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Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche

ABSTRACT: Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81+ PDGFRAlo trophocytes capably sustain ISC functions ex vivo. Here we show that mRNA and chromatin profiles of abundant CD81- PDGFRAlo mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands. Mesenchymal expression of key ISC-supportive factors extends along a spatial and molecular continuum from trophocytes into peri-cryptal CD81- CD55hi cells, which mimic trophocyte activity in organoid co-cultures. Graded expression of essential niche factors is not cell-autonomous but dictated by the distance from bone morphogenetic protein (BMP)-secreting PDGFRAhi myofibroblast aggregates. BMP signaling inhibits ISC-trophic genes in PDGFRAlo cells near high crypt tiers; that suppression is relieved in stromal cells near and below the crypt base, including trophocytes. Cell distances thus underlie a self-organized and polar ISC niche.

ORGANISM(S): Mus musculus

PROVIDER: GSE211275 | GEO | 2023/02/21

REPOSITORIES: GEO

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Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche

Project description:Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81+ PDGFRAlo trophocytes alone sustain ISC functions ex vivo. Here we show that mRNA and chromatin profiles of abundant CD81- PDGFRAlo stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands. Mesenchymal expression of key ISC-supportive factors extends along a spatial and molecular continuum from trophocytes into peri-cryptal CD81- CD55hi cells, which mimic trophocyte activity in organoid co-cultures. Graded expression of essential niche factors is not cell-autonomous but dictated by the distance from bone morphogenetic protein (BMP)-secreting PDGFRAhi myofibroblast aggregates. BMP signaling inhibits ISC-trophic genes in PDGFRAlo cells near high crypt tiers and that suppression is relieved in stromal cells near and below the crypt base, including trophocytes. Cell distances thus underlie a self-organized and polar ISC niche.

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Lymphatic endothelial cells, together with Rspo3+Grem1+ fibroblasts, support intestinal stem cells through the production of R-spondin3 in homeostasis and injury [scRNAseq]

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Lymphatic endothelial cells, together with Rspo3+Grem1+ fibroblasts, support intestinal stem cells through the production of R-spondin3 in homeostasis and injury [200909Yil]

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Lymphatic endothelial cells, together with Rspo3+Grem1+ fibroblasts, support intestinal stem cells through the production of R-spondin3 in homeostasis and injury [200211YilA]

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Gall2023 - Agent-based model of the intestinal epithelium

Project description:The small intestinal crypt exhibits a defined spatial organisation involving multiple cell types that undergo continuous proliferation and differentiation while migrating towards the villus. We have built a multi-scale agent-based model (ABM), with individual cells interacting in the crypt geometry, which reproduces the self-organizing stable behaviour reported for the crypt. In our ABM, spatial organization emerges from the dynamic interaction of multiple signalling pathways, which include the Wnt, Notch, BMP and RNF43/ZNRF3 pathways that orchestrate cellular fate and mechanisms of contact inhibition of proliferation as well as feedback loops that regulate the expansion of the niche and size of the crypt. Moreover, this dynamic signalling network interacts with the main cell cycle proteins, governing the progression of each cell across the division stages.

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Evidence that inflammation-associated fibroblasts (IAFs) originate from Edil3 stromal "mesitocytes" in the colon following radiation injury

Project description:Stromal cells present in the colon crypt provide proliferation and differentiation signals to the epithelial cells, thereby maintaining their integrity and stimulating the regeneration process. Cancer patients treated for tumors located in the abdominopelvic region may develop radiation proctitis, a condition characterized by a strong mucosal inflammation. In this work, single-cell RNA sequencing approaches were combined with spatial transcriptomics to characterize colonic stromal cells in depth, both in control conditions and in the context of radiation-induced ulceration. The present study identifies a novel stromal marker, Edil3 (EGF-like repeats and discoidin domains 3), which defines the major stromal population of the colon. This population is spatially and functionally distinct from telocytes and trophocytes and is expressed along the crypt with a functional proliferation-differentiation axis . This population, which we propose to name "mesitocytes," cooperates with vascular cells to control inflammation and epithelial proliferation. We demonstrate that radiation-induced ulcerated areas are characterized by the presence of inflammation-associated fibroblasts (IAFs) deriving from mesitocytes.

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Gene expression profiles of Lgr5-GFP high and Lgr5-GFP low cells in small intestines of Itgb7+/+ Lgr5-GFP mice and Itgb7-/- Lgr5-GFP mice

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.

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Lepr+ mesenchymal cells sense diet to modulate intestinal stem cells via the Leptin-Igf1-Igf1r axis

Project description:We demonstrated that Lepr+ mesenchymal cells surround intestinal crypts where ISCs and transit-amplifying (TA) cells localize. The abundance of these cells increased upon administration of a high-fat diet (HFD) but dramatically decreased upon fasting. Depletion of Lepr+ mesenchymal cells resulted in fewer ISCs, compromised architecture of crypt-villi axis and impaired intestinal regeneration. Furthermore, Lepr+ cell-derived Igf1 has been identified as an important effector that promotes the proliferation of ISCs and TA cells. Deletion of Igf1 in Lepr+ cells partially recapitulated Lepr+ cell-ablated intestinal phenotypes during both homeostasis and regeneration. Overall, Lepr+ mesenchymal cells sense diet alteration and function as a novel niche for ISCs via the stromal Igf1 - epithelial Igf1r axis, which is critical for intestinal homeostasis and regeneration. These findings revealed that Lepr+ mesenchymal cells are an important mediator that links diet to ISC function and might provide a novel therapeutic target for gut diseases.

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Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts

Project description:Wnt/b-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (PorcnDel/Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of PorcnDel organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable, and that stromal production of Wnts can fully support normal murine intestinal homeostasis. Microarray was performed on samples enriched for stromal or epithelial cells from small intestine from Porcn(Del)/Villin-Cre and Porcn(WT)/Villin-Cre male C57Bl/6 mice.

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Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Project description:The currently accepted intestinal epithelial cell organization model equates crypt base columnar (CBC) cells, marked by high levels of Lgr5 expression, with the intestinal stem cell (ISC). However, recent intestinal regeneration studies have uncovered limitations of the ‘Lgr5-CBC’ model, leading to two major views: one favoring the presence of a quiescent reserve stem cell population, the other calling for differentiated cell plasticity. To test if an alternative model may help reconcile these perspectives, we studied the hierarchical organization of crypt epithelial cells in an unbiased fashion, by combining high-resolution, single-cell profiling and lineage tracing in multiple transgenic mouse models. These show that Lgr5 is not a specific ISC marker; rather, cells located in the crypt isthmus, which include Lgr5low cells, comprise the ISCs that sustain tissue homeostasis. Following irradiation or intestinal injury, surviving ISCs and progenitors, but not differentiated cells, participate in intestinal regeneration, suggesting that neither de-differentiation nor reserve stem cell populations are drivers of intestinal regeneration. Our results provide a novel viewpoint for the intestinal crypt epithelium, in which ISCs localize to the crypt isthmus, and ISC potential is restricted to stem and progenitor cells.

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