The roles and controls of GATA factors in blood and cardiac development.

GATA factors play central roles in the programming of blood and cardiac cells during embryonic development. Using the experimentally accessible Xenopus and zebrafish models, we report observations regarding the roles of GATA-2 in the development of blood stem cells and GATA-4, -5, and -6 in cardiac development. We show that blood stem cells develop from the dorsal lateral plate mesoderm and GATA-2 is required at multiple stages. Firstly, GATA-2 is required to make the cells responsive to VEGF-A signalling by driving the synthesis of its receptor, FLK-1/KDR. This leads to differentiation into the endothelial cells that form the dorsal aorta. GATA-2 is again required for the endothelial-to-haematopoietic transition that takes place later in the floor of the dorsal aorta. GATA-2 expression is dependent on BMP signalling for each of these inputs into blood stem cell programming. GATA-4, -5, and -6 work together to ensure the specification of cardiac cells during development. We have demonstrated redundancy within the family and also some evolution of the functions of the different family members. Interestingly, one of the features that varies in evolution is the timing of expression relative to other key regulators such as Nkx2.5 and BMP. We show that the GATA factors, Nkx2.5 and BMP regulate each other and it would appear that what is critical is the mutually supportive network of expression rather than the order of expression of each of the component genes. In Xenopus and zebrafish, the cardiac mesoderm is adjacent to an anterior population of cells giving rise to blood and endothelium. This population is not present in mammals and we have shown that, like the cardiac population, the blood and endothelial precursors require GATA-4, -5, and -6 for their development. Later, blood-specific or cardiac-specific regulators determine the ultimate fate of the cells, and we show that these regulators act cross-antagonistically. Fibroblast growth factor (FGF) signalling drives the cardiac fate, and we propose that the anterior extension of the FGF signalling field during evolution led to the recruitment of the blood and endothelial precursors into the heart field ultimately resulting in a larger four chambered heart. Zebrafish are able to successfully regenerate their hearts after injury. To understand the pathways involved, with a view to determining why humans cannot do this, we profiled gene expression in the cardiomyocytes before and after injury, and compared those proximal to the injury with those more distal. We were able to identify an enhancement of the expression of regulators of the canonical Wnt pathway proximal to the injury, suggesting that changes in Wnt signalling are responsible for the repair response to injury.

Dendritic cells and pluripotency: unlikely allies in the pursuit of immunotherapy.

As the fulcrum on which the balance between the opposing forces of tolerance and immunity has been shown to pivot, dendritic cells (DC) hold significant promise for immune intervention in a variety of disease states. Here we discuss how the directed differentiation of human pluripotent stem cells may address many of the current obstacles to the use of monocyte-derived DC in immunotherapy, providing a novel source of previously inaccessible DC subsets and opportunities for their scale-up, quality control and genetic modification. Indeed, given that it is the immunological legacy DC leave behind that is of therapeutic value, rather than their persistence per se, we propose that immunotherapy should serve as an early target for the clinical application of pluripotent stem cells.

Diagnosis of myocardial infarction in women: are we doing our best? Interviewed by Caroline Telfer.

Dr Anoop Shah speaks to Caroline Telfer, Commissioning Editor. Dr Anoop Shah is a British Heart Foundation Clinical Research Fellow at the University of Edinburgh (UK). He completed his undergraduate training at the University of Edinburgh and is now in the process of completing his specialist training in cardiology. He has a keen interest in cardiovascular epidemiology. His areas of interest include acute coronary syndrome and cardiac biomarkers.

A profile of Keith AA Fox, cardiologist and researcher.

Professor Keith AA Fox speaks to Caroline Telfer, Commissioning Editor. Professor Keith AA Fox is the British Heart Foundation and the Duke of Edinburgh Professor of Cardiology at the University of Edinburgh (UK). He is a founding fellow of the European Society of Cardiology and is currently Chair of the Programme of the European Society of Cardiology. In addition, he was President of the British Cardiovascular Society from 2009 to 2012. Professor Fox gave the State-of-the-Art lecture on acute coronary syndromes at the American Heart Association, as well as the 2009 Plenary lecture at the European Society of Cardiology-American College of Cardiology Symposium, the Lord Rayner lecture of the Royal College of Physicians (London, UK) and the Sir Stanley Davidson Lecture of the Royal College (Edinburgh, UK). He was awarded the Silver Medal of the European Society of Cardiology in 2010. Professor Fox's major research interest lies in the mechanisms and manifestations of acute coronary arterial disease; his work extends from underlying biological mechanisms to in vitro and in vivo studies and clinical trials. He is the author of more than 587 scientific papers (H-index Web of Science 73, Citations: 30,261 to March 2013). Professor Fox is chairman of the RITA program, co-chairman of ROCKET-AF and OASIS program, and chair of the GRACE program (the largest multinational study in acute coronary syndromes), and a lead investigator for studies on novel antithrombins, anticoagulants and antiplatelets. He is an International Associate Editor of the European Heart Journal and a member of the editorial boards of a number of journals. His current areas of research include the inhibition of coronary thrombosis and the role of platelets and inflammation in acute coronary syndromes.

Interview: from Down's syndrome to basic epigenetics and back again.

Dr Jeanne Lawrence talks to Caroline Telfer, Commissioning Editor. Dr Jeanne Lawrence is an internationally recognized leader in the study of chromosome regulation by noncoding RNA and nuclear and genome organization. Her research bridges fundamental questions about genome regulation with clinical implications of recent advances in epigenetics. Her interest in chromosome structure and regulation has been a theme throughout her career and she has been honored for her work developing sensitive FISH technology for the detection of single copy genes, as well as RNAs. Her laboratory's publications include the initial demonstration of cell type-specific gene organization with nuclear subdomains; the novel biology of a noncoding RNA, XIST, which coats a whole X-chromosome to induce its silencing; and a new architectural role for a large noncoding RNA to scaffold a nuclear body. Her laboratory's work on epigenetic chromosome regulation in stem cells led to recent studies regarding unanticipated roles of repeat sequences in normal chromosome regulation and deregulation in cancer. Most recently, her laboratory has demonstrated a new approach to translate the basic mechanism of X-chromosome inactivation to correct a chromosomal dosage imbalance in patient-derived cells with trisomy 21 (Down's syndrome). Dr Lawrence has received awards from numerous agencies, including a Research Career Development Award from the National Center for Human Genome Research, career awards from the American Society of Cell Biology, the German Society for Biochemistry, the Muscular Dystrophy Association and a John Merck Fund Translational Research Award. She has served on the NIH National Advisory Council for Human Genome Research, numerous study sections and is currently a monitoring editor for the Journal of Cell Biology. Dr Lawrence has a BA in Biology and Music from Stephens College (MO, USA), a MS in Human Genetics and Genetic Counseling from Rutgers University (NJ, USA) and a PhD in Developmental Biology from Brown University (RI, USA). She is currently a Professor and Interim Chair of the Department of Cell and Developmental Biology at the University of Massachusetts Medical School (MA, USA).