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Danuta Jarocha, Karen K Vo, Randolph B Lyde, Vincent Hayes, Rodney M Camire, Mortimer Poncz
In vitro-grown megakaryocytes for generating platelets may have value in meeting the increasing demand for platelet transfusions. Remaining challenges have included the poor yield and quality of in vitro-generated platelets. We have shown that infusing megakaryocytes leads to intrapulmonary release of functional platelets. A Src kinase inhibitor (SU6656), a Rho-associated kinase inhibitor (Y27632), and an aurora B kinase inhibitor (AZD1152) have been shown to increase megakaryocyte ploidy and in vitro proplatelet release...
March 27, 2018: Blood Advances
Silvia Ravera, Maria Grazia Signorello, Martina Bartolucci, Sara Ferrando, Lucia Manni, Federico Caicci, Daniela Calzia, Isabella Panfoli, Alessandro Morelli, Giuliana Leoncini
BACKGROUND INFORMATION: Energy demand in human platelets is very high, to carry out their functions. As for most human cells, the aerobic metabolism represents the primary energy source in platelets, even though mitochondria are negligibly represented. Following the hypothesis that other structures could be involved in chemical energy production, in this work, we have investigated the functional expression of an extramitochondrial aerobic metabolism in platelets. RESULTS: Oximetric and luminometric analyses showed that platelets consume large amounts of oxygen and produce ATP in the presence of common respiring substrates, such as pyruvate + malate or succinate, although morphological electron microscopy analysis showed that these contain few mitochondria...
March 14, 2018: Biology of the Cell
Fumihiko Katakura, Yuji Sugie, Kiyotaka Hayashi, Kohei Nishiya, Jiro Miyamae, Masaharu Okano, Teruyuki Nakanishi, Tadaaki Moritomo
The development of mammalian megakaryocytes and platelets is regulated by numerous cytokine signals, primarily through the thrombopoietin (TPO)/c-MPL axis. Although non-mammalian vertebrates are known to possess nucleated thrombocytes functionally equivalent to mammalian platelets, the dynamics of the thrombocyte development remains unclear. Here we identified TPO and a splice variant (TPO-v) caused by the intron retention in common carp (Cyprinus carpio). Both the tpo and its variant transcripts were highly expressed in heart and liver...
March 6, 2018: Developmental and Comparative Immunology
Frédéric Adam, Alexandre Kauskot, Mathieu Kurowska, Nicolas Goudin, Isabelle Munoz, Jean-Claude Bordet, Jian-Dong Huang, Marijke Bryckaert, Alain Fischer, Delphine Borgel, Geneviève de Saint Basile, Olivier D Christophe, Gaël Ménasché
OBJECTIVE: Platelet secretion is crucial for many physiological platelet responses. Even though several regulators of the fusion machinery for secretory granule exocytosis have been identified in platelets, the underlying mechanisms are not yet fully characterized. APPROACH AND RESULTS: By studying a mouse model (cKO [conditional knockout]Kif5b ) lacking Kif5b (kinesin-1 heavy chain) in its megakaryocytes and platelets, we evidenced unstable hemostasis characterized by an increase of blood loss associated to a marked tendency to rebleed in a tail-clip assay and thrombus instability in an in vivo thrombosis model...
March 8, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Hailian Wang, Wei Ge, Yong Zhuang, Jinqiu Fu, Dong Li, Xiuli Ju
Background: Cord blood transplantation (CBT) can be a life-saving procedure in the treatment of a broad variety of disorders, including hematologic, immune, and genetic diseases. However, delayed platelet recovery hinders the application of CBT. Purpose: The aim of this study was to determine the optimal combination of cytokines to amplify megakaryocyte (Mk). Methods: CB CD34+ cells were obtained by immunomagnetic isolation and amplified under four different cytokine combinations...
January 2018: Journal of Cancer Research and Therapeutics
Xin Qing, Annie Qing, Ping Ji, Samuel W French, Holli Mason
BACKGROUND: Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome generated by the reciprocal translocation t(9,22)(q34;q11). The natural progression of the disease follows a biphasic or triphasic course. Most cases of CML are diagnosed in the chronic phase. Extramedullary blast crisis rarely occurs during the course of CML, and is extremely rare as the initial presentation of CML. CASE PRESENTATION: Here, we report the case of a 32-year-old female with enlarged neck lymph nodes and fatigue...
March 1, 2018: Experimental and Molecular Pathology
Kamaleldin E Elagib, Ashton T Brock, Adam N Goldfarb
Fetal megakaryocytes (Mk) differ from adult Mk in key parameters that affect their capacity for platelet production. However, despite being smaller, more proliferative, and less polyploid, fetal Mk generally mature in the same manner as adult. The phenotypic features unique to fetal Mk predispose patients to several disease conditions: infantile thrombocytopenia, infantile megakaryoblastic leukemias, and poor platelet recovery after umbilical cord blood stem cell transplants. Ontogenic Mk differences also affect new strategies being developed to address global shortages of platelet transfusion units...
February 28, 2018: Experimental Hematology
Winston Y Lee, Olga K Weinberg, Andrew G Evans, Geraldine S Pinkus
Objectives: Myeloid proliferative disorders associated with Down syndrome (MPD-DS), including transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome (DS), harbor mutations of GATA1, a transcription factor essential for erythroid and megakaryocytic development. These mutations result in a N-terminally truncated GATA1 (GATA1s) and prohibit the production of the full-length GATA1 (GATA1f). Here, we demonstrate the utility of immunohistochemical GATA1f reactivity in diagnosing MPD-DS...
March 7, 2018: American Journal of Clinical Pathology
Asuka Sakata, Satoshi Nishimura
Bone imaging using multiphoton microscopy enables dynamic observation of platelet formation in living animals. Two-photon excitation microscopy is superior to confocal microscopy as it enables deeper tissue penetration, efficient light detection, and reduced phototoxicity. Using this microscopy approach, thrombopoiesis by megakaryocytes is clearly visualized in the skull at significant depth from the surface. Here we describe our microscopy setup and dye recipe for visualization of bone marrow in the mouse skull...
2018: Methods in Molecular Biology
Marta Brambilla, Paolo Gelosa, Laura Rossetti, Laura Castiglioni, Chiara Zara, Paola Canzano, Elena Tremoli, Luigi Sironi, Marina Camera
OBJECTIVE: Hypertension is a well known risk factor for thrombotic events such as myocardial infarction and stroke. Platelets express tissue factor (TF), the key activator of blood coagulation and thrombus formation. The number of TF-positive platelets increases in pathological conditions characterized by thrombotic complications but whether this occurs in hypertension is unknown. Here we investigated whether platelet TF expression is increased in a hypertensive status through a mechanism acting on megakaryocytes; the phenomenon could be modulated by antihypertensive drug as captopril; angiotensin (AngII) influences platelet TF expression...
March 6, 2018: Journal of Hypertension
Alessandro Prestipino, Alica J Emhardt, Konrad Aumann, David O'Sullivan, Sivahari P Gorantla, Sandra Duquesne, Wolfgang Melchinger, Lukas Braun, Slavica Vuckovic, Melanie Boerries, Hauke Busch, Sebastian Halbach, Sandra Pennisi, Teresa Poggio, Petya Apostolova, Pia Veratti, Michael Hettich, Gabriele Niedermann, Mark Bartholomä, Khalid Shoumariyeh, Jonas S Jutzi, Julius Wehrle, Christine Dierks, Heiko Becker, Annette Schmitt-Graeff, Marie Follo, Dietmar Pfeifer, Jan Rohr, Sebastian Fuchs, Stephan Ehl, Frederike A Hartl, Susana Minguet, Cornelius Miething, Florian H Heidel, Nicolaus Kröger, Ioanna Triviai, Tilman Brummer, Jürgen Finke, Anna L Illert, Eliana Ruggiero, Chiara Bonini, Justus Duyster, Heike L Pahl, Steven W Lane, Geoffrey R Hill, Bruce R Blazar, Nikolas von Bubnoff, Erika L Pearce, Robert Zeiser
Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F -mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F -mutant cells...
February 21, 2018: Science Translational Medicine
M Salzmann, B Hoesel, M Haase, M Mussbacher, W C Schrottmaier, J B Kral-Pointner, M Finsterbusch, A Mazharian, A Assinger, J A Schmid
Transfusion of platelet concentrates represents an important treatment for various bleeding complications. However, the short half-life and frequent contaminations with bacteria restrict the availability of platelet concentrates and raise a clear demand for platelets generated ex vivo. Therefore, in vitro platelet generation from megakaryocytes represents an important research topic. A vital step for this process represents accurate analysis of thrombopoiesis and proplatelet formation, which is usually conducted manually...
February 20, 2018: Platelets
Shuiling Jin, Yanfang Mi, Jing Song, Peipei Zhang, Yanyan Liu
Protein arginine methyltransferase 1 (PRMT1) serves pivotal roles in various cellular processes. However, its role in megakaryocytic differentiation has not been clearly reported. The aim of the present study was to explore the role of the PRMT-RNA binding motif protein 15 (RBM15) axis in human MK differentiation and the feasibility of targeting PRMT1 for leukemia treatment. In the present study, PRMT1 was overexpressed and the RBM15 protein was knocked down in human umbilical cord blood cluster of differentiation (CD)34+ cells and the cells were then cultured in megakaryocytic differentiation medium...
March 2018: Experimental and Therapeutic Medicine
Sandra Pinho, Tony Marchand, Eva Yang, Qiaozhi Wei, Claus Nerlov, Paul S Frenette
The spatial localization of hematopoietic stem cells (HSCs) in the bone marrow (BM) remains controversial, with some studies suggesting that they are maintained in homogeneously distributed niches while others have suggested the contributions of distinct niche structures. Subsets of quiescent HSCs have been reported to associate with megakaryocytes (MK) or arterioles in the BM. However, these HSC subsets have not been prospectively defined. Here, we show that platelet and myeloid-biased HSCs, marked by von Willebrand factor (vWF) expression, are highly enriched in MK niches...
February 9, 2018: Developmental Cell
Timur Yorgan, Jean-Pierre David, Michael Amling, Thorsten Schinke
Bone remodeling is a continuously ongoing process mediated by bone-resorbing osteoclasts and bone-forming osteoblasts. One key regulator of bone formation is the putative Wnt co-receptor Lrp5, where activating mutations in the extracellular domain cause increased bone formation in mice and humans. We have previously reported that megakaryocyte numbers are increased the bone marrow of mice carrying a high bone mass mutation (HBM) of Lrp5 (Lrp5G170V ). Since megakaryocytes can promote bone formation, we addressed the question, if the bone remodeling phenotype of Lrp5G170V mice is affected by megakaryocyte depletion...
March 4, 2018: Biochemical and Biophysical Research Communications
Dirk Loeffler, Weijia Wang, Alois Hopf, Oliver Hilsenbeck, Paul E Bourgine, Fabian Rudolf, Ivan Martin, Timm Schroeder
Keeping track of individual cell identifications is imperative to the study of dynamic single cell behavior over time. Highly motile hematopoietic stem and progenitor cells (HSPCs) migrate quickly and do not adhere, and thus must be imaged very frequently to keep cell identifications. Even worse, they are also flushed away during medium exchange. To overcome these limitations, we tested antibody coating for reducing HSPC motility in vitro. Anti-CD43 and -CD44 antibody coating reduced cell motility of mouse and human HSPCs in a concentration dependent manner...
February 16, 2018: Blood
Xinyan Miao, Mohammed Ferdous-Ur Rahman, Lei Jiang, Yanan Min, Shuai Tan, Hong Xie, Linkiat Lee, Miao Wang, Rickard E Malmström, Weng-Onn Lui, Nailin Li
BACKGROUND: Platelets can synthesize proteins upon activation. Platelets contain a number of microRNAs (miRNA) and a fully functional miRNA effector machinery. It is, however, unclear if platelet miRNAs can regulate protein synthesis of platelets, and whether the regulation may produce a physiological impact. OBJECTIVES: To investigate if and how platelet miRNAs regulate de novo syntheses of angiogenic regulators and subsequently modulate platelet angiogenic activities...
February 14, 2018: Journal of Thrombosis and Haemostasis: JTH
Jung Ha Kim, Kabsun Kim, Inyoung Kim, Semun Seong, Nacksung Kim
The non-receptor tyrosine kinase c-Src participates in bone metabolism by regulating the activities of both the bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we investigated whether megakaryocyte-associated tyrosine kinase (Matk), a potent inhibitor of c-Src, affects the functions of murine osteoclasts and osteoblasts. Results revealed that the formation of osteoclasts with actin rings was attenuated by Matk overexpression in osteoclast precursor cells but was enhanced by Matk knockdown...
February 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Chunhong Liu, Tao Yu, Zhuo Xing, Xiaoling Jiang, Yichen Li, Annie Pao, Justin Mu, Paul K Wallace, George Stoica, Andrei V Bakin, Y Eugene Yu
Individuals with Down syndrome (DS) frequently have hematopoietic abnormalities, including transient myeloproliferative disorder and acute megakaryoblastic leukemia which are often accompanied by acquired GATA1 mutations that produce a truncated protein, GATA1s. The mouse has been used for modeling DS based on the syntenic conservation between human chromosome 21 (Hsa21) and three regions in the mouse genome located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. To assess the impact of the dosage increase of Hsa21 gene orthologs on the hematopoietic system, we characterized the related phenotype in the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ model which carries duplications spanning the entire Hsa21 orthologous regions on Mmu10, Mmu16 and Mmu17, and the Dp(10)1Yey /+; Dp(16)1Yey /+; Dp(17)1Yey/+ ; Gata1 Yeym2 model which carries a Gata1s mutation we engineered...
January 12, 2018: Oncotarget
Federico Comoglio, Hyun Jung Park, Stefan Schoenfelder, Iros Barozzi, Daniel Bode, Peter Fraser, Anthony R Green
Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cis- regulatory activity and chromatin architecture...
February 2, 2018: Genome Research
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