Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.

Atheromatous fibrous caps are produced by smooth muscle cells (SMCs) that are recruited to the subendothelial space. We tested whether the recruitment mechanisms are the same as in embryonic artery development, which relies prominently on Notch signaling to form the subendothelial medial SMC layers. Notch elements were expressed in regions of fibrous cap in human and mouse plaques. To assess the causal role of Notch signaling in cap formation, we studied atherosclerosis in mice where the Notch pathway was inactivated in SMCs by conditional knockout of the essential effector transcription factor RBPJ (recombination signal-binding protein for immunoglobulin kappa J region). The recruitment of cap SMCs was significantly reduced without major effects on plaque size. Lineage tracing revealed the accumulation of SMC-derived plaque cells in the cap region was unaltered but that Notch-defective cells failed to re-acquire the SMC phenotype in the cap. Conversely, to analyze whether the loss of Notch signaling is required for SMC-derived cells to accumulate in atherogenesis, we studied atherosclerosis in mice with constitutive activation of Notch signaling in SMCs achieved by conditional expression of the Notch intracellular domain. Forced Notch signaling inhibited the ability of medial SMCs to contribute to plaque cells, including both cap SMCs and osteochondrogenic cells, and significantly reduced atherosclerosis development. Sequential loss and gain of Notch signaling is needed to build the cap SMC population. The shared mechanisms with embryonic arterial media assembly suggest that the cap forms as a neo-media that restores the connection between endothelium and subendothelial SMCs, transiently disrupted in early atherogenesis.This study was supported by a grant from the Ministerio de Ciencia e Innovación with cofunding from the European Regional Development Fund (SAF2016- 75580-R and PID2019-108568RB-I00 to J.F. Bentzon and SAF2016-78370-R to J.L. de la Pompa) and from the Novo Nordisk Foundation (NNF17OC0030688 to. J.F. Bentzon). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Cholesterol lowering depletes atherosclerotic lesions of smooth muscle cell-derived fibromyocytes and chondromyocytes

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Aislamiento del DNA del complejo génico achete-scute de drosophila melanogaster. Obtención del mapa físico de 25 mutantes del complejo

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura 10-07-198

CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses

El copyright pertenece a The American Society for Clinical InvestigationCCR6 expression in dendritic, T, and B cells suggests that this b-chemokine receptor may regulate the migration and recruitment of antigen-presenting and immunocompetent cells during inflammatory and immunological responses. Here we demonstrate that CCR6–/– mice have underdeveloped Peyer’s patches, in which the myeloid CD11b+ CD11c+ dendritic-cell subset is not present in the subepithelial dome. CCR6–/– mice also have increased numbers in T-cell subpopulations within the intestinal mucosa. In 2,4-dinitrofluorobenzene–induced contact hypersensitivity (CHS) studies, CCR6–/– mice developed more severe and more persistent inflammation than wild-type (WT) animals. Conversely, in a delayedtype hypersensitivity (DTH) model induced with allogeneic splenocytes, CCR6–/– mice developed no inflammatory response. The altered responses seen in the CHS and DTH assays suggest the existence of a defect in the activation and/or migration of the CD4+ T-cell subsets that downregulate or elicit the inflammation response, respectively. These findings underscore the role of CCR6 in cutaneous and intestinal immunity and the utility of CCR6–/– mice as a model to study pathologies in these tissues.Peer reviewe

Tabanque : revista pedagógica

Resumen basado en el de la publicaciónTítulo, resumen y palabras clave disponibles en español y en inglésSe observa la situación de tres alumnos extranjeros, cómo es su relación con los compañeros y su trabajo en el aula de clase. La observación se realiza en un centro rural. Tiene un porcentaje de inmigración de aproximadamente un 22%. Tras esta observación en el centro se reflexiona sobre las necesidades detectadas y sobre las propuestas para iniciar el trabajo. Todo esto lleva a una conclusión: la necesidad de abrir los ojos, es decir, tomar conciencia ante las situaciones de exclusión que se dan en el aula.ES

Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs

Fibrous cap smooth muscle cells (SMCs) protect atherosclerotic lesions from rupturing and causing thrombosis, while other plaque SMCs may have detrimental roles in plaque development. To gain insight into recruitment of different plaque SMCs, we mapped their clonal architecture in aggregation chimeras of eGFP+Apoe-/- and Apoe-/- mouse embryos and in mice with a mosaic expression of fluorescent proteins in medial SMCs that were rendered atherosclerotic by PCSK9-induced hypercholesterolemia. Fibrous caps in aggregation chimeras were found constructed from large, endothelial-aligned layers of either eGFP+ or nonfluorescent SMCs, indicating substantial clonal expansion of a few cells. Similarly, plaques in mice with SMC-restricted Confetti expression showed oligoclonal SMC populations with little intermixing between the progeny of different medial SMCs. Phenotypes comprised both ACTA2+ SMCs in the cap and heterogeneous ACTA2- SMCs in the plaque interior, including chondrocyte-like cells and cells with intracellular lipid and crystalline material. Fibrous cap SMCs were invariably arranged in endothelium-aligned clonal sheets, confirming results in the aggregation chimeras. Analysis of the clonal structure showed that a low number of local medial SMCs partake in atherosclerosis and that single medial SMCs can produce several different SMC phenotypes in plaque. The combined results show that few medial SMCs proliferate to form the entire phenotypically heterogeneous plaque SMC population in murine atherosclerosis.The study was funded by grants from the Danish Independent Research Council (Sapere Aude Programme, 4004-00459B) and the Ministerio de Economia, Industria e Competividad (MEIC) with cofunding from the Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-75580-R) and by scholarships from the Danish Independent Research Council (to MBL) and the Novo Scholarship Program (to KJ). The CNIC is supported by MEIC and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). We would like to thank Leticia Gonzalez, Lisa Maria Roge, and Dorte Wilhart Qualmann for histology and genotyping; Lisbeth Ahm Hansen and Peter Kragh for embryo work; the CNIC microscopy Unit (Veronica Labrador, Elvira Arza, and Antonio Santos-Beneit) for support on confocal microscopy; and the CNIC Histopathology Unit (Roisin Doohan, Brenda Guijarro, and Antonio Molina) for histological stainings and tissue scans.S