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3.
Platelets ; 31(8): 1085-1089, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32857624

RESUMO

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.


Assuntos
Betacoronavirus/patogenicidade , Medula Óssea/patologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Trombose/patologia , Adulto , Idoso , Autopsia , Betacoronavirus/imunologia , Medula Óssea/imunologia , Medula Óssea/virologia , Núcleo Celular/imunologia , Núcleo Celular/patologia , Núcleo Celular/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Estado Terminal , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Evolução Fatal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-6/biossíntese , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Megacariócitos/imunologia , Megacariócitos/patologia , Megacariócitos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Trombopoese/imunologia , Trombose/complicações , Trombose/imunologia , Trombose/virologia
4.
Arterioscler Thromb Vasc Biol ; 40(10): e262-e272, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32814440

RESUMO

OBJECTIVE: The risk of thrombosis in myeloproliferative neoplasms, such as primary myelofibrosis varies depending on the type of key driving mutation (JAK2 [janus kinase 2], CALR [calreticulin], and MPL [myeloproliferative leukemia protein or thrombopoietin receptor]) and the accompanying mutations in other genes. In the current study, we sought to examine the propensity for thrombosis, as well as platelet activation properties in a mouse model of primary myelofibrosis induced by JAK2V617F (janus kinase 2 with valine to phenylalanine substitution on codon 617) mutation. Approach and Results: Vav1-hJAK2V617F transgenic mice show hallmarks of primary myelofibrosis, including significant megakaryocytosis and bone marrow fibrosis, with a moderate increase in red blood cells and platelet number. This mouse model was used to study responses to 2 models of vascular injury and to investigate platelet properties. Platelets derived from the mutated mice have reduced aggregation in response to collagen, reduced thrombus formation and thrombus size, as demonstrated using laser-induced or FeCl3-induced vascular injury models, and increased bleeding time. Strikingly, the mutated platelets had a significantly reduced number of dense granules, which could explain impaired ADP secretion upon platelet activation, and a diminished second wave of activation. CONCLUSIONS: Together, our study highlights for the first time the influence of a hyperactive JAK2 on platelet activation-induced ADP secretion and dense granule homeostasis, with consequent effects on platelet activation properties.


Assuntos
Coagulação Sanguínea , Plaquetas/enzimologia , Lesões das Artérias Carótidas/enzimologia , Janus Quinase 2/sangue , Megacariócitos/enzimologia , Ativação Plaquetária , Mielofibrose Primária/enzimologia , Trombose/enzimologia , Animais , Lesões das Artérias Carótidas/sangue , Lesões das Artérias Carótidas/genética , Modelos Animais de Doenças , Janus Quinase 2/genética , Camundongos Transgênicos , Mutação , Agregação Plaquetária , Mielofibrose Primária/sangue , Mielofibrose Primária/genética , Trombopoese , Trombose/sangue , Trombose/genética
5.
Rinsho Ketsueki ; 61(6): 628-633, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32624536

RESUMO

Since induced pluripotent stem (iPS) cell-derived blood products can be produced from any individual, they are expected to complement current transfusion products. However, a main problem is how to produce 10 U platelet preparations. Therefore, we established an immortalized megakaryocyte cell line (imMKCL) from iPS cells. We also found that turbulent flow was an essential physical factor for platelet generation in vivo. This knowledge enabled us to obtain 100 billion functional platelets from imMKCL using an 8 L bioreactor. We propose that the enhanced platelet production in the bioreactor occurs due to the turbulent flow that promoted the release of stress-induced cytokines.


Assuntos
Plaquetas , Reatores Biológicos , Células-Tronco Pluripotentes Induzidas , Megacariócitos , Trombopoese
6.
Exp Hematol ; 85: 33-46.e6, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32417303

RESUMO

Thrombopoietin (THPO) and its receptor myeloproliferative leukemia virus oncogene (MPL) regulate hematopoietic stem cell (HSC) quiescence and maintenance, but also megakaryopoiesis. Thrombocytopenias or aplastic anemias can be treated today with THPO peptide mimetics (romiplostim) or small-molecule THPO receptor agonists (e.g., eltrombopag). These THPO mimetics were designed for human application; however, many preclinical studies are performed in murine models. We investigated the activation of wild-type murine MPL (mMPL) by romiplostim. Romiplostim stimulated AKT, ERK1/2, and STAT5 phosphorylation without preference for one of these pathways, however, with a four- to fivefold lower phosphorylation intensity at high concentration. Faster internalization of mMPL after romiplostim binding could be one explanation of reduced signaling. In vitro megakaryocyte differentiation, proliferation, and maturation by romiplostim was less efficient compared with stimulation with mTHPO. We further dissected mMPL signaling by lentiviral overexpression of mMPL mutants with tyrosine (Y)-to-phenylalanine (F) substitutions in the distal cytoplasmic tyrosines 582 (Y582F), 616 (Y616F), and 621 (Y621F) individually and in combination (Y616F_Y621F) and in truncated receptors lacking 53 (Δ53) or 69 (Δ69) C-terminal amino acids. Mutation at tyrosine residue Y582F caused a gain-of-function with baseline activation and increased ERK1/2 phosphorylation upon stimulation. In agreement with this, proliferation in Y582F-32D cells was increased, yet did not rescue in vitro megakaryopoiesis from Mpl-deficient cells. Y616F and Y621F mutated receptors exhibited strongly impaired ERK1/2 and decreased AKT signaling and conferred reduced proliferation to 32D cells upon mTHPO stimulation but a partial correction of immature megakaryopoiesis in vitro.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação de Sentido Incorreto , Receptores de Trombopoetina/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Trombopoese/efeitos dos fármacos , Trombopoetina/farmacologia , Substituição de Aminoácidos , Animais , Linhagem Celular , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Receptores Fc , Receptores de Trombopoetina/genética , Trombopoese/genética
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 677-681, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319415

RESUMO

Immune thrombocytopenia (ITP) is an immune disease characterized by an increased risk of hemorrhagic disease caused by a decrease in platelet count. At present, the first line, second-line treatment can not completely or maintain continuous remission of ITP. New treatments in recent research include stimulating platelet-producing drugs, Syk inhibitors, and molecular-targeted drugs, etc., which can play a role in key steps of the progression of the disease. Among them, new types of drugs that stimulate thrombopoiesis shows a better therapeutic prospects with a comparative mechanism and clinical research, Syk inhibitors have a unique role in the treatment of malignant diseases in blood system, and the transplantation of mesenchymal stem cells is a new treatment idea. These treatments show the potential to improve the quality of life in patients with ITP. In this review, the latest research progress of new therapeutic drugs for ITP is summarized briefly.


Assuntos
Púrpura Trombocitopênica Idiopática , Adulto , Plaquetas , Humanos , Contagem de Plaquetas , Qualidade de Vida , Trombopoese
8.
Ann Hematol ; 99(6): 1205-1208, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32296910

RESUMO

Since December 2019, a novel coronavirus has spread throughout China and across the world, causing a continuous increase in confirmed cases within a short period of time. Some studies reported cases of thrombocytopenia, but hardly any studies mentioned how the virus causes thrombocytopenia. We propose several mechanisms by which coronavirus disease 2019 causes thrombocytopenia to better understand this disease and provide more clinical treatment options.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Trombocitopenia/etiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Humanos , Leucopenia/etiologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/terapia , Trombocitopenia/terapia , Trombopoese
9.
Pediatr Blood Cancer ; 67(5): e28232, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134181

RESUMO

OBJECTIVES: Pediatric myelofibrosis is a rare entity with the largest reported series of 19 cases. We describe here the clinicopathological spectrum and outcomes of 15 cases of pediatric myelofibrosis. METHODS: Case files of myelofibrosis of patients less than 18 years were retrieved from January 2016 to January 2019, and patients with idiopathic myelofibrosis after exhaustive work-up were studied. Their clinicopathological profiles were studied and then followed up for resolution and malignant transformation. RESULTS: Of the 15 cases of idiopathic myelofibrosis, transfusion-dependent anemia (14/15) was most common presentation. Only one patient showed leukoerythroblastosis with dacryocytes. Myeloid hyperplasia was seen in 13 of 15 patients and megakaryocytic hyperplasia in 10 patients. Dysmegakaryopoiesis was seen in 8 of 15 patients, and only three had small loose megakaryocytic clustering. None showed hyperchromatic megakaryocytes, intrasinusoidal hematopoiesis, or osteosclerosis. One patient with trisomy 8 tested positive for JAK2V617F. Bone marrow biopsy was hypercellular in 13, and 8 had world health organization (WHO) MF-3 fibrosis. None of the patients developed malignancy, one had spontaneous resolution, and one patient required allogenic stem cell transplant. CONCLUSIONS: Pediatric myelofibrosis is a distinct entity from primary myelofibrosis in adults and merits mention in the WHO manual as a distinct entity.


Assuntos
Transformação Celular Neoplásica , Janus Quinase 2 , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Trombopoese , Adolescente , Adulto , Substituição de Aminoácidos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Megacariócitos/metabolismo , Megacariócitos/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Estudos Retrospectivos
10.
Nat Commun ; 11(1): 356, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953383

RESUMO

Glycosylation is critical to megakaryocyte (MK) and thrombopoiesis in the context of gene mutations that affect sialylation and galactosylation. Here, we identify the conserved B4galt1 gene as a critical regulator of thrombopoiesis in MKs. ß4GalT1 deficiency increases the number of fully differentiated MKs. However, the resulting lack of glycosylation enhances ß1 integrin signaling leading to dysplastic MKs with severely impaired demarcation system formation and thrombopoiesis. Platelets lacking ß4GalT1 adhere avidly to ß1 integrin ligands laminin, fibronectin, and collagen, while other platelet functions are normal. Impaired thrombopoiesis leads to increased plasma thrombopoietin (TPO) levels and perturbed hematopoietic stem cells (HSCs). Remarkably, ß1 integrin deletion, specifically in MKs, restores thrombopoiesis. TPO and CXCL12 regulate ß4GalT1 in the MK lineage. Thus, our findings establish a non-redundant role for ß4GalT1 in the regulation of ß1 integrin function and signaling during thrombopoiesis. Defective thrombopoiesis and lack of ß4GalT1 further affect HSC homeostasis.


Assuntos
Galactosiltransferases/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Homeostase , Integrina beta1/metabolismo , Trombopoese/fisiologia , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Adesão Celular , Diferenciação Celular , Quimiocina CXCL12/metabolismo , Colágeno , Modelos Animais de Doenças , Fibronectinas , Galactosiltransferases/genética , Predisposição Genética para Doença , Hemorragia/genética , Hemorragia/metabolismo , Hemorragia/patologia , Integrina beta1/genética , Laminina , Ligantes , Megacariócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Trombopoese/genética , Trombopoetina/sangue
11.
Clin Exp Immunol ; 199(1): 97-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509227

RESUMO

Kidney injury significantly increases overall mortality. Neutrophilic granulocytes (neutrophils) are the most abundant human blood leukocytes. They are characterized by a high turnover rate, chiefly controlled by granulocyte colony stimulating factor (G-CSF). The role of kidney injury and uremia in regulation of granulopoiesis has not been reported. Kidney transplantation, which inherently causes ischemia-reperfusion injury of the graft, elevated human neutrophil expression of the surface glycoprotein CD177. CD177 is among the most G-CSF-responsive neutrophil genes and reversibly increased on neutrophils of healthy donors who received recombinant G-CSF. In kidney graft recipients, a transient rise in neutrophil CD177 correlated with renal tubular epithelial G-CSF expression. In contrast, CD177 was unaltered in patients with chronic renal impairment and independent of renal replacement therapy. Under controlled conditions of experimental ischemia-reperfusion and unilateral ureteral obstruction injuries in mice, renal G-CSF mRNA and protein expression significantly increased and systemic neutrophilia developed. Human renal tubular epithelial cell G-CSF expression was promoted by hypoxia and proinflammatory cytokine interleukin 17A in vitro. Clinically, recipients of ABO blood group-incompatible kidney grafts developed a larger rise in neutrophil CD177. Their grafts are characterized by complement C4d deposition on the renal endothelium, even in the absence of rejection. Indeed, complement activation, but not hypoxia, induced primary human endothelial cell G-CSF expression. Our data demonstrate that kidney injury induces renal G-CSF expression and modulates granulopoiesis. They delineate differential G-CSF regulation in renal epithelium and endothelium. Altered granulopoiesis may contribute to the systemic impact of kidney injury.


Assuntos
Basigina/metabolismo , Endotélio/metabolismo , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/biossíntese , Neutrófilos/metabolismo , Insuficiência Renal/metabolismo , Trombopoese , Animais , Basigina/imunologia , Modelos Animais de Doenças , Endotélio/imunologia , Endotélio/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos/imunologia , Humanos , Transplante de Rim , Masculino , Camundongos , Neutrófilos/imunologia , Neutrófilos/patologia , Insuficiência Renal/imunologia , Insuficiência Renal/patologia , Insuficiência Renal/cirurgia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Obstrução Ureteral/imunologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
12.
Platelets ; 31(3): 365-372, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31240987

RESUMO

Essential thrombocythemia (ET) is characterized by persistently elevated platelet counts and an increased risk of thromboembolic events. Dysregulated expression of small noncoding microRNAs (miRNAs) have been shown in ET and may influence platelet maturity and function in ET patients. In this study, we included 22 ET patients and 19 healthy controls to investigate the expression of 12 platelet miRNAs previously reported to be dysregulated in ET. Further, we investigated the correlation between the expression of selected miRNAs and platelet maturity and platelet function. Total RNA was isolated from platelets, and expression analyses were performed using TaqMan quantitative PCR (qPCR). Mean platelet volume (MPV) and immature platelet count and -fraction (IPC and IPF) were measured using the Sysmex XE-5000 automated haematology system. Platelet function was investigated by multiple electrode aggregometry (agonists: arachidonic acid (AA), thrombin-receptor-activating-peptide (TRAP) and adenosine diphosphate (ADP)), while platelet activation was determined by multi-colour flow cytometry (antibodies: bound-fibrinogen, CD63 and P-selectin (CD62p), agonists: AA, TRAP and ADP). We showed that miR-9 and miR-490 were significantly upregulated in ET patients compared with healthy controls (p-values < 0.01), while miR-10a, miR-28, miR-126, miR-155, miR-221, miR-222, miR-223 and miR-431 were significantly downregulated in ET patients (all p-values < 0.001). A significant positive correlation was observed between miR-431 and MPV, IPC and IPF (all p-values < 0.05). The expression of miR-126 was negatively correlated with platelet aggregation induced by AA and TRAP (p < 0.05). In addition, we found the expression of miR-9 and miR-490 to be negatively correlated with the percentage of fibrinogen-, CD63- and P-selectin- positive platelets using TRAP as agonist (p < 0.05). In conclusion, our data indicate that platelet microRNAs may play a role in ET and that specific microRNAs are correlated with platelet maturity and platelet function.


Assuntos
Plaquetas/citologia , Plaquetas/metabolismo , Diferenciação Celular/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Trombocitemia Essencial/genética , Trombocitemia Essencial/metabolismo , Biomarcadores , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Mutação , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Contagem de Plaquetas , Testes de Função Plaquetária , Interferência de RNA , Trombocitemia Essencial/diagnóstico , Trombopoese/genética
13.
Ann N Y Acad Sci ; 1466(1): 51-58, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31292976

RESUMO

Thrombopoietin (Thpo) and its receptor myeloid proliferative leukemia (Mpl) were initially identified as the cytokine signaling that stimulates megakaryopoiesis and platelet production. However, Thpo-Mpl signaling has also been widely characterized as one of the few cytokine systems that directly regulates hematopoietic stem and progenitor cells. The ability of Thpo signaling to stimulate hematopoietic stem cell (HSC) self-renewal has led to the development and utilization of Thpo mimetic drugs to treat hematopoietic diseases with restricted function of HSCs, such as aplastic anemia. This review will cover the mechanisms by which Thpo-Mpl signaling regulates HSCs.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Trombopoetina/fisiologia , Animais , Autorrenovação Celular/fisiologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Receptores de Trombopoetina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Trombopoese/fisiologia , Trombopoetina/farmacologia
14.
Blood Adv ; 3(20): 3092-3098, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648331

RESUMO

In addition to their primary roles in hemostasis and thrombosis, platelets participate in many other physiological and pathological processes, including, but not limited to inflammation, wound healing, tumor metastasis, and angiogenesis. Among their most interesting properties is the large number of bioactive proteins stored in their α-granules, the major storage granule of platelets. We previously showed that platelets differentially package pro- and antiangiogenic proteins in distinct α-granules that undergo differential release upon platelet activation. Nevertheless, how megakaryocytes achieve differential packaging is not fully understood. In this study, we use a mouse megakaryocyte culture system and endocytosis assay to establish when and where differential packaging occurs during platelet production. Live cell microscopy of primary mouse megakaryocytes incubated with fluorescently conjugated fibrinogen and endostatin showed differential endocytosis and packaging of the labeled proteins into distinct α-granule subpopulations. Super-resolution microscopy of mouse proplatelets and human whole-blood platelet α-granules simultaneously probed for 2 different membrane proteins (VAMP-3 and VAMP-8), and multiple granular content proteins (bFGF, ENDO, TSP, VEGF) confirmed differential packaging of protein contents into α-granules. These data suggest that megakaryocytes differentially sort and package α-granule contents, which are preserved as α-granule subpopulations during proplatelet extension and platelet production.


Assuntos
Plaquetas/metabolismo , Grânulos Citoplasmáticos/metabolismo , Megacariócitos/metabolismo , Animais , Transporte Biológico , Biomarcadores , Diferenciação Celular , Imunofluorescência , Humanos , Megacariócitos/citologia , Camundongos , Trombopoese
15.
Blood ; 134(21): 1847-1858, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31578203

RESUMO

During thrombopoiesis, megakaryocytes (MKs) form proplatelets within the bone marrow (BM) and release platelets into BM sinusoids. Phosphoinositide-dependent protein kinase-1 (PDK1) is required for Ca2+-dependent platelet activation, but its role in MK development and regulation of platelet production remained elusive. The present study explored the role of PDK1 in the regulation of MK maturation and polarization during thrombopoiesis using a MK/platelet-specific knockout approach. Pdk1-deficient mice (Pdk1-/-) developed a significant macrothrombocytopenia as compared with wild-type mice (Pdk1fl/fl). Pdk1 deficiency further dramatically increased the number of MKs without sinusoidal contact within the BM hematopoietic compartment, resulting in a pronounced MK hyperplasia and a significantly increased extramedullary thrombopoiesis. Cultured Pdk1-/- BM-MKs showed impaired spreading on collagen, associated with an altered actin cytoskeleton structure with less filamentous actin (F-actin) and diminished podosome formation, whereas the tubulin cytoskeleton remained unaffected. This phenotype was associated with abrogated phosphorylation of p21-activated kinase (PAK) as well as its substrates LIM domain kinase and cofilin, supporting the hypothesis that the defective F-actin assembly results from increased cofilin activity in Pdk1-deficient MKs. Pdk1-/- BM-MKs developed increased ploidy and exhibited an abnormal ultrastructure with disrupted demarcation membrane system (DMS). Strikingly, Pdk1-/- BM-MKs displayed a pronounced defect in DMS polarization and produced significantly less proplatelets, indicating that PDK1 is critically required for proplatelet formation. In human MKs, genetic PDK1 knockdown resulted in increased maturity but reduced platelet-like particles formation. The present observations reveal a pivotal role of PDK1 in the regulation of MK cytoskeletal dynamics and polarization, proplatelet formation, and thrombopoiesis.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Plaquetas/metabolismo , Citoesqueleto/metabolismo , Megacariócitos/metabolismo , Trombopoese/fisiologia , Animais , Plaquetas/citologia , Humanos , Megacariócitos/citologia , Camundongos , Camundongos Knockout
16.
Rinsho Ketsueki ; 60(9): 1063-1069, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597828

RESUMO

In modern hematology, research on hematopoiesis and blood cells in vertebrates, such as birds, reptiles, amphibians, and fish, is lagging. This is because there are many experimental constraints when selecting subjects other than humans and mice as research subjects. Currently, the availability of flow cytometry to count classified nucleated blood cells and utilization of whole genome information have led to novel findings. For example, in case of amphibian hematopoiesis studies, megakaryocytes have been found to be present in African clawed frogs (Xenopus laevis), which do not have platelets but have circulating nucleated thrombocytes. Moreover, we shed light on several mysteries, such as the C-terminal region in human TPO molecules not being found in birds, amphibians, and fish TPO molecules and the functional universalities of mutant CALR-MPL binding and EPO-EphB4 binding, in conjunction with comparative hematology.


Assuntos
Hematologia , Megacariócitos/citologia , Trombopoese , Vertebrados , Animais , Plaquetas , Genoma , Histologia Comparada , Humanos , Camundongos
17.
Blood ; 134(10): 791-792, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488457
18.
Biochem Pharmacol ; 169: 113634, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31513785

RESUMO

BACGROUND AND PURPOSE: Tumor chemotherapy and radiotherapy induces hematopoietic cell damage, resulting in thrombocytopenia. Conventional platelet transfusion strategies or drug therapies are used to treat thrombocytopenia. However, these therapies may result in a several side effects, including heightened susceptibility to infectious diseases and the formation of anti-TPO-antibodies. Therefore, a more secure strategy should be explored to overcome and compensate for the shortcomings of conventional strategies. EXPERIMENTAL APPROACH: Effects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were determined by analysing mRNA expression, promoter activity, protein expression. The molecular mechanisms of the effects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were investigated by determining the activation of VEGF-R II/NF-κB pathway. KEY RESULTS: Our results provide evidence that rhTyrRS (Y341A) activates NF-κB to upregulate VCAM-1 in a VEGF-R II/NF-κB pathway-dependent, resulting in megakaryocyte adhering to PVECs to induce platelet production. CONCLUSIONS: This study suggested that rhTyrRS (Y341A), a novel human tyrosyl-tRNA synthetase mutation, increased the platelet count under normal conditions. Further more, we confirmed that an NF-κB-mediated mechanism is involved in rhTyrRS (Y341A)-induced thrombopoiesis, which involves its interaction with VEGF-R II.


Assuntos
NF-kappa B/fisiologia , Trombopoese , Tirosina-tRNA Ligase/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Mutação , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Tirosina-tRNA Ligase/genética , Molécula 1 de Adesão de Célula Vascular/análise , Molécula 1 de Adesão de Célula Vascular/genética
19.
FEBS Lett ; 593(23): 3288-3303, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520530

RESUMO

In vitro cultured blood cells for transfusion purposes provide a safe alternative to donor blood, particularly for patients who require recurrent transfusions, and can be used as carriers of therapeutic molecules. In vitro derivation of hematopoietic cell types from human-induced pluripotent stem cells (iPSCs) allows for a constant, well-defined production pipeline for such advanced therapeutic and medicinal products. Application of selected iPSC-derived hematopoietic stem cells and hematopoietic effector cells in transplantation/transfusions would avoid the risk of alloimmunization and blood-borne diseases, as well as enable the production of enhanced blood cells expressing molecules that enforce blood cell function or endow novel therapeutic properties. Here, we discuss the state of the art approaches to produce erythroid, megakaryoid and myeloid cells from iPSCs and the biological and technical hurdles that we need to overcome prior to therapeutic application.


Assuntos
Células Eritroides/citologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Células Mieloides/citologia , Células Sanguíneas/citologia , Células Sanguíneas/transplante , Doadores de Sangue , Transfusão de Sangue/métodos , Diferenciação Celular/genética , Humanos , Trombopoese/genética
20.
Rinsho Ketsueki ; 60(7): 834-842, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391374

RESUMO

Bone marrow (BM), the tissue specializing in the production of hematopoietic cells, consists of multiple components (e.g., extracellular matrixes, vasculatures, and stromal cells) that generate a complex three-dimensional network and several localized microenvironment. These microenvironments regulate hematopoietic stem and progenitor cells, including megakaryocyte lineage cells. In this review, we first provide an overview of the microenvironment for hematopoietic stem cells as an introduction to bone marrow microenvironment and subsequently summarize the microenvironment for megakaryocyte differentiation and maturation (megakaryopoiesis). In the last portion, we describe megakaryocyte regulation by podoplanin-positive peri-arteriolar stromal cells in the mouse bone marrow.


Assuntos
Células da Medula Óssea/citologia , Medula Óssea , Lectinas Tipo C/fisiologia , Megacariócitos/citologia , Glicoproteínas de Membrana/fisiologia , Animais , Camundongos , Trombopoese
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