NOTCH-driven oscillations control cell fate decisions during intestinal homeostasis
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ABSTRACT:
PROVIDER: PRJNA1156195 | ENA |
REPOSITORIES: ENA
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Project description:Intestinal homeostasis requires tight regulation of stem cell maintenance and commitment to absorptive and secretory cells, two key intestinal lineages1,2. While major signalling pathways critical for this control have been identified3, how they achieve such a tight balance in cell type composition remains unclear. Here, we uncover dynamic expression of Hes1, a direct NOTCH target3, in intestinal stem and progenitor cells, and investigate its role in vivo and in vitro. A knock-in reporter4 reveals distinct, cell-specific period lengths in Hes1 oscillations that form a gradient along the crypt-villus axis. Whereas secretory precursors oscillate at low periods, absorptive precursors oscillate at higher periods before transitioning to a differentiated state. To test the function of different oscillation periods, we innovated a microfluidic system that modulates Hes1 oscillations in organoids. We find that varying the oscillation period modulates secretory cell differentiation: While 90-min oscillations promote Paneth cells, 130-min oscillations increase formation of other secretory subtypes. Moreover, low-period oscillations support stemness and a proliferative state. Our study provides the first clear evidence that information for tissue homeostasis in the intestine is encoded in the temporal dynamics of signalling components.
2025-09-01 | GSE276270 | GEO
Project description:Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells (hPSCs) of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and siRNA to Notch receptors we have demonstrated that Notch1, but not Notch2 activation, induced HES1 expression and generation of committed hematopoietic progenitors. Using gain and loss of function approaches, this was shown to be attributed to Notch signaling regulation through HES1, that dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs. endothelial fate specification. Human pluripotent stem cells (hPSCs) have differentiation potential into three embryonic germ layers including blood. Notch signaling is one of important signaling pathways involved in blood differentiation of hPSCs. Thus, in order to examine the effect of Notch signaling pathways during hematopoietic differentiation of hPSCs, embryoid bodies (EBs) were formed and cultured for 10 days in the combination of cytokines and growth factors (Chadwick, Blood, 2003; 300 ng/ml of SCF, 300 ng/ml of Flt-3L, 10 ng/ml of IL-3, 10 ng/ml of IL-6, and 50 ng/ml of G-CSF) to induce differentiation into blood. Additionally, CD31+CD45- bipotent hemogenic precursors were isolated from day10 hematopoietic EBs (Wang et al., Immunity, 2004)
2013-06-01 | E-GEOD-47466 | biostudies-arrayexpress
Project description:Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells (hPSCs) of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and siRNA to Notch receptors we have demonstrated that Notch1, but not Notch2 activation, induced HES1 expression and generation of committed hematopoietic progenitors. Using gain and loss of function approaches, this was shown to be attributed to Notch signaling regulation through HES1, that dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs. endothelial fate specification.
2013-06-01 | GSE47466 | GEO
Project description:O-GlcNAc Homeostasis Controls Cell Fate Decisions During Hematopoiesis
| PRJNA503593 | ENA
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171917 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171918 | GEO
Project description:Dll4-Notch signaling is required for cell fate decisions and neoplasias. However, emerging evidence suggests a role for Dll4-Notch signaling in metabolic and immune diseases. To date, there is no evidence of a direct effect of Dll4-Notch signaling inhibition on pancreatic islet function and insulin secretion.
2018-08-13 | PXD005333 | Pride
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171914 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171915 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171916 | GEO