Hepatocyte-to-intestinal Stem Cell Remote Communication Regulates Blood Glucose Homeostasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE317083 | GEO | 2026/05/19
REPOSITORIES: GEO
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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.
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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.
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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.
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Project description:To elucidate alterations in intestinal cell types under chronic stress, we conducted scRNA-seq analysis of intestinal crypts from NT and ES models. After that, we found that significant changes in ISCs in the ES group compared to the NT group. To validate the functional roles of ISCs, we performed RNA-seq of ISCs under different treatment conditions, we identified Chrm3-dependent differential genes between NT and ES groups, particularly noting downregulated genes associated with stemness and proliferation (e.g., Olfm4, Lgr5, and Mcm4), and upregulated genes linked to aging and calcium signaling pathways (e.g., Cdkn1a, Orai1, and Chp2), which contribute to ISC aging. These findings provided mechanistic insights into targeting these pathways to enhance intestinal function and integrity. Furthermore, to assess the impact of stress-induced changes in microbiota composition on ISC stemness, we synchronized microbiota between NT and ES groups through co-housing conditions and employed 16S rDNA sequencing. This analysis aimed to ascertain the possibility that changes in the microbiota composition whether contribute to the decline in ISC stemness under stress conditions. scRNA-seq of crypts were used to to characterize the diversity of cell lines under chronic stress. RNA-seq of ISC in Chrm3Lgr5+/+ and Chrm3Lgr5-/- mice from NT and ES mice were taken to delineate altered pathways and the mechanisms underlying ISC changes in ES model. 16S rDNA-seq (available in PRJNA1090629) were employed to confirm microbiota synchronization between NT and ES groups under co-housing conditions.
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Project description:To elucidate alterations in intestinal cell types under chronic stress, we conducted scRNA-seq analysis of intestinal crypts from NT and ES models. After that, we found that significant changes in ISCs in the ES group compared to the NT group. To validate the functional roles of ISCs, we performed RNA-seq of ISCs under different treatment conditions, we identified Chrm3-dependent differential genes between NT and ES groups, particularly noting downregulated genes associated with stemness and proliferation (e.g., Olfm4, Lgr5, and Mcm4), and upregulated genes linked to aging and calcium signaling pathways (e.g., Cdkn1a, Orai1, and Chp2), which contribute to ISC aging. These findings provided mechanistic insights into targeting these pathways to enhance intestinal function and integrity. Furthermore, to assess the impact of stress-induced changes in microbiota composition on ISC stemness, we synchronized microbiota between NT and ES groups through co-housing conditions and employed 16S rDNA sequencing. This analysis aimed to ascertain the possibility that changes in the microbiota composition whether contribute to the decline in ISC stemness under stress conditions. scRNA-seq of crypts were used to to characterize the diversity of cell lines under chronic stress. RNA-seq of ISC in Chrm3Lgr5+/+ and Chrm3Lgr5-/- mice from NT and ES mice were taken to delineate altered pathways and the mechanisms underlying ISC changes in ES model. 16S rDNA-seq were employed to confirm microbiota synchronization between NT and ES groups under co-housing conditions.
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Project description:Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas, activates Wnt signaling, hence conferring fitness on mutant intestinal stem cells (ISCs). Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.
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