Uncovering the Number and Clonal Dynamics of Mesp1 Progenitors during Heart Morphogenesis.

The heart arises from distinct sources of cardiac progenitors that independently express Mesp1 during gastrulation. The precise number of Mesp1 progenitors that are specified during the early stage of gastrulation, and their clonal behavior during heart morphogenesis, is currently unknown. Here, we used clonal and mosaic tracing of Mesp1-expressing cells combined with quantitative biophysical analysis of the clonal data to define the number of cardiac progenitors and their mode of growth during heart development. Our data indicate that the myocardial layer of the heart derive from ∼250 Mesp1-expressing cardiac progenitors born during gastrulation. Despite arising at different time points and contributing to different heart regions, the temporally distinct cardiac progenitors present very similar clonal dynamics. These results provide insights into the number of cardiac progenitors and their mode of growth and open up avenues to decipher the clonal dynamics of progenitors in other organs and tissues.S.C. and N.M. are supported by fellowship of the FRS/FRIA. F.L has been supported by the EMBO longterm fellowship. B.D.S. and S.R. are supported by Wellcome Trust (grant number 098357/Z/12/Z). C.B. is an investigator of WELBIO. This work was supported by the FNRS, the ULB foundation, the European Research Council (ERC), and the foundation Bettencourt Schueller (C.B. and F.L.).This is the final version of the article. It first appeared from Elsevier/Cell Press via http://dx.doi.org/10.1016/j.celrep.2015.12.01

Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium.

Epithelial lineages have been studied at cellular resolution in multiple organs that turn over rapidly. However, many epithelia, including those of the lung, liver, pancreas, and prostate, turn over slowly and may be regulated differently. We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate. We confirmed the molecular and functional differences within the basal population by using single-cell qRT-PCR and further lineage labeling. Additionally, we show that self-renewal of short-lived secretory cells is a feature of homeostasis. We have thus revealed early luminal commitment of cells that are morphologically indistinguishable from stem cells.This study was supported by the Medical Research Council (G0900424 to E.R.), European Union grant EuroSyStem (200720; FP7/2008), the Newton Trust (to E.R.), the Wellcome Trust (098357/Z/12/Z to B.D.S.). Core grants from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.celrep.2015.06.01

Defining stem cell dynamics and migration during wound healing in mouse skin epidermis.

Wound healing is essential to repair the skin after injury. In the epidermis, distinct stem cells (SCs) populations contribute to wound healing. However, how SCs balance proliferation, differentiation and migration to repair a wound remains poorly understood. Here, we show the cellular and molecular mechanisms that regulate wound healing in mouse tail epidermis. Using a combination of proliferation kinetics experiments and molecular profiling, we identify the gene signatures associated with proliferation, differentiation and migration in different regions surrounding the wound. Functional experiments show that SC proliferation, migration and differentiation can be uncoupled during wound healing. Lineage tracing and quantitative clonal analysis reveal that, following wounding, progenitors divide more rapidly, but conserve their homoeostatic mode of division, leading to their rapid depletion, whereas SCs become active, giving rise to new progenitors that expand and repair the wound. These results have important implications for tissue regeneration, acute and chronic wound disorders.This work was supported by the FNRS, TELEVIE, the PAI programme, a research grant from the Fondation contre le Cancer, the ULB fondation, the foundation Bettencourt Schueller, the foundation Baillet Latour and a consolidator grant the European Research Council (ERC-EXPAND)

Defining the Design Principles of Skin Epidermis Postnatal Growth

Summary During embryonic and postnatal development, organs and tissues grow steadily to achieve their final size at the end of puberty. However, little is known about the cellular dynamics that mediate postnatal growth. By combining in vivo clonal lineage tracing, proliferation kinetics, single-cell transcriptomics, and in vitro micro-pattern experiments, we resolved the cellular dynamics taking place during postnatal skin epidermis expansion. Our data revealed that harmonious growth is engineered by a single population of developmental progenitors presenting a fixed fate imbalance of self-renewing divisions with an ever-decreasing proliferation rate. Single-cell RNA sequencing revealed that epidermal developmental progenitors form a more uniform population compared with adult stem and progenitor cells. Finally, we found that the spatial pattern of cell division orientation is dictated locally by the underlying collagen fiber orientation. Our results uncover a simple design principle of organ growth where progenitors and differentiated cells expand in harmony with their surrounding tissues.Peer reviewe

Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis

Lineage-tracing experiments show that the origin of specialized mechanosensory Merkel cells in the skin is epidermal progenitors, not the neural crest

Defining the clonal dynamics leading to mouse skin tumour initiation.

The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is dependent not only on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin.C.B. is an investigator of WELBIO. A.S-D. and JC.L. are supported by a fellowship of the FNRS and FRIA respectively. B.D.S. and E.H. are supported by the Wellcome Trust (grant number 098357/Z/12/Z and 110326/Z/15/Z). EH is supported by a fellowship from Trinity College, Cambridge. This work was supported by the FNRS, the IUAP program, the Fondation contre le Cancer, the ULB fondation, the foundation Bettencourt Schueller, the foundation Baillet Latour, a consolidator grant of the European Research Council.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nature1906

Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids

Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein–coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42–p44 MAP kinases, through the Gi class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs

El Estado colombiano ante el emprendimiento en clave de género

La formulación de políticas públicas diferenciadas tiene como base no sólo las demandas internacionales a las que se ha acogido el Estado colombiano, sino también las realidades del territorio como lo es el porcentaje de crecimiento del grupo de mujeres: De acuerdo con las proyecciones de crecimiento poblacional (DANE, 2005), para 2011, las mujeres representarían el 50,6% de la población total colombiana, equivalente a 23.313.302 millones de mujeres, frente a 22.731.299 millones de hombres que representarían el 49,4%. Con una mayor concentración en las zonas urbanas, con el 75,6%. Con base en las anteriores consideraciones, es fundamental traer a colación a la población femenina que abarca más del 50% de la población colombiana. Por lo tanto, es pertinente el presente trabajo de grado al tener como principal énfasis las políticas públicas del Estado colombiano para las mujeres enfocadas en el área del emprendimiento, ya que su potencialización llevaría al Estado a contar con una herramienta para la erradicación de la pobreza y lograr un país más equitativo no solo desde la formulación de políticas sino en su implementación. Se hace necesario, en un primer momento, identificar los principales debates teóricos sobre la relación de las mujeres y su participación política en cuanto al emprendimiento y a la construcción social de país. En contraposición a los enfoques institucionales que han posicionado a la mujer desde un paradigma asistencialista, seguido por uno de riesgo, vulnerabilidad y violencia, para, finalmente, llegar a un enfoque de desarrollo integral. El análisis se presenta en el primer capítulo. En un segundo momento, es decir el capítulo dos, se presentará el componente teórico del desarrollo del emprendimiento en Colombia. Posteriormente, en el tercer capítulo, se analizarán las entrevistas realizadas a mujeres emprendedoras de los diferentes niveles sociales y a hombres, empleados y funcionarios tanto del sector público como privado. El análisis da cuenta de la influencia de las políticas públicas de emprendimiento, al tener como punto de referencia las relaciones instituciones estatales como mujer emprendedora y sus relaciones dentro de organizaciones y cómo esto repercute en su participación política y en la construcción del desarrollo social en Colombia. Se identificarán, igualmente, las causas y variables que impiden llevar a la realidad las políticas públicas de emprendimiento en clave de género y así medir o cualificar la manera en que el Estado colombiano aporta al desarrollo de los emprendimientos de las mujeres en el periodo 2000 – 2018.The formulation of differentiated public policies is based not only on the international demands to which the Colombian State has accepted, but also on the realities of the territory, as is the percentage of growth of the group of women: According to the projections of population growth (DANE, 2005), for 2011, women would represent 50.6% of the total Colombian population, equivalent to 23,313,302 million women, compared to 22,731,299 million men who would represent 49.4%. With a greater concentration in urban areas, with 75.6%. Based on the above considerations, it is essential to bring up the female population that covers more than 50% of the Colombian population. Therefore, the present degree work is relevant, having as main emphasis the public policies of the Colombian State for women focused in the area of entrepreneurship, because that potentialization would lead the State to have a tool for the eradication of poverty and achieve a more equitable country not only from the formulation of policies, but also in its implementation. It is necessary, at first, to identify the main theoretical debates on the relationship of women and their political participation in terms of entrepreneurship and the social construction of the country. In contrast to the institutional approaches that have positioned women from a welfare paradigm, followed by one of risk, vulnerability and violence, to finally reach an integral development approach. The analysis is presented in the first chapter. In a second moment, that is to say chapter two, the theoretical component of the development of entrepreneurship in Colombia will be presented. Subsequently, in the third chapter, the interviews conducted with women entrepreneurs from different social levels and men, employees and officials from both the public and private sectors will be analyzed. The analysis explains of the influence of public policies on entrepreneurship, having as a point of reference the relations between state institutions as an entrepreneur and their relationships within organizations and how this affects their political participation and the construction of social development in Colombia. It will also identify the causes and variables that prevent the realization of public policies of entrepreneurship in terms of gender and thus measure or qualify the way in which the Colombian State contributes to the development of women's enterprises in the period 2000 - 2018Magíster en Estudios PolíticosMaestrí