-specific gene expression during nutrient depletion, and loss of NT reduced crypt cell proliferation and impaired ISC function and Lgr5 expression in the intestine during fasting. Conclusion: Collectively, our findings establish an evolutionarily conserved role for NT in ISC maintenance during nutritional stress.
2021-09-29 | GSE182828 | GEO
Project description:Shavenbaby (Svb) transcription factor is involved in the homeostasis of intestinal stem cells (ISCs), and the differentiation of their enteroblast progeny (EB) into enterocytes (EC). Svb is produced as a long repressor protein called SvbRepressor (SvbREP). In presence of Pri peptides SvbREP is processed into a shorter activator form (SvbACT) through partial proteasomal degradation of the REP domain. In ISCs/EBs, Pri triggers SvbREP to ACT maturation, while SvbREP form accumulates in differentiated enterocytes. The absence of Svb promote the apoptosis of the intestinal stem cells. In ISCs/EBs, the ectopic expression of SvbREP form promotes the differentiation and the overexpression of SvbACT promotes hyperplasia. (Al Hayek, et al 2020) Based on these functional analyses, Svb appears to control ISC/EB survival and behavior, balancing proliferation and differentiation through a molecular switch between its 2 antagonistic isoforms. In this study, we determine the Svb target genes in different cell types along the intestinal cell lineage. This particular metadata sheet refers to early enterocytes (mEC) transcriptomic data (RNAseq) in control condition and upon modulation of Svb function.
2023-12-14 | GSE220560 | GEO
Project description:Shavenbaby (Svb) transcription factor is involved in the homeostasis of intestinal stem cells (ISCs), and the differentiation of their enteroblast progeny (EB) into enterocytes (EC). Svb is produced as a long repressor protein called SvbRepressor (SvbREP). In presence of Pri peptides SvbREP is processed into a shorter activator form (SvbACT) through partial proteasomal degradation of the REP domain. In ISCs/EBs, Pri triggers SvbREP to ACT maturation, while SvbREP form accumulates in differentiated enterocytes. The absence of Svb promote the apoptosis of the intestinal stem cells. In ISCs/EBs, the ectopic expression of SvbREP form promotes the differentiation and the overexpression of SvbACT promotes hyperplasia. (Al Hayek, et al 2020) Based on these functional analyses, Svb appears to control ISC/EB survival and behavior, balancing proliferation and differentiation through a molecular switch between its 2 antagonistic isoforms. In this study, we determine the Svb target genes in different cell types along the intestinal cell lineage. This particular metadata sheet refers to early enterocytes (eEC) transcriptomic data (RNAseq) in control condition and upon modulation of Svb function.
2023-12-14 | GSE220558 | GEO
Project description:Aging-related intestinal dysfunctions include loss of barrier integrity, altered stress responses, nutrient malabsorption, and cancer formation. Influence of aging on intestinal stem cell (ISC) and their niches can explain underlying causes for perturbation in ISC function during aging. However, molecular mechanisms for such decrease in functionality of ISCs during aging remain largely undetermined. Using different transcriptome-wide approaches including single-cell RNA-seq from intestinal crypt cells and immune cells of lamina propria, we characterized age-specific transcriptional programs in the intestinal epithelium. We found that aged ISCs strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes leading to a compromised homeostasis of the intestinal epithelium. Mechanistically, increase of interferon gamma (IFNgamma) release by cytotoxic CD4 T cells and innate lymphoid type 2 cells (ILC2) in lamina propria of aged intestine lead to induction of Stat1 in ISCs that trigger MHC class II expression and prime them towards a secretory fate. Altogether these findings, clarify the cross talk between immune cells and ISC in aged intestine and identified the IFNgamma-Stat1-MHCII axis as the key gene network driving intestinal inflammaging phenotype and loss of tissue homeostasis. Our data provide basic and complementary knowledge for the development of therapeutic intervention for aging-related intestinal dysfunction and diseases.
2023-09-05 | GSE174297 | GEO
Project description:Intestinal epithelial stem cells (ISCs) are the focus of recent intense study. Current in vitro models rely on supplementation with the Wnt agonist R-spondin1 to support robust growth, ISC self-renewal, and differentiation. Intestinal subepithelial myofibroblasts (ISEMFs) are important supportive cells within the ISC niche. We hypothesized that co-culture with ISEMF enhances the growth of ISCs in vitro and allows for their successful in vivo implantation and engraftment. ISC-containing small intestinal crypts, FACS-sorted single ISCs, and ISEMFs were procured from C57BL/6 mice. Crypts and single ISCs were grown in vitro into enteroids, in the presence or absence of ISEMFs. ISEMFs enhanced the growth of intestinal epithelium in vitro in a proximity-dependent fashion, with co-cultures giving rise to larger enteroids than monocultures. Co-culture of ISCs with supportive ISEMFs relinquished the requirement of exogenous R-spondin1 to sustain long-term growth and differentiation of ISCs. Mono- and co-cultures were implanted subcutaneously in syngeneic mice. Co-culture with ISEMFs proved necessary for successful in vivo engraftment and proliferation of enteroids; implants without ISEMFs did not survive. ISEMF whole transcriptome sequencing and qPCR demonstrated high expression of specific R-spondins, well-described Wnt agonists that supports ISC growth. Specific non-supportive ISEMF populations had reduced expression of R-spondins. The addition of ISEMFs in intestinal epithelial culture therefore recapitulates a critical element of the intestinal stem cell niche and allows for its experimental interrogation and biodesign-driven manipulation. Two samples of intestinal subepithelial myofibroblasts were used in this study.
2013-12-20 | E-GEOD-52402 | biostudies-arrayexpress
Project description:Imbalance in intestinal stem cell (ISC) homeostasis leads to cancer and metabolic disease. Therefore intense efforts are underway to understand ISC hierarchy and the niche signals that control stem cell fate. Several ISC populations have been described according to their marker expression, cell-cycle behavior and lineage potential. Actively cycling Lgr5+ ISCs ensure homeostatic renewal. A less well-defined and minor population of quiescent and label-retaining cells (LRCs) is viewed as a reserve stem cell pool. However, the existence of quiescent stem cells distinct from the Lgr5+ ISCs is controversial. Indeed, recent findings identified quiescent intestinal cells as a subpopulation of Lgr5+ ISCs that are committed to the secretory fate, but the signals that maintain and activate quiescent cells/LRCs remain elusive.
2020-09-11 | GSE94090 | GEO