Study of star-forming galaxies in SDSS up to redshift 0.4 II. Evolution from the fundamental parameters: mass, metallicity & SFR

To understand the formation and evolution of galaxies, it is important to have a full comprehension of the role played by the metallicity, star formation rate (SFR), morphology, and color. The interplay of these parameters at different redshifts will substantially affect the evolution of galaxies and, as a consequence, the evolution of them will provide important clues and constraints on the galaxy evolution models. In this work we focus on the evolution of the SFR, metallicity of the gas, and morphology of galaxies at low redshift in search of signs of evolution. We use the S2N2 diagnostic diagram as a tool to classify star--forming, composite, and AGN galaxies. We analyzed the evolution of the three principal BPT diagrams, estimating the SFR and specific SFR (SSFR) for our samples of galaxies, studying the luminosity and mass-metallicity relations, and analyzing the morphology of our sample of galaxies through the g-r color, concentration index, and SSFR. We found that the S2N2 is a reliable diagram to classify star--forming, composite, and AGNs galaxies. We demonstrate that the three principal BPT diagrams show an evolution toward higher values of [OIII]5007/Hb due to a metallicity decrement. We found an evolution in the mass-metallicity relation of ~ 0.2 dex for the redshift range 0.3 < z < 0.4 compared to our local one. From the analysis of the evolution of the SFR and SSFR as a function of the stellar mass and metallicity, we discovered a group of galaxies with higher SFR and SSFR at all redshift samples, whose morphology is consistent with those of late-type galaxies. Finally, the comparison of our local (0.04<z<0.1) with our higher redshift sample (0.3<z<0.4), show that the metallicity, the SFR and morphology, evolve toward lower values of metallicity, higher SFRs, and late--type morphologies for the redshift range 0.3<z<0.4Comment: 16 pages, 15 figures. Accepted for publication in A&

Evolution of the optical Tully-Fisher relation up to z=1.3

The study of the evolution of the Tully-Fisher relation has been controversial in the past years. The main difficulty is in determining the required parameters for intermediate and high redshift galaxies. This work aims to identify the main problems of the study of the Tully-Fisher relation at high redshift using optical emission lines, in order to draw conclusions about the possible evolution of this relation in the B, R, and I-bands. With this aim, the rotational velocities obtained from the widths of different optical lines using DEEP2 spectra are compared. Morphology has been determined via HST images, using and comparing different methodologies. Instrumental magnitudes are then corrected for K and extinction and the absolute magnitudes derived for the concordance cosmological model. Finally, the optical Tully-Fisher relations in B, R, and I-bands at different redshifts up to z = 1.3 are derived. Although most studies (this one included) find evidence of evolution, the results are not conclusive enough, since the possible luminosity evolution is within the scattering of the relation, and the evolution in slope is difficult to determine because at high redshift only the brightest galaxies can be measured. Nevertheless, our study shows a clear tendency, which is the same for all bands studied, that favours a luminosity evolution where galaxies were brighter in the past for the same rotation velocity. This result also implies that the colour of the Tully-Fisher relation does not change with redshift, supporting the collapse model versus the accretion model of disc galaxy formation.Comment: 10 pages, 8 figures, accepted by A&

Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis

Age related variations in gene expression patterns of renal cell carcinoma - Biological and translational implications

Renal cell carcinoma (RCC) is known to occur across a wide age spectrum traversing age-related organismal changes, however little is known as to how the aging process may affect the course of RCC and the repertoire of genes involved. I therefore examined associations between patient age and the gene expression profiles in RCC tumors and normal kidney tissues. Datasets from The Cancer Genome Atlas (TCGA, n=436) and the International Cancer Genome Consortium (ICGC) Cancer Genomics of the Kidney (CAGEKID, n=89) were analyzed for pathways and cellular processes that are affected by aging in RCC. My analysis revealed different age dependent gene expression spectra in RCC tumors and normal kidney tissues. These findings were significant and reproducible in both datasets examined (p < 2.2 × 10-16). Age-upregulated genes, that is genes that show higher expression in older patients, in normal cells were significantly enriched (FDR<0.05) for pathways associated with immune response, collagen formation and semaphorin signaling, whereas age-upregulated genes in tumors were enriched for metabolism and oxidation pathways. Strikingly, age-downregulated genes in normal cells were also enriched for metabolism and oxidation, while those in tumors were enriched for extracellular matrix organization. Further in silico analysis of potential drug targets using connectivity mapping tools predicted preferential efficacy of Phosphoinositide 3-kinase (PI3K) inhibitors or immunotherapy in association with age.Conclusion: I report on hitherto unrecognized interrelations between human life cycle and RCC, suggesting possible effects of age on response to drug treatments.Le carcinome à cellules rénales (CCR) est connu pour se manifester à travers un large spectre d'âges traversant les changements organiques liés à l'âge, mais on en connait peu sur la façon dont le processus de vieillissement peut affecter l'évolution du CCR et le répertoire des gènes impliqués. J'ai donc examiné les associations entre l'âge des patients et les profils d'expression génique dans les tumeurs CCR et les tissus rénaux normaux. Les données de The Cancer Genome Atlas (TCGA, n = 436) et du International Cancer Genome Consortium (ICGC) Cancer Genomics of the Kidney (CAGEKID, n = 89) ont été analysées afin d'identifier les voies et les processus cellulaires affectés par le vieillissement dans le contexte du CCR.Mon analyse a révélé différents spectres d'expression génique dépendant de l'âge dans les tumeurs CCR et les tissus rénaux normaux. Ces résultats étaient significatifs et reproductibles dans les deux ensembles de données examinés (p < 2.2 × 10-16). Dans les cellules normales, les gènes ayant une expression plus élevée chez les patients âgés étaient significativement enrichis (FDR <0.05) pour les voies associées à la réponse immunitaire, à la formation de collagène et à la signalisation de la sémaphorine, tandis que dans les cellules cancéreuses ces gènes étaient enrichis pour les voies de métabolisme et d'oxydation. De manière frappante, les gènes ayant une expression moins élevée chez les patients âgés dans les cellules normales étaient également enrichis pour le métabolisme et l'oxydation, tandis que ceux des tumeurs étaient enrichis pour l'organisation de la matrice extracellulaire. Une analyse in silico des cibles médicamenteuses potentielles utilisant des outils de cartographie de la connectivité a prédit l'efficacité préférentielle des inhibiteurs de la phosphoinositide 3-kinase (PI3K) ou de l'immunothérapie en association avec l'âge.Conclusion: Je rapporte des interrelations jusqu'alors méconnues entre le cycle de vie humain et le CCR, suggérant des effets possibles de l'âge sur la réponse aux traitements médicamenteux

Endocardial Regulation of Cardiac Development

The endocardium is a specialized form of endothelium that lines the inner side of the heart chambers and plays a crucial role in cardiac development. While comparatively less studied than other cardiac cell types, much progress has been made in understanding the regulation of and by the endocardium over the past two decades. In this review, we will summarize what is currently known regarding endocardial origin and development, the relationship between endocardium and other cardiac cell types, and the various lineages that endocardial cells derive from and contribute to. These processes are driven by key molecular mechanisms such as Notch and BMP signaling. These pathways in particular have been well studied, but other signaling pathways and mechanical cues also play important roles. Finally, we will touch on the contribution of stem cell modeling in combination with single cell sequencing and its potential translational impact for congenital heart defects such as bicuspid aortic valves and hypoplastic left heart syndrome. The detailed understanding of cellular and molecular processes in the endocardium will be vital to further develop representative stem cell-derived models for disease modeling and regenerative medicine in the future

Developmental role of macrophages modeled in human pluripotent stem cell-derived intestinal tissue

Summary: Macrophages populate the embryo early in gestation, but their role in development is not well defined. In particular, specification and function of macrophages in intestinal development remain little explored. To study this event in the human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrate into the organoid, proliferate, and occupy the emerging microanatomical niches of epithelial crypts and ganglia. They also acquire a transcriptomic profile similar to that of fetal intestinal macrophages and display tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to the regulation of metabolism and growth of the developing intestine

Developmental role of macrophages modeled in human pluripotent stem cell-derived intestinal tissue

Macrophages populate the embryo early in gestation, but their role in development is not well defined. In particular, specification and function of macrophages in intestinal development remain little explored. To study this event in the human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrate into the organoid, proliferate, and occupy the emerging microanatomical niches of epithelial crypts and ganglia. They also acquire a transcriptomic profile similar to that of fetal intestinal macrophages and display tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to the regulation of metabolism and growth of the developing intestine

Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1

Abstract Muscle stem cells, the engine of muscle repair, are affected in myotonic dystrophy type 1 (DM1); however, the underlying molecular mechanism and the impact on the disease severity are still elusive. Here, we show using patients’ samples that muscle stem cells/myoblasts exhibit signs of cellular senescence in vitro and in situ. Single cell RNAseq uncovers a subset of senescent myoblasts expressing high levels of genes related to the senescence-associated secretory phenotype (SASP). We show that the levels of interleukin-6, a prominent SASP cytokine, in the serum of DM1 patients correlate with muscle weakness and functional capacity limitations. Drug screening revealed that the senolytic BCL-XL inhibitor (A1155463) can specifically remove senescent DM1 myoblasts by inducing their apoptosis. Clearance of senescent cells reduced the expression of SASP, which rescued the proliferation and differentiation capacity of DM1 myoblasts in vitro and enhanced their engraftment following transplantation in vivo. Altogether, this study identifies the pathogenic mechanism associated with muscle stem cell defects in DM1 and opens a therapeutic avenue that targets these defective cells to restore myogenesis