PIEZO-dependent mechano-sensing of the niche is essential for intestinal stem cell fate decision and maintenance
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE277223 | GEO | 2024/12/27
REPOSITORIES: GEO
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Project description:The propeller-shaped blades of the PIEZO1 and PIEZO2 ion channels partition into the plasma membrane and respond to indentation or stretching of the lipid bilayer, thus converting mechanical forces into signals that can be interpreted by cells, in the form of calcium flux and changes in membrane potential. While PIEZO channels participate in diverse physiological processes, from sensing the shear stress of blood flow in the vasculature to detecting a light touch on the surface of the skin, the molecular details that enable these mechanosensors to tune their responses over a vast dynamic range of forces remain largely uncharacterized. To survey the molecular landscape surrounding PIEZO channels at the cell surface, we employed a mass spectrometry-based proteomic approach to capture and identify extracellularly exposed proteins in the vicinity of PIEZO1. This PIEZO1-proximal interactome was enriched in surface proteins localized to cell junctions and signaling hubs within the plasma membrane. Functional screening of these interaction candidates by calcium imaging and electrophysiology in an overexpression system identified the adhesion molecule CADM1/SynCAM that slows the inactivation kinetics of PIEZO1 with little effect on PIEZO2. Conversely, we found that CADM1 knockdown accelerates inactivation of endogenous PIEZO1 in Neuro-2a cells. Systematic deletion of CADM1 domains indicate that the transmembrane region is critical for the observed effects on PIEZO1, suggesting that modulation of inactivation is mediated by interactions in or near the lipid bilayer.
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Project description:It is unclear that osteoclast lineages can sense mechanical stimuli, mainly by lack of information about the presence or absence of mechano-sensing organelles in these cells. Primary cilium is a microtubule-based organelle, which can translate mechanical loading signals into biochemical and transcriptional responses. We first identified the presence of primary cilia in tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells (preosteoclasts) prior to form TRAP-positive multinuclear cells (osteoclasts), suggesting that preosteoclasts can sense mechanical stimuli. To understand a role of primary cilia in preosteoclasts, we generated osteoclast-specific Ift88 or Kif3a knockout Cathepsin K-Cre transgenic mice. Deletion of Ift88 or Kif3a reduced the number of cilia in preosteoclasts. Micro-CT analysis display that mice with conditional deletion of Ift88 or Kif3a in osteoclast lineages led to a decrease in femoral cortical bone tissue area and bone marrow area under exercise conditions, implying that disruption of primary cilia in preosteoclasts/osteoclasts narrowed the femoral cortical bone shape. In contrast, the trabecular and cortical bone mass was not altered in these mice. Mechanistic studies showed that shear stress suppressed osteoclastogenesis by c-fos degradation. Also, shear stress increased periostin levels in conditioned media from preosteoclasts, resulting in increased differentiation and bone nodule formation of osteoblasts through activation of LRP6/-catenin. All shear stress-induced changes were near completely blocked by knock-downs of Ift88 and Kif3a in preosteoclasts. These findings first suggest that preosteoclasts may sense mechanical stimuli with a primary cilium, and that mechanical stress-mediated primary cilia activation of preosteoclasts may play an important role in controlling bone modeling and shaping by modulating both bone resorption and formation.
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Project description:Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions.We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
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Project description:The retina is often subjected to tractional forces in a variety of conditions, for instance, pathological myopia, proliferative vitreoretinopathy. As the predominant glial element in the sensory retina, Muller cells are responsible for the homeostatic and metabolic support of retinal neurons and active players in virtually all forms of retinal injury and disease. Besides, Muller cells span the entire retinal thickness, extending from the inner to the outer limiting membranes, with cell bodies located in the inner nuclear layer and lateral processes expanding into the plexiform layers of the tissue. Because of this unique morphology, Muller cells can sense even minute changes in the retinal structure because of the mechanical stretching of their long processes or side branches. Thus, itM-bM-^@M-^Ys reasonable to infer that Muller cells also participate in ocular diseases when the retina is overstretched. In this study, we aim to investigate the whole genome regulation of Muller cells under mechanical stretching, which may help in excluding possible molecular mechanisms that would account for many retinal diseases in which the retina is often subjected to mechanical forces. We used microarrays to identify patterns of gene expression changes induced by cyclic mechanical stretching in Muller cells. Rat Muller cells were seeded onto flexible bottom culture plates and subjected to a cyclic stretching regimen of 15% equibiaxial stretching for 1 and 24 h.Muller cells cultured under the same conditions but with no applied mechanical strain were considered as the unstretched control. At each time points (1 and 24 h), three totally independent experiments (3 stretched samples and 3 control samples) were conducted. Muller cells were selected for RNA extraction and hybridization on Affymetrix microarrays. Stretch (S); Control (C)
2013-01-16 | E-GEOD-43516 | 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
Project description:Background & Aims: Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions. Methods: We generated mice with intestinal epithelial-specific disruption of Cul4b (pVillin-cre; Cul4bfn/Y), inducible disruption of Cul4b (Lgr5-creERT2; Cul4bfn/Y, CAG-creERT2; Cul4bfn/Y) and their control (Cul4bfn/Y). Intestinal tissues were analyzed by histology, immunofluorescence, RNA sequencing and mass spectrum. Intestinal organoids deprived from mice with pVillin-Cre; Cul4bfn/Y, Lgr5-Cre; Cul4bfn/Y, Tg-Cul4b and their controls were used in assays to measure intestinal self-renewal, proliferation and differentiation. Wnt signaling and intestinal markers were analyzed by immunofluorescence and immunoblot assays. Differential proteins upon Cul4b ablation or Cul4b-interacting proteins were identified by mass spectrometry. Results: Cul4b specifically located at ISCs zone. Block of Cul4b impaired intestinal homeostasis maintenance by reduced self-renewal and proliferation. Transcriptome analysis revealed that Cul4b-null intestine lose ISC characterization and showed disturbed ISC niche. Mechanistically, reactivated Wnt pathway could recover intestinal dysfunction of Cul4b knockout mice. Analysis of differential total and ubiquitylated proteins uncovered the novel targeting substrate of Cullin-Ring ubiquitin ligase 4b (CRL4b), immunity-related GTPase family M member 1 (Irgm1) in intestine. Decreased Irgm1 rescued abnormally interferon signaling, overemphasized autophagy and downstream phosphate proteins in Cul4b knockout mice. Conclusion: We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
2022-08-11 | PXD021528 | Pride
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Project description:The trabecular meshwork (TM) responsible for IOP homeostasis in the eye could sense the IOP fluctuations dynamically and adapt to the mechanical changes appropriately. Cationic mechanosensitive channels (CMCs) have been reported with critical roles in mediating the TM responding to many mechanical forces. However, the mechanism of how CMCs influence the TM cellular function in aqueous humor drainage and against mechanical damage is still elusive. Gene ontology enrichment analysis demonstrated that prohibition of CMCs significantly influenced the mechanical changes in the TM, such as store-operated calcium channel activity, microtubule cytoskeleton polarity, toll-like receptor signaling pathway, and neuron cell fate specification. Our results indicated that they might be the critical downstream signals of CMCs adapting to mechanical forces and mediating AH outflow.
2022-03-14 | PXD032288 |
Project description:The retina is often subjected to tractional forces in a variety of conditions, for instance, pathological myopia, proliferative vitreoretinopathy. As the predominant glial element in the sensory retina, Muller cells are responsible for the homeostatic and metabolic support of retinal neurons and active players in virtually all forms of retinal injury and disease. Besides, Muller cells span the entire retinal thickness, extending from the inner to the outer limiting membranes, with cell bodies located in the inner nuclear layer and lateral processes expanding into the plexiform layers of the tissue. Because of this unique morphology, Muller cells can sense even minute changes in the retinal structure because of the mechanical stretching of their long processes or side branches. Thus, it’s reasonable to infer that Muller cells also participate in ocular diseases when the retina is overstretched. In this study, we aim to investigate the whole genome regulation of Muller cells under mechanical stretching, which may help in excluding possible molecular mechanisms that would account for many retinal diseases in which the retina is often subjected to mechanical forces. We used microarrays to identify patterns of gene expression changes induced by cyclic mechanical stretching in Muller cells.
2013-01-16 | GSE43516 | GEO