Similar Datasets
Project description:Intrinsic mechanisms and microenvironmental cues fine-tune plasticity of esophageal progenitors
| PRJNA1372224 | ENA
Project description:Rho signaling is a conserved mechanism for generating forces through activation of contractile actomyosin. How this pathway can produce different cell morphologies is poorly understood. In the Drosophila embryonic epithelium, we investigate how Rho signaling controls force asymmetry to drive morphogenesis. We study a distinct morphogenetic process termed 'alignment'. This process results in striking columns of rectilinear cells connected by aligned cell-cell contacts. We found that this is driven by contractile actomyosin cables that elevate tension along aligning interfaces. Our data show that polarization of Rho effectors, Rok and Dia, directs formation of these cables. Constitutive activation of these effectors causes aligning cells to instead invaginate. This suggests that moderating Rho signaling is essential to producing the aligned geometry. Therefore, we tested for feedback that could fine-tune Rho signaling. We discovered that F-actin exerts negative feedback on multiple nodes in the pathway. Further, we present evidence that suggests that Rok in part mediates feedback from F-actin to Rho in a manner independent of Myo-II. Collectively, our work suggests that multiple feedback mechanisms regulate Rho signaling, which may account for diverse morphological outcomes.
| S-EPMC6503953 | biostudies-literature
Project description:Autoregulation of transcription factors and cross-antagonism between lineage-specific transcription factors are a recurrent theme in cell differentiation. An equally prevalent event that is frequently overlooked in lineage commitment models is the upregulation of lineage-specific receptors, often through lineage-specific transcription factors. Here, we use a minimal model that combines cell-extrinsic and cell-intrinsic elements of regulation in order to understand how both instructive and stochastic events can inform cell commitment decisions in hematopoiesis. Our results suggest that cytokine-mediated positive receptor feedback can induce a "switch-like" response to external stimuli during multilineage differentiation by providing robustness to both bipotent and committed states while protecting progenitors from noise-induced differentiation or decommitment. Our model provides support to both the instructive and stochastic theories of commitment: cell fates are ultimately driven by lineage-specific transcription factors, but cytokine signaling can strongly bias lineage commitment by regulating these inherently noisy cell-fate decisions with complex, pertinent behaviors such as ligand-mediated ultrasensitivity and robust multistability. The simulations further suggest that the kinetics of differentiation to a mature cell state can depend on the starting progenitor state as well as on the route of commitment that is chosen. Lastly, our model shows good agreement with lineage-specific receptor expression kinetics from microarray experiments and provides a computational framework that can integrate both classical and alternative commitment paths in hematopoiesis that have been observed experimentally.
| S-EPMC2736398 | biostudies-literature
Project description:A precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable prognosis, whereas patients with low miR-223 expression levels were associated with worse outcome. Furthermore, miR-223 was hierarchically expressed in AML subpopulations, with lower expression in leukemic stem cell-containing fractions. Genetic depletion of miR-223 decreased the leukemia initiating cell (LIC) frequency in a myelomonocytic AML mouse model, but it was not mandatory for rapid-onset AML. To relate these observations to physiologic myeloid differentiation, we knocked down or ectopically expressed miR-223 in cord-blood CD34⁺ cells using lentiviral vectors. Although miR-223 knockdown delayed myeloerythroid precursor differentiation in vitro, it increased myeloid progenitors in vivo following serial xenotransplantation. Ectopic miR-223 expression increased erythropoiesis, T lymphopoiesis, and early B lymphopoiesis in vivo. These findings broaden the role of miR-223 as a regulator of the expansion/differentiation equilibrium in hematopoietic stem and progenitor cells where its impact is dose- and differentiation-stage-dependent. This also explains the complex yet minor role of miR-223 in AML, a heterogeneous disease with variable degree of myeloid differentiation.
| S-EPMC4860732 | biostudies-literature
Project description:It is envisaged that the creation of cellular environments at multiple length scales, that recapitulate in vivo bioactive and structural roles, may hold the key to creating functional, complex tissues in the laboratory. This review considers recent advances in biofabrication and bioprinting techniques across different length scales. Particular focus is placed on 3D printing of hydrogels and fabrication of biomaterial fibres that could extend the feature resolution and material functionality of soft tissue constructs. The outlook from this review discusses how one might create and simulate microenvironmental cues in vitro. A fabrication platform that integrates the competencies of different biofabrication technologies is proposed. Such a multi-process, multiscale fabrication strategy may ultimately translate engineering capability into an accessible life sciences toolkit, fulfilling its potential to deliver in vitro disease models and engineered tissue implants.
| S-EPMC6267274 | biostudies-other
Project description:TNF is an important inflammatory mediator and a target for intervention. TNF is produced by many cell types and is involved in innate inflammation as well as adaptive immune responses. CD8 T cells produce TNF and can also respond to TNF. Deficiency of TNF or TNFR2 has been shown to affect anti-viral immunity. However, as the complete knockout of TNF or its receptors has effects on multiple cell types as well as on lymphoid architecture, it has been difficult to assess the role of TNF directly on T cells during viral infection. Here we have addressed this issue by analyzing the effect of CD8 T cell intrinsic TNF/TNFR2 interactions during respiratory influenza infection in mice, using an adoptive transfer model in which only the T cells lack TNF or TNFR2. During a mild influenza infection, the capacity of the responding CD8 T cells to produce TNF increases from day 6 through day 12, beyond the time of viral clearance. Although T cell intrinsic TNF is dispensable for initial expansion of CD8 T cells up to day 9 post infection, intrinsic TNF/TNFR2 interactions potentiate contraction of the CD8 T cell response in the lung between day 9 and 12 post infection. On the other hand, TNF or TNFR2-deficient CD8 T cells in the lung express lower levels of IFN-γ and CD107a per cell than their wild type counterparts. Comparison of TNF levels on the TNFR2 positive and negative T cells is consistent with TNF/TNFR2 interactions inducing feedback downregulation of TNF production by T cells, with greater effects in the lung compared to spleen. Thus CD8 T cell intrinsic TNF/TNFR2 interactions fine-tune the response to influenza virus in the lung by modestly enhancing effector functions, but at the same time potentiating the contraction of the CD8 T cell response post-viral clearance.
| S-EPMC3706430 | biostudies-literature
Project description:Social interactions have important consequences for individual fitness. Collective actions, however, are notoriously context-dependent and identifying how animals rapidly weigh the actions of others despite environmental uncertainty remains a fundamental challenge in biology. By exposing zebrafish (Danio rerio) to virtual fish silhouettes in a maze we isolated how the relative strength of a visual feature guides individual directional decisions and, subsequently, tunes social influence. We varied the relative speed and coherency with which a portion of silhouettes adopted a direction (leader/distractor ratio) and established that solitary zebrafish display a robust optomotor response to follow leader silhouettes that moved much faster than their distractors, regardless of stimulus coherency. Although recruitment time decreased as a power law of zebrafish group size, individual decision times retained a speed-accuracy trade-off, suggesting a benefit to smaller group sizes in collective decision-making. Directional accuracy improved regardless of group size in the presence of the faster moving leader silhouettes, but without these stimuli zebrafish directional decisions followed a democratic majority rule. Our results show that a large difference in movement speeds can guide directional decisions within groups, thereby providing individuals with a rapid and adaptive means of evaluating social information in the face of uncertainty.
| S-EPMC6023868 | biostudies-literature
Project description:Gliomas are diffusely infiltrating brain tumors whose prognosis is strongly influenced by their extent of invasion into the surrounding brain tissue. While lower-grade gliomas present more circumscribed borders, high-grade gliomas are aggressive tumors with widespread brain infiltration and dissemination. Glioblastoma (GBM) is known for its high invasiveness and association with poor prognosis. Its low survival rate is due to the certainty of its recurrence, caused by microscopic brain infiltration which makes surgical eradication unattainable. New insights into GBM biology at the single-cell level have enabled the identification of mechanisms exploited by glioma cells for brain invasion. In this review, we explore the current understanding of several molecular pathways and mechanisms used by tumor cells to invade normal brain tissue. We address the intrinsic biological drivers of tumor cell invasion, by tackling how tumor cells interact with each other and with the tumor microenvironment (TME). We focus on the recently discovered neuronal niche in the TME, including local as well as distant neurons, contributing to glioma growth and invasion. We then address the mechanisms of invasion promoted by astrocytes and immune cells. Finally, we review the current literature on the therapeutic targeting of the molecular mechanisms of invasion.
| S-EPMC10932253 | biostudies-literature
Project description:Cellular organisms regulate electrolyte composition in the cytosol to optimize intracellular molecular interactions at the same time as balancing external osmotic pressure. While osmotic pressure can be tuned using multiple ionic, zwitterionic, and nonionic solutes, interactions between proteins and other macromolecules are sensitive to the precise composition of the medium. Nonetheless, the roles of individual ions and nonionic solutes in mediating cellular interactions remain relatively unexplored, and standard buffer solutions used in laboratory studies often contain only a few simple salts. Here, we report on model experiments investigating the combined effect of ionic and zwitterionic solutes on interaction forces across electrolytes, revealing a clear role for zwitterions in modifying interactions compared to simple salt solutions. First, we find that zwitterions act to disrupt water layering at interfaces, leading to smoothed interaction potentials. Second, we find that zwitterions strengthen electrostatic repulsions by enhancing effective surface charge. Third, zwitterions enhance the effective dielectric permittivity of the solution, and this "dielectricizer" effect extends the range of electrostatic repulsions compared to solutions without zwitterion present. The latter two effects are likely important in stabilizing proteins and other macromolecules when external osmotic and mechanical pressure are very high and simple ionic solutes alone would lead to collapse.
| S-EPMC9974414 | biostudies-literature
Project description:Mechanosensitive ion channels rely on membrane composition to transduce physical stimuli into electrical signals. The Piezo1 channel mediates mechanoelectrical transduction and regulates crucial physiological processes, including vascular architecture and remodeling, cell migration, and erythrocyte volume. The identity of the membrane components that modulate Piezo1 function remain largely unknown. Using lipid profiling analyses, we here identify dietary fatty acids that tune Piezo1 mechanical response. We find that margaric acid, a saturated fatty acid present in dairy products and fish, inhibits Piezo1 activation and polyunsaturated fatty acids (PUFAs), present in fish oils, modulate channel inactivation. Force measurements reveal that margaric acid increases membrane bending stiffness, whereas PUFAs decrease it. We use fatty acid supplementation to abrogate the phenotype of gain-of-function Piezo1 mutations causing human dehydrated hereditary stomatocytosis. Beyond Piezo1, our findings demonstrate that cell-intrinsic lipid profile and changes in the fatty acid metabolism can dictate the cell's response to mechanical cues.
| S-EPMC6416271 | biostudies-literature