Evolution of irreversible somatic differentiation.
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ABSTRACT:
SUBMITTER: Gao Y
PROVIDER: S-EPMC8514237 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AIMS: Differentiation of cardiac fibroblasts (Fbs) into myofibroblasts (MyoFbs) is responsible for connective tissue build-up in myocardial remodelling. We examined MyoFb differentiation and reversibility. METHODS AND RESULTS: Adult rat cardiac Fbs were cultured on a plastic substratum providing mechanical stress, with conditions to obtain different levels of Fb differentiation. Fb spontaneously differentiated to proliferating MyoFb (p-MyoFb) with stress fibre formation decorated with alpha-smooth muscle actin (?-SMA). Transforming growth factor-?1 (TGF-?1) promoted differentiation into ?-SMA-positive MyoFb showing near the absence of proliferation, i.e. non-p-MyoFb. SD-208, a TGF-?-receptor-I (TGF-?-RI) kinase blocker, inhibited p-MyoFb differentiation as shown by stress fibre absence, low ?-SMA expression, and high proliferation levels. Fb seeded in collagen matrices induced no contraction, whereas p-MyoFb and non-p-MyoFb induced 2.5- and four-fold contraction. Fb produced little collagen but high levels of interleukin-10. Non-p-MyoFb had high collagen production and high monocyte chemoattractant protein-1 and tissue inhibitor of metalloproteinases-1 levels. Transcriptome analysis indicated differential activation of gene networks related to differentiation of MyoFb (e.g. paxilin and PAK) and reduced proliferation of non-p-MyoFb (e.g. cyclins and cell cycle regulation). Dedifferentiation of p-MyoFb with stress fibre de-polymerization, but not of non-p-MyoFb, was induced by SD-208 despite maintained stress. Stress fibre de-polymerization could also be induced by mechanical strain release in p-MyoFb and non-p-MyoFb (2-day cultures in unrestrained 3-D collagen matrices). Only p-MyoFb showed true dedifferentiation after long-term 3-D cultures. CONCLUSIONS: Fb, p-MyoFb, and non-p-MyoFb have a distinct gene expression, ultrastructural, and functional profile. Both reduction in mechanical strain and TGF-?-RI kinase inhibition can reverse p-MyoFb differentiation but not non-p-MyoFb.
| S-EPMC3928002 | biostudies-literature
Project description:Aim: Differentiation of cardiac fibroblasts (Fb) into myofibroblasts (MyoFb) is responsible for connective tissue buildup in myocardial remodeling. We examined reversibility of MyoFb differentiation. Methods and Results: Adult rat cardiac Fb were cultured on a plastic substratum providing mechanical stress, with conditions to obtain different Fb phenotypes. Fb spontaneously differentiated to proliferating MyoFb (p-MyoFb) with stress fiber formation decorated with alpha-smooth muscle actin (M-NM-1-SMA). Transforming growth factor-M-NM-21 (TGF-M-NM-21) promoted terminal differentiation into M-NM-1-SMA positive MyoFb showing near absence of proliferation i.e. non-p-MyoFb (2-fold increase in cell number after 12 days vs 11-fold for p-MyoFb). SD-208, a TGF-M-NM-2-receptor-I kinase blocker, inhibited p-MyoFb differentiation as shown by stress fiber absence, low levels of M-NM-1-SMA protein expression, and high levels of proliferation (32-fold increase after 12 days). Fb seeded in collagen matrices induced no contraction, whereas p-MyoFb and non-p-MyoFb induced 2.5- and 4-fold contraction. Fb produced low levels of collagen and secreted high levels of IL-10. Non-p-MyoFb showed high collagen production and high MCP-1 and TIMP-1 secretion. Transcriptome analysis indicated differential gene expression between all phenotypes. Dedifferentiation of p-MyoFb, but not of non-p-MyoFb, was induced by SD-208 despite maintained stress, shown by stress fiber de-polymerization in 30% of p-MyoFb vs in 8% of non-p-MyoFb. Stress fiber de-polymerization could be induced by mechanical strain release in p-MyoFb and non-p-MyoFb (2 day culture in unrestrained 3-D collagen matrices). Only p-MyoFb showed true dedifferentiation after long-term 3-D culture. Conclusions: Both reduction in mechanical strain and TGF-M-NM-2-receptor-I kinase inhibition can reverse p-MyoFb differentiation but not in non-p-MyoFb. Fibroblasts isolated from each rat heart (n= 4) were cultured in specific conditions to obtain different fibroblast phenotypes: 1) spontaneously differentiation into proliferating myofibroblasts (code RC), 2) terminal differentiation into non-proliferating myofibroblasts with TGF-M-NM-21 (code RT) and 3) inhibition of myofibroblast differentiation with SD-208, a TGF-M-NM-2-receptor-I kinase blocker (code RS). RNA concentration and purity from a total of 12 samples were determined spectrophotometrically using the Nanodrop ND-1000 (Nanodrop Technologies) and RNA integrity was assessed using a Bioanalyser 2100 (Agilent). Using the Ambion WT Expression Kit, per sample, an amount of 100 ng of total RNA spiked with bacterial poly-A RNA positive controls (Affymetrix) was converted to double stranded cDNA in a reverse transcription reaction. Next the sample was converted and amplified to antisense cRNA in an in vitro transcription reaction which was subsequently converted to single stranded sense cDNA. Finally, samples were fragmented and labeled with biotin in a terminal labeling reaction according to the Affymetrix WT Terminal Labeling Kit. A mixture of fragmented biotinylated cDNA and hybridisation controls (Affymetrix) was hybridised on Affymetrix GeneChipM-BM-. Rat Gene 2.0 ST array followed by staining and washing in a GeneChipM-BM-. fluidics station 450 (Affymetrix) according to the manufacturerM-bM-^@M-^Ys procedures. To assess the raw probe signal intensities, chips were scanned using a GeneChipM-BM-. scanner 3000 (Affymetrix).
2014-01-07 | E-GEOD-51824 | biostudies-arrayexpress
Project description:Tumorigenesis in humans is thought to be a multistep process where certain mutations confer a selective advantage, allowing lineages derived from the mutated cell to outcompete other cells. Although molecular cell biology has substantially advanced cancer research, our understanding of the evolutionary dynamics that govern tumorigenesis is limited. This paper analyzes the computational implications of cancer progression presented by Hanahan and Weinberg in The Hallmarks of Cancer. We model the complexities of tumor progression as a small set of underlying rules that govern the transformation of normal cells to tumor cells. The rules are implemented in a stochastic multistep model. The model predicts that (i) early-onset cancers proceed through a different sequence of mutation acquisition than late-onset cancers; (ii) tumor heterogeneity varies with acquisition of genetic instability, mutation pathway, and selective pressures during tumorigenesis; (iii) there exists an optimal initial telomere length which lowers cancer incidence and raises time of cancer onset; and (iv) the ability to initiate angiogenesis is an important stage-setting mutation, which is often exploited by other cells. The model offers insight into how the sequence of acquired mutations affects the timing and cellular makeup of the resulting tumor and how the cellular-level population dynamics drive neoplastic evolution.
| S-EPMC1550273 | biostudies-literature
Project description:In setting up a stochastic description of the time evolution of a financial index, the challenge consists in devising a model compatible with all stylized facts emerging from the analysis of financial time series and providing a reliable basis for simulating such series. Based on constraints imposed by market efficiency and on an inhomogeneous-time generalization of standard simple scaling, we propose an analytical model which accounts simultaneously for empirical results like the linear decorrelation of successive returns, the power law dependence on time of the volatility autocorrelation function, and the multiscaling associated to this dependence. In addition, our approach gives a justification and a quantitative assessment of the irreversible character of the index dynamics. This irreversibility enters as a key ingredient in a novel simulation strategy of index evolution which demonstrates the predictive potential of the model.
| S-EPMC2148368 | biostudies-literature
Project description:Many multicellular organisms produce two cell lineages: germ cells, whose descendants produce the next generation, and somatic cells, which support, protect, and disperse the germ cells. This germ-soma demarcation has evolved independently in dozens of multicellular taxa but is absent in unicellular species. A common explanation holds that in these organisms, inefficient intercellular nutrient exchange compels the fitness cost of producing nonreproductive somatic cells to outweigh any potential benefits. We propose instead that the absence of unicellular, soma-producing populations reflects their susceptibility to invasion by nondifferentiating mutants that ultimately eradicate the soma-producing lineage. We argue that multicellularity can prevent the victory of such mutants by giving germ cells preferential access to the benefits conferred by somatic cells. The absence of natural unicellular, soma-producing species previously prevented these hypotheses from being directly tested in vivo: to overcome this obstacle, we engineered strains of the budding yeast Saccharomyces cerevisiae that differ only in the presence or absence of multicellularity and somatic differentiation, permitting direct comparisons between organisms with different lifestyles. Our strains implement the essential features of irreversible conversion from germ line to soma, reproductive division of labor, and clonal multicellularity while maintaining sufficient generality to permit broad extension of our conclusions. Our somatic cells can provide fitness benefits that exceed the reproductive costs of their production, even in unicellular strains. We find that nondifferentiating mutants overtake unicellular populations but are outcompeted by multicellular, soma-producing strains, suggesting that multicellularity confers evolutionary stability to somatic differentiation.
| S-EPMC4968738 | biostudies-literature
Project description:Aim: Differentiation of cardiac fibroblasts (Fb) into myofibroblasts (MyoFb) is responsible for connective tissue buildup in myocardial remodeling. We examined reversibility of MyoFb differentiation. Methods and Results: Adult rat cardiac Fb were cultured on a plastic substratum providing mechanical stress, with conditions to obtain different Fb phenotypes. Fb spontaneously differentiated to proliferating MyoFb (p-MyoFb) with stress fiber formation decorated with alpha-smooth muscle actin (α-SMA). Transforming growth factor-β1 (TGF-β1) promoted terminal differentiation into α-SMA positive MyoFb showing near absence of proliferation i.e. non-p-MyoFb (2-fold increase in cell number after 12 days vs 11-fold for p-MyoFb). SD-208, a TGF-β-receptor-I kinase blocker, inhibited p-MyoFb differentiation as shown by stress fiber absence, low levels of α-SMA protein expression, and high levels of proliferation (32-fold increase after 12 days). Fb seeded in collagen matrices induced no contraction, whereas p-MyoFb and non-p-MyoFb induced 2.5- and 4-fold contraction. Fb produced low levels of collagen and secreted high levels of IL-10. Non-p-MyoFb showed high collagen production and high MCP-1 and TIMP-1 secretion. Transcriptome analysis indicated differential gene expression between all phenotypes. Dedifferentiation of p-MyoFb, but not of non-p-MyoFb, was induced by SD-208 despite maintained stress, shown by stress fiber de-polymerization in 30% of p-MyoFb vs in 8% of non-p-MyoFb. Stress fiber de-polymerization could be induced by mechanical strain release in p-MyoFb and non-p-MyoFb (2 day culture in unrestrained 3-D collagen matrices). Only p-MyoFb showed true dedifferentiation after long-term 3-D culture. Conclusions: Both reduction in mechanical strain and TGF-β-receptor-I kinase inhibition can reverse p-MyoFb differentiation but not in non-p-MyoFb.
2014-01-07 | GSE51824 | GEO
Project description:Many recent efforts to analyze cancer genomes involve aggregation of mutations within reference maps of molecular pathways and protein networks. Here, we find these pathway studies are impeded by molecular interactions that are functionally irrelevant to cancer or the patient's tumor type, as these interactions diminish the contrast of driver pathways relative to individual frequently mutated genes. This problem can be addressed by creating stringent tumor-specific networks of biophysical protein interactions, identified by signatures of epistatic selection during tumor evolution. Using such an evolutionarily selected pathway (ESP) map, we analyze the major cancer genome atlases to derive a hierarchical classification of tumor subtypes linked to characteristic mutated pathways. These pathways are clinically prognostic and predictive, including the TP53-AXIN-ARHGEF17 combination in liver and CYLC2-STK11-STK11IP in lung cancer, which we validate in independent cohorts. This ESP framework substantially improves the definition of cancer pathways and subtypes from tumor genome data.
| S-EPMC6175900 | biostudies-other
Project description:BackgroundDespite the known importance of somatic cells for oocyte developmental competence acquisition, the overall mechanisms underlying the acquisition of full developmental competence are far from being understood, especially in non-mammalian species. The present work aimed at identifying key molecular signals from somatic origin that would be shared by vertebrates.ResultsUsing a parallel transcriptomic analysis in 4 vertebrate species - a teleost fish, an amphibian, and two mammals - at similar key steps of developmental competence acquisition, we identified a large number of species-specific differentially expressed genes and a surprisingly high number of orthologous genes exhibiting similar expression profiles in the 3 tetrapods and in the 4 vertebrates. Among the evolutionary conserved players participating in developmental competence acquisition are genes involved in key processes such as cellular energy metabolism, cell-to-cell communications, and meiosis control. In addition, we report many novel molecular actors from somatic origin that have never been studied in the vertebrate ovary. Interestingly, a significant number of these new players actively participate in Drosophila oogenesis.ConclusionsOur study provides a comprehensive overview of evolutionary-conserved mechanisms from somatic origin participating in oocyte developmental competence acquisition in 4 vertebrates. Together our results indicate that despite major differences in ovarian follicular structure, some of the key players from somatic origin involved in oocyte developmental competence acquisition would be shared, not only by vertebrates, but also by metazoans. The conservation of these mechanisms during vertebrate evolution further emphasizes the important contribution of the somatic compartment to oocyte quality and paves the way for future investigations aiming at better understanding what makes a good egg.
| S-EPMC3532176 | biostudies-literature
Project description:Rationale and objectivesIrreversible electroporation (IRE) is a promising non-thermal ablation technique for the treatment of patients with hepatocellular carcinoma. Early differentiation of the IRE zone from surrounding reversibly electroporated (RE) penumbra is vital for the evaluation of treatment response. In this study, an advanced statistical learning framework was developed by evaluating standard MRI data to differentiate IRE ablation zones, and to correlate with histological tumor biomarkers.Materials and methodsFourteen rabbits with VX2 liver tumors were scanned following IRE ablation and forty-six features were extracted from T1w and T2w MRI. Following identification of key imaging variables through two-step feature analysis, multivariable classification and regression models were generated for differentiation of IRE ablation zones, and correlation with histological markers reflecting viable tumor cells, microvessel density, and apoptosis rate. The performance of the multivariable models was assessed by measuring accuracy, receiver operating characteristics curve analysis, and Spearman correlation coefficients.ResultsThe classifiers integrating four radiomics features of T1w, T2w, and T1w+T2w MRI data distinguished IRE from RE zones with an accuracy of 97%, 80%, and 97%, respectively. Also, pixelwise classification models of T1w, T2w, and T1w+T2w MRI labeled each voxel with an accuracy of 82.8%, 66.5%, and 82.9%, respectively. Regression models obtained a strong correlation with behavior of viable tumor cells (0.62 ≤ r2 ≤ 0.85, p < 0.01), apoptosis (0.40 ≤ r2 ≤ 0.82, p < 0.01), and microvessel density (0.48 ≤ r2 ≤ 0.58, p < 0.01).ConclusionMRI radiomics features provide descriptive power for early differentiation of IRE and RE zones while observing strong correlations among multivariable MRI regression models and histological tumor biomarkers.
| S-EPMC10029937 | biostudies-literature
Project description:BackgroundThe evolution of multi-cellular animals has produced a conspicuous trend toward increased body size. This trend has introduced at least two novel problems: an expected elevated risk of somatic disorders, such as cancer, and declining evolvability due to generally reduced population size, lower reproduction rate and extended generation time. Low population size is widely recognized to explain the high mutation rates in animals by limiting the presumed universally negative selection acting on mutation rates.ResultsHere, we present evidence from stochastic modeling that the direction and strength of selection acting on mutation rates is highly dependent on the evolution of somatic maintenance, and thus longevity, which modulates the cost of somatic mutations.ConclusionsWe argue that the impact of the evolution of longevity on mutation rates may have been critical in facilitating animal evolution.
| S-EPMC6708161 | biostudies-literature