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https://www.readbyqxmd.com/read/29327472/mesenchymal-stem-cell-deficiency-influences-megakaryocytopoiesis-through-the-tnfaip3-nf-%C3%AE%C2%BAb-smad-pathway-in-patients-with-immune-thrombocytopenia
#1
Yun He, Lin-Lin Xu, Fei-Er Feng, Qian-Ming Wang, Xiao-Lu Zhu, Chen-Cong Wang, Jia-Min Zhang, Hai-Xia Fu, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang, Xiao-Hui Zhang
Immune thrombocytopenia (ITP) is an autoimmune disease. Mesenchymal stem cells (MSCs) play important roles in the physiology and homeostasis of the haematopoietic system, including supporting megakaryocytic differentiation from CD34+ haematopoietic progenitor cells. Tumour necrosis factor alpha-induced protein 3 (TNFAIP3, also termed A20) plays a key role in terminating NF-κB signalling. Human genetic studies showed that the polymorphisms of the TNFAIP3 gene may contribute to ITP susceptibility. In this study, we showed a significant decrease in TNFAIP3 and increase in NF-κB/SMAD7 in ITP-MSCs...
January 12, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29296828/gene-editing-rescue-of-a-novel-mpl-mutant-associated-with-congenital-amegakaryocytic-thrombocytopenia
#2
Cédric Cleyrat, Romain Girard, Eun H Choi, Éric Jeziorski, Thierry Lavabre-Bertrand, Sylvie Hermouet, Serge Carillo, Bridget S Wilson
Thrombopoietin (Tpo) and its receptor (Mpl) are the principal regulators of early and late thrombopoiesis and hematopoietic stem cell maintenance. Mutations in MPL can drastically impair its function and be a contributing factor in multiple hematologic malignancies, including congenital amegakaryocytic thrombocytopenia (CAMT). CAMT is characterized by severe thrombocytopenia at birth, which progresses to bone marrow failure and pancytopenia. Here we report unique familial cases of CAMT that presented with a previously unreported MPL mutation: T814C (W272R) in the background of the activating MPL G117T (K39N or Baltimore) mutation...
September 26, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296823/mature-murine-megakaryocytes-present-antigen-mhc-class-i-molecules-to-t-cells-and-transfer-them-to-platelets
#3
Anne Zufferey, Edwin R Speck, Kellie R Machlus, Rukhsana Aslam, Li Guo, Mark J McVey, Michael Kim, Rick Kapur, Eric Boilard, Joseph E Italiano, John W Semple
Megakaryocytes (MKs) are bone marrow-derived cells that are primarily responsible for generating platelets for the maintenance of hemostasis. Although MK can variably express major histocompatibility complex (MHC) class I and II molecules during their differentiation, little is known whether they can elicit nonhemostatic immune functions such as T-cell activation. Here, we demonstrate that mature CD34- MHC class II- CD41+ MKs can endocytose exogenous ovalbumin (OVA) and proteolytically generate its immunogenic peptide ligand, which is crosspresented on their surface in association with MHC class I molecules...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29274361/development-of-a-new-knock-in-mouse-model-and-evaluation-of-pharmacological-activities-of-lusutrombopag-a-novel-nonpeptidyl-small-molecule-agonist-of-the-human-thrombopoietin-receptor-c-mpl
#4
Hiroshi Yoshida, Hajime Yamada, Wataru Nogami, Keiji Dohi, Tomomi Kurino-Yamada, Koji Sugiyama, Koji Takahashi, Yoshinari Gahara, Motoji Kitaura, Minoru Hasegawa, Itsuki Oshima, Kenji Kuwabara
Lusutrombopag (S-888711), an oral small-molecule thrombopoietin receptor (TPOR) agonist, has gained first approval as a drug to treat thrombocytopenia of chronic liver disease in patients undergoing elective invasive procedures in Japan. Preclinical studies were performed to evaluate its efficacy against megakaryopoiesis and thrombopoiesis. To investigate the proliferative activity and efficacy of megakaryocytic colony formation via human TPOR, lusutrombopag was applied to cultured human c-Mpl-expressing Ba/F3 (Ba/F3-hMpl) cells and human bone marrow-derived CD34-positive cells, respectively...
December 20, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29239275/activation-of-lysophosphatidic-acid-receptor-3-inhibits-megakaryopoiesis-in-human-hematopoietic-stem-cells-and-zebrafish
#5
Kuan-Hung Lin, Meng-Wei Li, Ya-Chi Chang, Yu-Nung Lin, Ya-Hsuan Ho, Wei-Chun Weng, Chang-Jen Huang, Bei-En Chang, Chao-Ling Yao, Hsinyu Lee
Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid that exists in the plasma and platelets. It exerts its functions through activation of various LPA receptors (LPARs), which belong to the family of G protein-coupled receptors (GPCRs). Activation of LPARs has important roles in stem cell differentiation. However, how LPA affects human hematopoietic stem cell (HSC) differentiation remains elusive. In our previous studies, we have suggested that LPA receptor 2 (LPA<sub>2</sub>) and LPA receptor 3 (LPA<sub>3</sub>) play opposing roles, and may act as a molecular switch during megakaryocytic differentiation in K562 cells...
December 14, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/29153694/evaluation-of-bone-marrow-function-with-immature-platelet-fraction-in-normal-pregnancy
#6
Ulrike Ratsch, Thorsten Kaiser, Holger Stepan, Alexander Jank
BACKGROUND: Bone marrow function in pregnancy is influencing blood cell concentration of platelets. The steady state of consumption, recovery and production of platelets is essential for coagulation and bleeding prevention. Reticulated platelets are an intermediate form of thrombocytes during thrombopoiesis representing platelet production. The immature platelet fraction (IPF) represents these platelets as percentage of all thrombocytes. Until now, there is little knowledge on IPF during pregnancy...
October 2017: Pregnancy Hypertension
https://www.readbyqxmd.com/read/29119850/dopamine-induces-platelet-production-from-megakaryocytes-via-oxidative-stress-mediated-signaling-pathways
#7
Shilei Chen, Mengjia Hu, Mingqiang Shen, Yang Xu, Cheng Wang, Xinmiao Wang, Fengju Li, Dongfeng Zeng, Fang Chen, Gaomei Zhao, Mo Chen, Fengchao Wang, Tianmin Cheng, Yongping Su, Jinghong Zhao, Song Wang, Junping Wang
Dopamine (DA), a catecholamine neurotransmitter, is known to for its diverse roles on hematopoiesis, yet its function in thrombopoiesis remains poorly understood. This study shows that DA stimulation can directly induce platelet production from megakaryocytes (MKs) in the final stages of thrombopoiesis via a reactive oxygen species (ROS)-dependent pathway. The mechanism was suggested by the results that DA treatment could significantly elevate the ROS levels in MKs, and time-dependently activate oxidative stress-mediated signaling, including p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, and caspase-3 signaling pathways, while the antioxidants N-acetylcysteine and L-glutathione could effectively inhibit the activation of these signaling pathways, as well as the ROS increase and platelet production triggered by DA...
November 9, 2017: Platelets
https://www.readbyqxmd.com/read/29117724/reference-intervals-for-absolute-and-percentage-immature-platelet-fraction-using-the-sysmex-xn-10-automated-haematology-analyser-in-a-uk-population
#8
Usman Ali, Gavin Knight, Roz Gibbs, Dimitris A Tsitsikas
BACKGROUND: Immature platelet fraction (IPF) estimation is a non-invasive and sensitive test that is available on recently introduced Sysmex XN-series of automated haematology analysers. It is a direct cellular indicator of thrombopoiesis. The aim of this study was to establish reference intervals for IPF, for both absolute (A-IPF) and percentage (%-IPF) measurements. MATERIAL AND METHODS: A total of 2366 samples that met the inclusion criteria were assayed for full blood count on the Sysmex XN-10 and a non-parametric percentile method was used for calculating the reference intervals...
November 9, 2017: Scandinavian Journal of Clinical and Laboratory Investigation
https://www.readbyqxmd.com/read/29028771/mechanisms-of-thrombocytopenia-during-septic-shock-a-multiplex-cluster-analysis-of-endogenous-sepsis-mediators
#9
Alexandre Bedet, Keyvan Razazi, Florence Boissier, Mathieu Surenaud, Sophie Hue, Stéphane Giraudier, Christian Brun-Buisson, Armand Mekontso Dessap
BACKGROUND: Thrombocytopenia is a common feature of sepsis and may involve various mechanisms often related to the inflammatory response. This study aimed at evaluating factors associated with thrombocytopenia during human septic shock. In particular, we used a multiplex analysis to assess the role of endogenous sepsis mediators. METHODS: Prospective, observational study. Thrombocytopenia was defined as an absolute platelet count <100 G/L or a 50% relative decrease in platelet count during the first week of septic shock...
October 12, 2017: Shock
https://www.readbyqxmd.com/read/29019736/clinical-and-laboratory-assessment-of-a-patient-with-thrombocytosis
#10
Niamh Appleby, Daniel Angelov
Elevated platelet counts are frequently encountered in hospital medicine and arise from both physiological and pathological mechanisms. Thrombocytosis may be secondary, reflecting an inflammatory state, iron deficiency, recent surgery or point towards an underlying neoplasm. Thrombocytosis may be the presenting sign of solid tumours and haematological conditions. The discovery of the activating mutations affecting thrombopoiesis led to greater understanding of the pathobiology of essential thrombocythaemia and other myeloproliferative neoplasms...
October 2, 2017: British Journal of Hospital Medicine
https://www.readbyqxmd.com/read/28973980/fucoidan-and-fucosylated-chondroitin-sulfate-stimulate-hematopoiesis-in-cyclophosphamide-induced-mice
#11
Natalia Anisimova, Nadezhda Ustyuzhanina, Maria Bilan, Fedor Donenko, Anatolii Usov, Mikhail Kiselevskiy, Nikolay Nifantiev
Application of cytostatics in cancer patients' chemotherapy results in a number of side effects, including the inhibition of various parts of hematopoiesis. Two sulfated polysaccharides, fucoidan from the seaweed Chordaria flagelliformis (PS-Fuc) and fucosylated chondroitin sulfate from the sea cucumber Massinium magnum (PS-FCS), were studied as stimulators of hematopoiesis after cyclophosphamide immunosuppression in mice. Recombinant granulocyte colony-stimulating factor (r G-CSF) was applied as a reference...
September 30, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28960117/the-effects-of-signal-transducer-and-activator-of-transcription-three-mutations-on-human-platelets
#12
Floor E Aleva, Frank L van de Veerdonk, Yang Li, Rahajeng N Tunjungputri, Sami Simons, Philip G De Groot, Mihai M Netea, Yvonne F Heijdra, Quirijn de Mast, André J A M van der Ven
Involvement of signal transducer and activator of transcription 3 (STAT3) in inflammation is well known. Recently, a role for STAT3 in platelet activation and platelet production has been suggested. Platelets exhibit important immune functions and engagement of STAT3 in platelet physiology may link inflammation and hemostasis. This study investigated the effects of STAT3 loss-of-function mutations and single nucleotide polymorphisms (SNPs) in STAT3 on glycoprotein VI (GPVI)-mediated platelet activation and platelet numbers in humans...
September 29, 2017: Platelets
https://www.readbyqxmd.com/read/28943044/prolyl-isomerase-pin1-promotes-proplatelet-formation-of-megakaryocytes-via-tau
#13
Taiki Shimizu, Chiyoko Uchida, Ritsuko Shimizu, Hozumi Motohashi, Takafumi Uchida
Here we show that Pin1, a peptidyl-prolyl cis/trans isomerase which catalyzes the isomerization of phosphorylated Ser/Thr-Pro, is a regulatory molecule of thrombopoiesis. We found that mice lacking the Pin1 gene (Pin1(-⁄-) mice) formed more megakaryocytes (MKs) than wild type mice (WT mice), and that the proplatelet formation of MKs was poorer in Pin1(-⁄-) mice than WT mice. Treatment of Meg-01 cells, a megakaryoblastic floating cell line, with shRNA against Pin1 suppressed the proplatelet formation. Expression of tau, a microtubule associated protein was induced in MKs during proplatelet formation...
November 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28928125/ck2%C3%AE-critically-regulates-thrombopoiesis-and-ca-2-triggered-platelet-activation-in-arterial-thrombosis-in-vivo
#14
Patrick Münzer, Britta Walker-Allgaier, Sascha Geue, Friederike Langhauser, Eva Geuss, David Stegner, Katja Aurbach, Daniela Semeniak, Madhumita Chatterjee, Irene Gonzalez Menendez, Melanie Märklin, Leticia Quintanilla-Martinez, Helmut R Salih, David W Litchfield, Thierry Buchou, Christoph Kleinschnitz, Florian Lang, Bernhard Nieswandt, Irina Pleines, Harald Schulze, Meinrad Gawaz, Oliver Borst
Platelets, anucleated megakaryocyte-derived cells, play a major role in hemostasis and arterial thrombosis. While protein kinase Casein Kinase 2 (CK2) is readily detected in megakaryocytes and platelets, the impact of CK2-dependent signaling on megakaryocyte/platelet (patho-) physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. Megakaryocyte/platelet-specific genetic deletion of CK2β (ck2β(-/-) ) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with enhanced proportion of premature platelets...
September 19, 2017: Blood
https://www.readbyqxmd.com/read/28865245/the-sh2b3-and-kcnk5-loci-may-be-implicated-in-regulation-of-platelet-count-volume-and-maturity
#15
Morten K Christiansen, Sanne B Larsen, Mette Nyegaard, Søs Neergaard-Petersen, Morten Würtz, Erik L Grove, Anne-Mette Hvas, Henrik K Jensen, Steen D Kristensen
INTRODUCTION: In recent genome-wide association studies, coronary artery disease (CAD) and myocardial infarction (MI) have been linked to a number of genetic variants, but their role in thrombopoiesis is largely unknown. AIM: We investigated the association between CAD and MI-associated genetic variants and five thrombopoiesis-related indices: platelet count (PC), mean platelet volume (MPV), immature platelet count (IPC), immature platelet fraction (IPF), and serum thrombopoietin (TPO)...
August 18, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28821815/epac1-deficient-mice-have-bleeding-phenotype-and-thrombocytes-with-decreased-gpib%C3%AE-expression
#16
Gyrid Nygaard, Lars Herfindal, Kathrine S Asrud, Ronja Bjørnstad, Reidun K Kopperud, Eystein Oveland, Frode S Berven, Lene Myhren, Erling A Hoivik, Turid Helen Felli Lunde, Marit Bakke, Stein O Døskeland, Frode Selheim
Epac1 (Exchange protein directly activated by cAMP 1) limits fluid loss from the circulation by tightening the endothelial barrier. We show here that Epac1(-/-) mice, but not Epac2(-/-) mice, have prolonged bleeding time, suggesting that Epac1 may limit fluid loss also by restraining bleeding. The Epac1(-/-) mice had deficient in vitro secondary hemostasis. Quantitative comprehensive proteomics analysis revealed that Epac1(-/-) mouse platelets (thrombocytes) had unbalanced expression of key components of the glycoprotein Ib-IX-V (GPIb-IX-V) complex, with decrease of GP1bβ and no change of GP1bα...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28752663/platelet-production-from-induced-pluripotent-stem-cells
#17
N Sugimoto, K Eto
Ex vivo production of human platelets has been pursued as an alternative measure to resolve limitations in the supply and safety of current platelet transfusion products. To this end, induced pluripotent stem cells (iPSCs) are considered an ideal global source, as they are not only pluripotent and self-renewing, but are also available from basically any person, have relatively few ethical issues, and are easy to manipulate. From human iPSCs, megakaryocyte (MK) lines with robust proliferation capacity have been established by the introduction of specified sets of genes...
July 28, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28743899/thrombopoiesis-is-spatially-regulated-by-the-bone-marrow-vasculature
#18
David Stegner, Judith M M vanEeuwijk, Oğuzhan Angay, Maximilian G Gorelashvili, Daniela Semeniak, Jürgen Pinnecker, Patrick Schmithausen, Imke Meyer, Mike Friedrich, Sebastian Dütting, Christian Brede, Andreas Beilhack, Harald Schulze, Bernhard Nieswandt, Katrin G Heinze
In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool...
July 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28730545/platelet-first-responders-in-wound-response-cancer-and-metastasis
#19
REVIEW
David G Menter, Scott Kopetz, Ernest Hawk, Anil K Sood, Jonathan M Loree, Paolo Gresele, Kenneth V Honn
Platelets serve as "first responders" during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity, and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities...
June 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28693791/etv6-and-etv7-siblings-in-hematopoiesis-and-its-disruption-in-disease
#20
REVIEW
Parisa Rasighaemi, Alister C Ward
ETV6 (TEL1) and ETV7 (TEL2) are closely-related members of the ETS family of transcriptional regulators. Both ETV6 and ETV7 have been demonstrated to play key roles in hematopoiesis, particularly with regard to maintenance of hematopoietic stem cells and control of lineage-specific differentiation, with evidence of functional interactions between both proteins. ETV6 has been strongly implicated in the molecular etiology of a number of hematopoietic diseases, including as a tumor suppressor, an oncogenic fusion partner, and an important regulator of thrombopoiesis, but recent evidence has also identified ETV7 as a potential oncogene in certain malignancies...
August 2017: Critical Reviews in Oncology/hematology
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