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Milena B Furtado

Milena B Furtado, Muneer Hasham
This chapter will discuss the role of cardiac fibroblasts as a target of various immunological inputs as well as an immunomodulatory hub of the heart through interaction with immune cell types and chemokine or cytokine signaling. While the purpose of this chapter is to explore the immunomodulatory properties of cardiac fibroblasts, it is important to note that cardiac fibroblasts are not a homogeneous cell type, but have a unique embryological origin and molecular identity. Specific properties of cardiac fibroblasts may influence the way they interact with the heart microenvironment to promote healthy homeostatic function or respond to pathological insults...
2017: Advances in Experimental Medicine and Biology
Hieu T Nim, Milena B Furtado, Mirana Ramialison, Sarah E Boyd
BACKGROUND: Quantitative high-throughput data deposited in consortia such as International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) present opportunities and challenges for computational analyses. METHODS: We present a computational strategy to systematically rank and investigate a large number (2(10)-2(20)) of clinically testable gene sets, using combinatorial gene subset generation and disease-free survival (DFS) analyses. This approach integrates protein-protein interaction networks, gene expression, DNA methylation, and copy number data, in association with DFS profiles from patient clinical records...
2017: Frontiers in Oncology
Milena B Furtado, Julia C Wilmanns, Anjana Chandran, Joelle Perera, Olivia Hon, Christine Biben, Taylor J Willow, Hieu T Nim, Gurpreet Kaur, Stephanie Simonds, Qizhu Wu, David Willians, Ekaterina Salimova, Nicolas Plachta, James M Denegre, Stephen A Murray, Diane Fatkin, Michael Cowley, James T Pearson, David Kaye, Mirana Ramialison, Richard P Harvey, Nadia A Rosenthal, Mauro W Costa
Mutations in the Nkx2-5 gene are a main cause of congenital heart disease. Several studies have addressed the phenotypic consequences of disrupting the Nkx2-5 gene locus, although animal models to date failed to recapitulate the full spectrum of the human disease. Here, we describe a new Nkx2-5 point mutation murine model, akin to its human counterpart disease-generating mutation. Our model fully reproduces the morphological and physiological clinical presentations of the disease and reveals an understudied aspect of Nkx2-5 -driven pathology, a primary right ventricular dysfunction...
March 23, 2017: JCI Insight
Milena B Furtado
No abstract text is available yet for this article.
September 2016: Differentiation; Research in Biological Diversity
Thiruma V Arumugam, Silvia Manzanero, Milena Furtado, Patrick J Biggins, Yu-Hsuan Hsieh, Mathias Gelderblom, Kelli Pa MacDonald, Ekaterina Salimova, Yu-I Li, Othmar Korn, Deborah Dewar, I Mhairi Macrae, Robert B Ashman, Sung-Chun Tang, Nadia A Rosenthal, Marc J Ruitenberg, Tim Magnus, Christine A Wells
The C-type lectin Mincle is implicated in innate immune responses to sterile inflammation, but its contribution to associated pathologies is not well understood. Herein, we show that Mincle exacerbates neuronal loss following ischemic but not traumatic spinal cord injury. Loss of Mincle was beneficial in a model of transient middle cerebral artery occlusion but did not alter outcomes following heart or gut ischemia. High functional scores in Mincle KO animals using the focal cerebral ischemia model were accompanied by reduced lesion size, fewer infiltrating leukocytes and less neutrophil-derived cytokine production than isogenic controls...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Milena B Furtado, Mauro W Costa, Nadia A Rosenthal
The mammalian heart is responsible for supplying blood to two separate circulation circuits in a parallel manner. This design provides efficient oxygenation and nutrients to the whole body through the left-sided pump, while the right-sided pump delivers blood to the pulmonary circulation for re-oxygenation. In order to achieve this demanding job, the mammalian heart evolved into a highly specialised organ comprised of working contractile cells or cardiomyocytes, a directional and insulated conduction system, capable of independently generating and conducting electric impulses that synchronises chamber contraction, valves that allow the generation of high pressure and directional blood flow into the circulation, coronary circulation, that supplies oxygenated blood for the heart muscle high metabolically active pumping role and inlet/outlet routes, as the venae cavae and pulmonary veins, aorta and pulmonary trunk...
September 2016: Differentiation; Research in Biological Diversity
Milena B Furtado, Julia C Wilmanns, Anjana Chandran, Mary Tonta, Christine Biben, Michael Eichenlaub, Harold A Coleman, Silke Berger, Romaric Bouveret, Reena Singh, Richard P Harvey, Mirana Ramialison, James T Pearson, Helena C Parkington, Nadia A Rosenthal, Mauro W Costa
Nkx2-5 is one of the master regulators of cardiac development, homeostasis and disease. This transcription factor has been previously associated with a suite of cardiac congenital malformations and impairment of electrical activity. When disease causative mutations in transcription factors are considered, NKX2-5 gene dysfunction is the most common abnormality found in patients. Here we describe a novel mouse model and subsequent implications of Nkx2-5 loss for aspects of myocardial electrical activity. In this work we have engineered a new Nkx2-5 conditional knockout mouse in which flox sites flank the entire Nkx2-5 locus, and validated this line for the study of heart development, differentiation and disease using a full deletion strategy...
January 2016: Differentiation; Research in Biological Diversity
Milena B Furtado, Hieu T Nim, Sarah E Boyd, Nadia A Rosenthal
In the adult, tissue repair after injury is generally compromised by fibrosis, which maintains tissue integrity with scar formation but does not restore normal architecture and function. The process of regeneration is necessary to replace the scar and rebuild normal functioning tissue. Here, we address this problem in the context of heart disease, and discuss the origins and characteristics of cardiac fibroblasts, as well as the crucial role that they play in cardiac development and disease. We discuss the dual nature of cardiac fibroblasts, which can lead to scarring, pathological remodelling and functional deficit, but can also promote heart function in some contexts...
February 1, 2016: Development
Milena B Furtado, Hieu T Nim, Jodee A Gould, Mauro W Costa, Nadia A Rosenthal, Sarah E Boyd
Heart failure is one of the leading causes of death worldwide [1-4]. Current therapeutic strategies are inefficient and cannot cure this chronic and debilitating condition [5]. Ultimately, heart transplants are required for patient survival, but donor organs are scarce in availability and only prolong the life-span of patients for a limited time. Fibrosis is one of the main pathological features of heart failure [6,7], caused by inappropriate stimulation of fibroblasts and excessive extracellular matrix production...
December 2014: Genomics Data
Hieu T Nim, Milena B Furtado, Mauro W Costa, Nadia A Rosenthal, Hiroaki Kitano, Sarah E Boyd
BACKGROUND: Existing de novo software platforms have largely overlooked a valuable resource, the expertise of the intended biologist users. Typical data representations such as long gene lists, or highly dense and overlapping transcription factor networks often hinder biologists from relating these results to their expertise. RESULTS: VISIONET, a streamlined visualisation tool built from experimental needs, enables biologists to transform large and dense overlapping transcription factor networks into sparse human-readable graphs via numerically filtering...
2015: BMC Bioinformatics
Marcus Vinícius Pinheiro Mendonça, Ticiana Ferreira Larocca, Bruno Solano de Freitas Souza, Cristiane Flora Villarreal, Luiz Flávio Maia Silva, André Costa Matos, Marco Antonio Novaes, Cláudia Maria Pinheiro Bahia, Ana Carine de Oliveira Melo Martinez, Carla Martins Kaneto, Sissi Brandão Carneiro Furtado, Geraldo Pedral Sampaio, Milena Botelho Pereira Soares, Ricardo Ribeiro dos Santos
INTRODUCTION: The administration of stem cells holds promise as a potential therapy for spinal cord injury (SCI). Mesenchymal stem cells have advantages for clinical applications, since they can be easily obtained, are suitable for autologous transplantation and have been previously shown to induce regeneration of the spinal cord in experimental settings. Here we evaluated the feasibility, safety and potential efficacy of autologous transplantation of mesenchymal stem cells in subjects with chronic complete SCI...
November 17, 2014: Stem Cell Research & Therapy
Milena B Furtado, Mauro W Costa, Edward A Pranoto, Ekaterina Salimova, Alexander R Pinto, Nicholas T Lam, Anthony Park, Paige Snider, Anjana Chandran, Richard P Harvey, Richard Boyd, Simon J Conway, James Pearson, David M Kaye, Nadia A Rosenthal
RATIONALE: Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment, but appreciation of their contribution has suffered from incomplete characterization and lack of cell-specific markers. OBJECTIVE: To generate an unbiased comparative gene expression profile of the cardiac fibroblast pool, identify and characterize the role of key genes in cardiac fibroblast function, and determine their contribution to myocardial development and regeneration...
April 25, 2014: Circulation Research
Mauro W Costa, Stella Lee, Milena B Furtado, Li Xin, Duncan B Sparrow, Camila G Martinez, Sally L Dunwoodie, Eleonora Kurtenbach, Tim Mohun, Nadia Rosenthal, Richard P Harvey
Reversible post-translational protein modifications such as SUMOylation add complexity to cardiac transcriptional regulation. The homeodomain transcription factor Nkx2-5/Csx is essential for heart specification and morphogenesis. It has been previously suggested that SUMOylation of lysine 51 (K51) of Nkx2-5 is essential for its DNA binding and transcriptional activation. Here, we confirm that SUMOylation strongly enhances Nkx2-5 transcriptional activity and that residue K51 of Nkx2-5 is a SUMOylation target...
2011: PloS One
Kylie Lopes Floro, Stanley T Artap, Jost I Preis, Diane Fatkin, Gavin Chapman, Milena B Furtado, Richard P Harvey, Hiroshi Hamada, Duncan B Sparrow, Sally L Dunwoodie
Cited2 is a transcriptional coactivator that is required for normal development of the embryo and placenta. Cited2-null mice die during gestation with fully penetrant heart defects and partially penetrant laterality defects. The laterality defects occur due to the loss of Nodal expression in the left lateral plate mesoderm (LPM). The cause of the heart defects that arise independently of laterality defects is unknown; they might occur due to an intrinsic requirement for Cited2 in the developing heart, or to disturbances in left-right patterning of the early embryo...
March 15, 2011: Human Molecular Genetics
Milena B Furtado, Christine Biben, Hidetaka Shiratori, Hiroshi Hamada, Richard P Harvey
To aid in detection and tracking of cells targeted by the left-right (LR) pathway in the heart throughout morphogenesis, expression from a Pitx2c-lacZ transgene (P2Ztg) was analysed in detail. β-galactosidase expression from P2Ztg was robust, allowing reliable visualisation of low-level Pitx2c expression, and was virtually entirely dependent upon NODAL signalling in the heart. P2Ztg showed expression in trabecular and septal, as well as non-trabecular, myocardium, and a strong expression bias in myocardium associated with individual endocardial cushions of the atrioventricular canal and outflow tract, which are essential for cardiac septation...
January 2011: Developmental Dynamics: An Official Publication of the American Association of Anatomists
Limin Shang, Nanthakumar Thirunarayanan, Abel Viejo-Borbolla, Andrea P Martin, Milena Bogunovic, Federica Marchesi, Jay C Unkeless, Yin Ho, Glaucia C Furtado, Antonio Alcami, Miriam Merad, Lloyd Mayer, Sergio A Lira
BACKGROUND & AIMS: Chemokines are small proteins that direct leukocyte trafficking under homeostatic and inflammatory conditions. We analyzed the differential expression of chemokines in distinct segments of the intestine and investigated the importance of chemokines for the distribution of leukocytes in the intestine during homeostatic and inflammatory conditions. METHODS: We analyzed messenger RNA for all known chemokines in different segments of the gut by quantitative polymerase chain reaction...
September 2009: Gastroenterology
Milena B Furtado, Mark J Solloway, Vanessa J Jones, Mauro W Costa, Christine Biben, Orit Wolstein, Jost I Preis, Duncan B Sparrow, Yumiko Saga, Sally L Dunwoodie, Elizabeth J Robertson, Patrick P L Tam, Richard P Harvey
Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta (TGFbeta) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward and feedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling sets a repressive threshold in the LPM essential for the integrity of LR signaling...
November 1, 2008: Genes & Development
Owen W J Prall, Mary K Menon, Mark J Solloway, Yusuke Watanabe, Stéphane Zaffran, Fanny Bajolle, Christine Biben, Jim J McBride, Bronwyn R Robertson, Hervé Chaulet, Fiona A Stennard, Natalie Wise, Daniel Schaft, Orit Wolstein, Milena B Furtado, Hidetaka Shiratori, Kenneth R Chien, Hiroshi Hamada, Brian L Black, Yumiko Saga, Elizabeth J Robertson, Margaret E Buckingham, Richard P Harvey
During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the homeodomain factor Nkx2-5. We now show that feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology. In the cardiac fields of Nkx2-5 mutants, genes controlling cardiac specification (including Bmp2) and maintenance of the progenitor state were upregulated, leading initially to progenitor overspecification, but subsequently to failed SHF proliferation and OFT truncation...
March 9, 2007: Cell
David A Elliott, Mark J Solloway, Natalie Wise, Christine Biben, Mauro W Costa, Milena B Furtado, Martin Lange, Sally Dunwoodie, Richard P Harvey
Homeodomain factor Nkx2-5 is a central component of the transcription factor network that guides cardiac development; in humans, mutations in NKX2.5 lead to congenital heart disease (CHD). We have genetically defined a novel conserved tyrosine-rich domain (YRD) within Nkx2-5 that has co-evolved with its homeodomain. Mutation of the YRD did not affect DNA binding and only slightly diminished transcriptional activity of Nkx2-5 in a context-specific manner in vitro. However, the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo...
April 2006: Development
Fiona A Stennard, Mauro W Costa, Donna Lai, Christine Biben, Milena B Furtado, Mark J Solloway, David J McCulley, Christiana Leimena, Jost I Preis, Sally L Dunwoodie, David E Elliott, Owen W J Prall, Brian L Black, Diane Fatkin, Richard P Harvey
The genetic hierarchies guiding lineage specification and morphogenesis of the mammalian embryonic heart are poorly understood. We now show by gene targeting that murine T-box transcription factor Tbx20 plays a central role in these pathways, and has important activities in both cardiac development and adult function. Loss of Tbx20 results in death of embryos at mid-gestation with grossly abnormal heart morphogenesis. Underlying these disturbances was a severely compromised cardiac transcriptional program, defects in the molecular pre-pattern, reduced expansion of cardiac progenitors and a block to chamber differentiation...
May 2005: Development
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