IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158451 | GEO | 2021/02/11
REPOSITORIES: GEO
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Project description:IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis.
| PRJNA665247 | ENA
Project description:Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates at late gestation in humans and the early postnatal period in the mouse. Alveolar septation is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene (Igf1r) expression by a subset of pulmonary fibroblasts is required for normal alveologenesis in mice. Postnatal deletion of Igf1r caused alveolar simplification, disrupting alveolar elastin networks and extracellular matrix without altering myofibroblast differentiation or proliferation. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and inhibited myosin light chain (MLC) phosphorylation and mechanotransductive nuclear YAP activity. Activation of p-AKT, p-MLC, and nuclear YAP in myofibroblasts was dependent on Igf1r. Pharmacologic activation of AKT enhanced MLC phosphorylation, increased YAP activation, and ameliorated alveolar simplification in vivo. IGF1R controls mechanosignaling in myofibroblasts required for lung alveologenesis.
| S-EPMC8026181 | biostudies-literature
Project description:IGF1 and IGF1 receptors (IGF1R) are present in the adult heart and have been shown to be essential for myocardial performance. Insulin-like growth factor 1 (IGF1) is produced in numerous tissues particularly by the liver in response to growth hormone stimulation and is an important factor in the regulation of post-natal growth and development. We have generated and characterized transgenic mice over-expressing the IGF1R. We crossed IGF1R transgenic mice with dominant negative (dn)PI3K (p110) and with constitutively active (ca)PI3K(p110) transgenic mice. Expression profiling was performed on the ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age. Non-transgenic littermates were used as controls.
2007-09-29 | E-GEOD-1143 | biostudies-arrayexpress
Project description:Alveolar formation increases the surface area for gas-exchange and is key to the physiological function of the lung. Alveolar epithelial cells, myofibroblasts and endothelial cells undergo coordinated morphogenesis to generate epithelial folds (secondary septa) within the saccules to form alveoli. A mechanistic understanding of alveologenesis remains incomplete. We found that the planar cell polarity (PCP) pathway is required in both alveolar epithelial cells and myofibroblasts for alveologenesis. Our studies uncovered a Wnt5a–Ror2–Vangl2 cascade that endows cellular properties and thus novel mechanisms of alveologenesis. This includes PDGF secretion from alveolar type I and type II cells, cell shape changes of type I cells and migration of myofibroblasts. All these cellular properties are conferred by changes in the cytoskeleton and represent a new facet of PCP function. These results extend our current model of PCP signaling from polarizing a field of epithelial cells to conferring new properties at subcellular levels to regulate collective cell behavior.
2020-03-03 | GSE140779 | GEO
Project description:All samples are conditioned media from primary cultured human gastric myofibroblasts, derived from either carcinoma tissue, or adjacent non cancerous tissue. In each experiment the cancer-derived myofibroblasts are compared against the non-cancer derived myofibroblasts from the same patient. All of the experiments were samples from Patient 1, except for 648, which is from Patient 2. SILAC labelling in each case is; 567 - Methionine COFRADIC; Cancer-derived = Heavy, Non-cancer = Light 575 - N-terminal COFRADIC; Cancer-derived = Heavy, Non-cancer = Light 646 - Cancer-derived = Light, Non-cancer = Heavy 647 - Non-cancer = Heavy, Non-cancer = Light (same cell line labelled twice to create a control experiment) 648 - Cancer-derived = Heavy, Non-cancer = Light
2013-06-20 | PRD000744 | Pride
Project description:Cancer-associated fibroblasts are a major component of the cancer stroma. Here we focus on gastric cancer associated myofibroblasts (CAMs). CAMs secrete factors that increase the migration, invasion and proliferation of cancer cells when compared to adjacent tissue myofibroblasts (ATMs), or normal tissue myofibroblasts (NTMs). In this study we identified and quantified the proteins secreted by normoxic (21% O2) and hypoxic (1% O2) myofibroblast cells.
2019-03-04 | PXD008104 | Pride
Project description:To investigate genes that might influence resistance to infection through IGF1R, we screened human breast cancer-derived OCUB-M cells transfected with expression vector encoding IGF1R using microarray analysis. Keywords: overexpression comparison
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Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA
2008-11-20 | E-GEOD-11196 | biostudies-arrayexpress
Project description:The mesenchyme consists of heterogeneous cell populations that support neighboring structures and are integral to intercellular signaling. Despite such importance, mesenchymal cell types are poorly defined morphologically and molecularly, lagging behind their counterparts in the epithelial, endothelial, and immune lineages. Leveraging single-cell RNA-seq, three-dimensional imaging, and lineage tracing, we classify the mouse lung mesenchyme into three proximal-distal axes that are associated with the endothelium, epithelium, and interstitium, respectively. From proximal to distal, (1) the vascular axis includes vascular smooth muscle cells and pericytes that transition as arterioles and venules ramify into capillaries; (2) the epithelial axis includes airway smooth muscle cells and two populations of myofibroblasts: ductal myofibroblasts, surrounding alveolar ducts and marked by CDH4, HHIP, and LGR6, which persist post-alveologenesis, and alveolar myofibroblasts, surrounding alveoli and marked by high expression of PDGFRA, which undergo developmental apoptosis; (3) the interstitial axis, residing between the epithelial and vascular trees and sharing a newly-identified marker MEOX2, includes fibroblasts in the bronchovascular bundle and the alveolar interstitium that are marked by IL33 and Wnt2, respectively. Single-cell imaging reveals distinct morphology of each mesenchymal cell population. This classification provides a conceptual and experimental framework applicable to other organs.
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