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In the published publication [...].
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The Wilms tumor suppressor gene (Wt1) encodes a C2H2-type zinc-finger transcription factor that participates in transcriptional regulation, RNA metabolism, and protein-protein interactions. WT1 is involved in the development of several organs, including the kidneys and gonads, heart, spleen, adrenal glands, liver, diaphragm, and neuronal system. We previously provided evidence of transient WT1 expression in about 25% of cardiomyocytes of mouse embryos. Conditional deletion of Wt1 in the cardiac troponin T lineage caused abnormal cardiac development. A low expression of WT1 has also been reported in adult cardiomyocytes. Therefore, we aimed to explore its function in cardiac homeostasis and in the response to pharmacologically induced damage. Silencing of Wt1 in cultured neonatal murine cardiomyocytes provoked alterations in mitochondrial membrane potential and changes in the expression of genes related to calcium homeostasis. Ablation of WT1 in adult cardiomyocytes by crossing αMHCMerCreMer mice with homozygous WT1-floxed mice induced hypertrophy, interstitial fibrosis, altered metabolism, and mitochondrial dysfunction. In addition, conditional deletion of WT1 in adult cardiomyocytes increased doxorubicin-induced damage. These findings suggest a novel role of WT1 in myocardial physiology and protection against damage.
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The Spanish Society for Developmental Biology (SEBD) organized its 17th meeting in November 2020 (herein referred to as SEBD2020). This meeting, originally programmed to take place in the city of Bilbao, was forced onto an online format due to the SARS-CoV2, COVID-19 pandemic. Although, we missed the live personal interactions and missed out on the Bilbao social scene, we were able to meet online to present our work and discuss our latest results. An overview of the activities that took place around the meeting, the different scientific sessions and the speakers involved are presented here. The pros and cons of virtual meetings are discussed.
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Biología Evolutiva/métodos , Biología Evolutiva/tendencias , Animales , Biología Celular/tendencias , Biología Evolutiva/educación , Humanos , Internet , Modelos Animales , Sistema Nervioso , Revisión por Pares , Publicaciones , Edición , Regeneración , Instituciones Académicas , Sociedades Médicas , EspañaRESUMEN
Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1+ myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature.
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Corazón/crecimiento & desarrollo , Vasos Linfáticos , Macrófagos/metabolismo , Animales , Receptor 1 de Quimiocinas CX3C/genética , Adhesión Celular , Línea Celular , Células Endoteliales , Regulación del Desarrollo de la Expresión Génica , Técnicas de Sustitución del Gen , Humanos , Inflamación , Linfangiogénesis , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Organogénesis/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Saco VitelinoRESUMEN
As we age, our tissues become a mosaic of random mutations, many of which are oncogenic and promote the expansion of their carrier cells. In this issue of Cell Stem Cell, Fernandez-Antoran et al. (2019) show how commonly used medical procedures modify cell selection dynamics to either expand or eliminate cells carrying oncogenic p53 mutations.
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Oncogenes , Proteína p53 Supresora de Tumor , Esófago , Mutación , Oxidación-ReducciónRESUMEN
Myc is considered an essential transcription factor for heart development, but cardiac defects have only been studied in global Myc loss-of-function models. Here, we eliminated Myc by recombining a Myc floxed allele with the Nkx2.5Cre driver. We observed no anatomical, cellular or functional alterations in either fetuses or adult cardiac Myc-deficient mice. We re-examined Myc expression during development and found no expression in developing cardiomyocytes. In contrast, we confirmed that Mycn is essential for cardiomyocyte proliferation and cardiogenesis. Mosaic Myc overexpression in a Mycn-deficient background shows that Myc can replace Mycn function, recovering heart development. We further show that this recovery involves the elimination of Mycn-deficient cells by cell competition. Our results indicate that Myc is dispensable in cardiomyocytes both during cardiogenesis and for adult heart homeostasis, and that Mycn is exclusively responsible for cardiomyocyte proliferation during heart development. Nonetheless, our results show that Myc can functionally replace Mycn We also show that cardiomyocytes compete according to their combined Myc and Mycn levels and that cell competition eliminates flawed cardiomyocytes, suggesting its relevance as a quality control mechanism in cardiac development.
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Proliferación Celular , Corazón/embriología , Miocitos Cardíacos/metabolismo , Proteína Proto-Oncogénica N-Myc/deficiencia , Organogénesis , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Femenino , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-myc/genéticaRESUMEN
Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal. In the mammalian adult heart, however, the persistent influx of immune cells, coupled with the lack of an inherent regenerative capacity, results in cardiac fibrosis. Here, we reveal that stimulation of cardiac lymphangiogenesis with VEGF-C improves clearance of the acute inflammatory response after MI by trafficking immune cells to draining mediastinal lymph nodes (MLNs) in a process dependent on lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1 in mice, preventing docking and transit of leukocytes through the lymphatic endothelium, results in exacerbation of chronic inflammation and long-term deterioration of cardiac function. Our findings support targeting of the lymphatic/immune cell axis as a therapeutic paradigm to promote immune modulation and heart repair.
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Movimiento Celular , Leucocitos/metabolismo , Linfangiogénesis , Sistema Linfático/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Leucocitos/patología , Sistema Linfático/patología , Ratones , Ratones Noqueados , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocitos Cardíacos/patología , Factor C de Crecimiento Endotelial Vascular/genética , Factor C de Crecimiento Endotelial Vascular/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin ß4 (Tß4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin-remodelling complex, is required for expression of Wilms' tumour 1 (Wt1), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tß4 and is recruited by CCAAT/enhancer-binding protein ß (C/EBPß) to discrete regulatory elements in the Wt1 locus. BRG1-Tß4 co-operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin-remodelling in the activation of EPDCs during cardiovascular development and repair.
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ADN Helicasas/metabolismo , Epigénesis Genética , Genes del Tumor de Wilms , Corazón/crecimiento & desarrollo , Proteínas Nucleares/metabolismo , Timosina/metabolismo , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Ensamble y Desensamble de Cromatina , Secuencia Conservada , Regulación de la Expresión Génica , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Infarto del Miocardio/metabolismo , Pericardio/citología , Pericardio/metabolismo , Elementos Reguladores de la TranscripciónRESUMEN
Myc is an essential regulator of cell growth and proliferation. Myc overexpression promotes the homeostatic expansion of cardiomyocyte populations by cell competition, however whether this applies to other cardiac lineages remains unknown. The epicardium contributes signals and cells to the developing and adult injured heart and exploring strategies for modulating its activity is of great interest. Using inducible genetic mosaics, we overexpressed Myc in the epicardium and determined the differential expansion of Myc-overexpressing cells with respect to their wild type counterparts. Myc-overexpressing cells overcolonized all epicardial-derived lineages and showed increased ability to invade the myocardium and populate the vasculature. We also found massive colonization of the myocardium by Wt1Cre-derived Myc-overexpressing cells, with preservation of cardiac development. Detailed analyses showed that this contribution is unlikely to derive from Cre activity in early cardiomyocytes but does not either derive from established epicardial cells, suggesting that early precursors expressing Wt1Cre originate the recombined cardiomyocytes. Myc overexpression does not modify the initial distribution of Wt1Cre-recombined cardiomyocytes, indicating that it does not stimulate the incorporation of early expressing Wt1Cre lineages to the myocardium, but differentially expands this initial population. We propose that strategies using epicardial lineages for heart repair may benefit from promoting cell competitive ability.
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Corazón/crecimiento & desarrollo , Miocardio/metabolismo , Organogénesis/genética , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Proliferación Celular/genética , Vasos Coronarios/crecimiento & desarrollo , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Regulación del Desarrollo de la Expresión Génica , Integrasas/genética , Ratones , Miocitos Cardíacos/metabolismo , Pericardio/crecimiento & desarrollo , Pericardio/metabolismoRESUMEN
Heterogeneous anabolic capacity in cell populations can trigger a phenomenon known as cell competition, through which less active cells are eliminated. Cell competition has been induced experimentally in stem/precursor cell populations in insects and mammals and takes place endogenously in early mouse embryonic cells. Here, we show that cell competition can be efficiently induced in mouse cardiomyocytes by mosaic overexpression of Myc during both gestation and adult life. The expansion of the Myc-overexpressing cardiomyocyte population is driven by the elimination of wild-type cardiomyocytes. Importantly, this cardiomyocyte replacement is phenotypically silent and does not affect heart anatomy or function. These results show that the capacity for cell competition in mammals is not restricted to stem cell populations and suggest that stimulated cell competition has potential as a cardiomyocyte-replacement strategy.
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Corazón/fisiología , Miocitos Cardíacos/citología , Animales , Apoptosis , Embrión de Mamíferos/metabolismo , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Corazón/anatomía & histología , Corazón/crecimiento & desarrollo , Proteína Homeótica Nkx-2.5 , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Integrasas/genética , Integrasas/metabolismo , Proteínas con Homeodominio LIM/metabolismo , Masculino , Ratones , Miocitos Cardíacos/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Recombinación Genética , Células Madre/citología , Células Madre/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The first blood and endothelial cells of amniote embryos appear in close association in the blood islands of the yolk sac (YS). This association and in vitro lineage analyses have suggested a common origin from mesodermal precursors called hemangioblasts, specified in the primitive streak during gastrulation. Fate mapping and chimera studies, however, failed to provide strong evidence for a common origin in the early mouse YS. Additional in vitro studies suggest instead that mesodermal precursors first generate hemogenic endothelium, which then generate blood cells in a linear sequence. We conducted an in vivo clonal analysis to determine the potential of individual cells in the mouse epiblast, primitive streak, and early YS. We found that early YS blood and endothelial lineages mostly derive from independent epiblast populations, specified before gastrulation. Additionally, a subpopulation of the YS endothelium has hemogenic activity and displays characteristics similar to those found later in the embryonic hemogenic endothelium. Our results show that the earliest blood and endothelial cell populations in the mouse embryo are specified independently, and that hemogenic endothelium first appears in the YS and produces blood precursors with markers related to definitive hematopoiesis.