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Kira Behrens, Warren S Alexander
Platelets are anuclear blood cells required for haemostasis and are implicated in other processes including inflammation and metastasis. Platelets are produced by megakaryocytes, specialized cells that are themselves generated by a process of controlled differentiation and maturation of bone-marrow stem and progenitor cells. This process of megakaryopoiesis involves the coordinated interplay of transcription factor-controlled cellular programming with extra-cellular cues produced locally in supporting niches or as circulating factors...
October 15, 2018: Growth Factors
Florentien E M In 't Hout, Jolanda van Duren, Davide Monteferrario, Emma Brinkhuis, Niccolo Mariani, Theresia M Westers, Dana Chitu, Gorica Nikoloski, Arjan A van de Loosdrecht, Bert A van der Reijden, Joop H Jansen, Gerwin Huls
Transcription factor 4 (TCF4) is implicated in lymphoid cell differentiation and its expression predicts outcome in acute myeloid leukemia. Here, we investigated the role of TCF4 in myelopoiesis. Overexpression of TCF4 (TCF4OE) in umbilical cord blood (UCB) cells resulted in a 2-fold increase in erythroid colony forming units (CFU-Es), while knock-down of TCF4 (TCF4KD) caused a dramatic decrease in the number of erythroid colonies. In CFU-MKs, both TCF4KD and TCF4OE inhibited megakaryocyte colony formation...
October 10, 2018: Experimental Hematology
Jacqueline Reinhard, Susanne Wiemann, Stephanie C Joachim, Marina Palmhof, Julia Woestmann, Bernd Denecke, Yingchun Wang, Gregory P Downey, Andreas Faissner
Glaucomatous neurodegeneration represents one of the major causes of irreversible blindness worldwide. Yet, the detailed molecular mechanisms that initiate optic nerve damage and retinal ganglion cell (RGC) loss are not fully understood. Members of the protein tyrosine phosphatase (PTP) superfamily are key players in numerous neurodegenerative diseases. In order to investigate the potential functional relevance of the PTP megakaryocyte 2 (Meg2) in retinal neurodegeneration, we analyzed Meg2 knockout (KO) and heterozygous (HET)-synonym protein-tyrosine phosphatase non-receptor type 9 (Ptpn9)-mice...
October 12, 2018: Molecular Neurobiology
Sharissa L Latham, Nadja Ehmke, Patrick Y A Reinke, Manuel H Taft, Dorothee Eicke, Theresia Reindl, Werner Stenzel, Michael J Lyons, Michael J Friez, Jennifer A Lee, Ramona Hecker, Michael C Frühwald, Kerstin Becker, Teresa M Neuhann, Denise Horn, Evelin Schrock, Indra Niehaus, Katharina Sarnow, Konrad Grützmann, Luzie Gawehn, Barbara Klink, Andreas Rump, Christine Chaponnier, Constanca Figueiredo, Ralf Knöfler, Dietmar J Manstein, Nataliya Di Donato
Germline mutations in the ubiquitously expressed ACTB, which encodes β-cytoplasmic actin (CYA), are almost exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF). Here, we report six patients with previously undescribed heterozygous variants clustered in the 3'-coding region of ACTB. Patients present with clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy. Using patient-derived fibroblasts, we demonstrate cohort specific changes to β-CYA filament populations, which include the enhanced recruitment of thrombocytopenia-associated actin binding proteins (ABPs)...
October 12, 2018: Nature Communications
Naoshi Sugimoto, Koji Eto
Platelet transfusion products derived from induced pluripotent stem cells (iPSCs) have been pursued as a blood donor-independent and genetically manipulative measure to complement or as an alternative to current platelet products. Platelets are enucleate blood cells indispensable for hemostasis. Thus, platelet transfusions have been clinically established to treat patients with severe thrombocytopenia. However, current blood products face issues in the balance of supply and demand, alloimmune responses, and infections and are expected to meet the shortage of donors in aging societies...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Samik Upadhaya, Catherine M Sawai, Efthymia Papalexi, Ali Rashidfarrokhi, Geunhyo Jang, Pratip Chattopadhyay, Rahul Satija, Boris Reizis
Adult hematopoiesis has been studied in terms of progenitor differentiation potentials, whereas its kinetics in vivo is poorly understood. We combined inducible lineage tracing of endogenous adult hematopoietic stem cells (HSCs) with flow cytometry and single-cell RNA sequencing to characterize early steps of hematopoietic differentiation in the steady-state. Labeled cells, comprising primarily long-term HSCs and some short-term HSCs, produced megakaryocytic lineage progeny within 1 wk in a process that required only two to three cell divisions...
October 5, 2018: Journal of Experimental Medicine
Maho Ishikawa, Akira Matsuda, Daisuke Okamura, Tomoya Maeda, Nobutaka Kawai, Norio Asou, Masami Bessho
Thrombopoietin (TPO) is a critical regulator of hematopoiesis. We previously reported that a severe aplastic anemia (SAA) who received a short-term administration of pegylated recombinant human megakaryocyte growth and development factor (rHuMGDF). A trilineage hematologic response was induced, however the patient was diagnosed with leukemia after nine years and eight months from administration of rHuMGDF. In recent reports, somatic mutations in myeloid cancer candidate genes were present in one-third of the AA...
September 5, 2018: Hematology Reports
Hiroto Tamaru, Kenichi Fujii, Satoru Otsuji, Shin Takiuchi, Katsuyuki Hasegawa, Kasumi Ishibuchi, Rui Ishii, Wataru Yamamoto, Sho Nakabayashi, Mikio Kakishita, Motoaki Ibuki, Shinya Nagayama, Yorihiko Higashino
Essential thrombocytosis (ET) is a myeloproliferative disorder with abnormal proliferation of the megakaryocytes and is manifested clinically by the overproduction of dysfunctional platelets, leading to thrombus formation. Therefore, the accurate evaluation of the morphological features for coronary stenosis and initiation of appropriate treatment may be life-saving for ET patients. In this report, we describe a case of the rapid development of repeated stenosis in the native coronary artery in an ET patient, and optical frequency domain imaging confirmed the etiology of the stenoses...
August 2018: Journal of Cardiology Cases
Amber B Ouweneel, Menno Hoekstra, Ezra J van der Wel, Frank H Schaftenaar, Olga S C Snip, Jasmin Hassan, Suzanne J A Korporaal, Miranda Van Eck
BACKGROUND AND AIMS: Thrombocytopenia in scavenger receptor BI (SR-BI) knockout mice is suggested to result from augmented platelet clearance induced by elevated intracellular unesterified cholesterol (UC) levels. We hypothesize that SR-BI deficiency may also influence platelet production at the level of its precursor cell in the bone marrow, the megakaryocyte. METHODS: In this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice...
September 22, 2018: Atherosclerosis
Yuka Nakamura, Motoshi Ichikawa, Hideaki Oda, Ieharu Yamazaki, Ko Sasaki, Kinuko Mitani
The RUNX1-EVI1 gene generated by the t(3;21) translocation encodes a chimeric transcription factor and is a causative gene in the development of de novo acute megakaryoblastic leukemia and leukemic transformation of hematopoietic stem cell tumors. Heterozygous RUNX1-EVI1 knock-in mice die in utero due to hemorrhage in the central nervous system and spinal cord and complete abolishment of definitive hematopoiesis in the fetal liver. On the other hand, the chimeric knock-in mouse develops acute megakaryoblastic leukemia...
September 26, 2018: Leukemia Research
Constance C F M J Baaten, Stuart Meacham, Susanne M de Witt, Marion A H Feijge, David J Adams, Jan-Willem N Akkerman, Judith M E M Cosemans, Luigi Grassi, Steve Jupe, Myrto Kostadima, Nadine J A Mattheij, Martin H Prins, Ramiro Ramirez-Solis, Oliver Soehnlein, Frauke Swieringa, Christian Weber, Jacqueline K White, Willem H Ouwehand, Johan W M Heemskerk
Antithrombotic therapies reduce cardiovascular diseases by preventing arterial thrombosis and thromboembolism, but at expense of increased bleeding risks. Arterial thrombosis studies using genetically modified mice have been invaluable for identification of new molecular targets. Because of low sample sizes and heterogeneity in approaches or methodologies, a formal meta-analysis to compare studies of mice with single gene defects encountered major limitations. To overcome these, we developed a novel synthesis approach to quantitatively scale 1514 published studies of arterial thrombus formation (in vivo and in vitro), thromboembolism and tail bleeding of genetically modified mice...
October 1, 2018: Blood
Marc Payton, Hung-Kam Cheung, Maria Stefania S Ninniri, Christian Marinaccio, William C Wayne, Kelly Hanestad, John D Crispino, Gloria Juan, Angela Coxon
Aurora kinase A and B have essential and non-overlapping roles in mitosis, with elevated expression in a subset of human cancers, including acute myeloid leukemia (AML). In this study, pan-aurora kinase inhibitor (AKI) AMG 900 distinguishes itself as an anti-leukemic agent that is more uniformly potent against a panel of AML cell lines than are isoform-selective AKIs and classic AML drugs. AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis. AMG 900 and aurora-B selective inhibitor AZD1152-hQPA showed comparable cellular effects on AML lines that do not harbor a FLT3-ITD mutation...
September 28, 2018: Molecular Cancer Therapeutics
Alice Plein, Alessandro Fantin, Laura Denti, Jeffrey W Pollard, Christiana Ruhrberg
The earliest blood vessels in mammalian embryos are formed when endothelial cells differentiate from angioblasts and coalesce into tubular networks. Thereafter, the endothelium is thought to expand solely by proliferation of pre-existing endothelial cells. Here we show that a complementary source of endothelial cells is recruited into pre-existing vasculature after differentiation from the earliest precursors of erythrocytes, megakaryocytes and macrophages, the erythro-myeloid progenitors (EMPs) that are born in the yolk sac...
October 2018: Nature
Felix Eisinger, Harald F Langer
Platelets are known to be central regulators of haemostasis, inflammation and immune response. Formed by megakaryocytes in the bone marrow and the lungs, platelets express a broad range of adhesion receptors and release cytokines and platelet microparticles which enable them to interact with both immune cells and pathogens. In bacterial and viral infections, thrombophilia and thrombocytopenia are commonly seen symptoms, indicating the close relationship between haemostasis and immune defence. Indeed, platelets contribute both directly and via immune mediation to pathogen clearance...
September 25, 2018: Hämostaseologie
Begoña Hurtado, Marianna Trakala, Pilar Ximénez-Embún, Aicha El Bakkali, David Partida, Belén Sanz-Castillo, Mónica Álvarez-Fernández, María Maroto, Ruth Sánchez-Martínez, Lola Martínez, Javier Muñoz, Pablo García de Frutos, Marcos Malumbres
MASTL, a Ser/Thr kinase that inhibits PP2A-B55 complexes during mitosis, is mutated in autosomal dominant thrombocytopenia. However, the connections between the cell cycle machinery and this human disease remain unexplored. We report here that, whereas Mastl ablation in megakaryocytes prevented proper maturation of these cells, mice carrying the thrombocytopenia-associated mutation developed thrombocytopenia as a consequence of aberrant activation and survival of platelets. Activation of mutant platelets was characterized by hyper-stabilized pseudopods mimicking the effect of PP2A inhibition and actin polymerization defects...
September 25, 2018: Journal of Clinical Investigation
Zhiwei Wang, Jianan Ren, Qinjie Liu, Jiayang Li, Xiuwen Wu, Weiping Wang, Jie Wu, Gefei Wang, Jieshou Li
INTRODUCTION: Different Klebsiella pneumoniae strains carry different virulence factors and antibiotic resistance and may cause thrombocytopenia. This study aimed to investigate the effects of different infections caused by K. pneumoniae on platelets. METHODS: Two hypermucoviscous K. pneumoniae strains and two classic strains were collected from clinical blood culture, and in both groups, there was a carbapenem-resistant strain and a carbapenem-sensitive strain...
September 20, 2018: Thrombosis Research
Aaron Seo, Suleyman Gulsuner, Sarah Pierce, Miri Ben-Harosh, Hanna Shalev, Tom Walsh, Tanya Krasnov, Orly Dgany, Sergei Doulatov, Hannah Tamary, Akiko Shimamura, Mary-Claire King
Severe thrombocytopenia, characterized by dysplastic megakaryocytes and intracranial bleeding, was diagnosed in six individuals from a consanguineous kindred. Three of the individuals were successfully treated by bone marrow transplant. Whole exome sequencing and homozygosity mapping of multiple family members, coupled with whole genome sequencing to reveal shared non-coding variants, revealed one potentially functional variant segregating with thrombocytopenia under a recessive model: GALE p.R51W (c.C151T, NM_001127621)...
September 20, 2018: Human Molecular Genetics
Pompei Bolfa, Chris Larson, Andrea Peda, David Hilchie, Mary M Christopher, Mary Anna Thrall
Case summary: A 6-year-old neutered male domestic shorthair cat presented with non-regenerative macrocytic anemia of 2 years' duration and minimally ambulatory paraparesis. Neurologic examination suggested an upper motor neuron paresis or T3-L3 myelopathy. The cat was positive for feline immunodeficiency virus (FIV), neutropenic, had polyclonal gammopathy and was euthanized following a hemolytic crisis. At autopsy, multifocal bilateral dark red masses were observed subpleurally around the costochondral junctions, extradurally and paraspinally in the spinal canal, and paravertebrally, on the lateral and ventral subpleural surfaces of the T4-11 vertebrae...
July 2018: JFMS open reports
Pasupuleti Santhosh Kumar, Chodimella Chandrasekhar, Lokanathan Srikanth, Potukuchi Venkata Gurunadha Krishna Sarma
Megakaryocytopoiesis results in the formation of platelets, which are essential for hemostasis. Decreased production or increased destruction of platelets can cause thrombocytopenia, in which platelet transfusion is the mode of treatment. The present study is aimed in generation of megakaryocytes (MKs) and platelet from human hematopoietic stem cells (HSCs). The purity of HSCs was assessed through Flow cytometry and immunocytochemistry (ICC) studies. These pure HSCs were induced with thrombopoietin (TPO), similarly with Andrographis paniculata extract (APE) for 21 days to generate MKs...
September 19, 2018: Biochemical and Biophysical Research Communications
Stuart Hay, Kyle Ferchen, Kashish Chetal, H Leighton Grimes, Nathan Salomonis
The Human Cell Atlas (HCA) is expected to facilitate the creation of reference cell profiles, marker genes, and gene regulatory networks that will provide a deeper understanding of healthy and disease cell types from clinical biospecimens. The hematopoietic system includes dozens of distinct, transcriptionally coherent cell types, including intermediate transitional populations that have not been previously described at a molecular level. Using the first data release from the HCA bone marrow tissue project, we resolved common, rare, and potentially transitional cell populations from over 100,000 hematopoietic cells spanning 35 transcriptionally coherent groups across eight healthy donors using emerging new computational approaches...
September 21, 2018: Experimental Hematology
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