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Ulhas P Naik - One of the best experts on this subject based on the ideXlab platform.
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dual role for cib1 in Thrombopoiesis cib1 suppresses megakaryocyte quantities but supports adhesion migration and proplatelet formation
Blood, 2011Co-Authors: John C. Kostyak, Ulhas P NaikAbstract:Abstract 2384 Megakaryocytes (MKs) are large polyploid cells that produce platelets through a process known as Thrombopoiesis. Thrombopoietin (Tpo) is the major cytokine that regulates a variety of steps in this process, including hematopoietic stem cell (HSC) differentiation to MKs, proplatelet formation, and platelet release into the circulation. However, the molecular mechanism of Thrombopoiesis is poorly understood. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in Thrombopoiesis, we utilized a Cib1 −/− mouse model. We observed that Cib1 −/− mice have a slightly elevated number of platelets and bone marrow (BM)-derived MKs than wild-type (WT) controls (p Cib1 −/− and WT mice, suggesting that the defective clearance is not the cause of the observed elevated platelet number. In order to determine if the HSC differentiation is dysregulated by the ablation of Cib1, we analyzed MK-colony forming unit production, which revealed an increase in the colony forming cells with Cib1 deletion compared to WT (p Cib1 −/− mice, cultured with Tpo for 24 hours, produced more highly polyploid MKs than WT BM (p Y925 phosphorylation in Cib1 −/− BM-derived MKs treated with Tpo. Consequently, Akt and ERK1/2 activation downstream of Tpo was enhanced. These results suggested that Cib1 inhibits Tpo signaling by augmenting FAK activation. Interestingly, platelet recovery in Cib1 −/− mice following platelet depletion by experimental immunothrombocytopenia was attenuated compared to WT (p Cib1 −/− MKs compared to WT (p Cib1 −/− MKs formed fewer proplatelets compared to WT (p Disclosures: No relevant conflicts of interest to declare.
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dual role for cib1 in Thrombopoiesis cib1 suppresses megakaryocyte quantities but supports adhesion migration and proplatelet formation
Blood, 2011Co-Authors: John C. Kostyak, Ulhas P NaikAbstract:Abstract 2384 Megakaryocytes (MKs) are large polyploid cells that produce platelets through a process known as Thrombopoiesis. Thrombopoietin (Tpo) is the major cytokine that regulates a variety of steps in this process, including hematopoietic stem cell (HSC) differentiation to MKs, proplatelet formation, and platelet release into the circulation. However, the molecular mechanism of Thrombopoiesis is poorly understood. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in Thrombopoiesis, we utilized a Cib1 −/− mouse model. We observed that Cib1 −/− mice have a slightly elevated number of platelets and bone marrow (BM)-derived MKs than wild-type (WT) controls (p Cib1 −/− and WT mice, suggesting that the defective clearance is not the cause of the observed elevated platelet number. In order to determine if the HSC differentiation is dysregulated by the ablation of Cib1, we analyzed MK-colony forming unit production, which revealed an increase in the colony forming cells with Cib1 deletion compared to WT (p Cib1 −/− mice, cultured with Tpo for 24 hours, produced more highly polyploid MKs than WT BM (p Y925 phosphorylation in Cib1 −/− BM-derived MKs treated with Tpo. Consequently, Akt and ERK1/2 activation downstream of Tpo was enhanced. These results suggested that Cib1 inhibits Tpo signaling by augmenting FAK activation. Interestingly, platelet recovery in Cib1 −/− mice following platelet depletion by experimental immunothrombocytopenia was attenuated compared to WT (p Cib1 −/− MKs compared to WT (p Cib1 −/− MKs formed fewer proplatelets compared to WT (p Disclosures: No relevant conflicts of interest to declare.
John C. Kostyak - One of the best experts on this subject based on the ideXlab platform.
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dual role for cib1 in Thrombopoiesis cib1 suppresses megakaryocyte quantities but supports adhesion migration and proplatelet formation
Blood, 2011Co-Authors: John C. Kostyak, Ulhas P NaikAbstract:Abstract 2384 Megakaryocytes (MKs) are large polyploid cells that produce platelets through a process known as Thrombopoiesis. Thrombopoietin (Tpo) is the major cytokine that regulates a variety of steps in this process, including hematopoietic stem cell (HSC) differentiation to MKs, proplatelet formation, and platelet release into the circulation. However, the molecular mechanism of Thrombopoiesis is poorly understood. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in Thrombopoiesis, we utilized a Cib1 −/− mouse model. We observed that Cib1 −/− mice have a slightly elevated number of platelets and bone marrow (BM)-derived MKs than wild-type (WT) controls (p Cib1 −/− and WT mice, suggesting that the defective clearance is not the cause of the observed elevated platelet number. In order to determine if the HSC differentiation is dysregulated by the ablation of Cib1, we analyzed MK-colony forming unit production, which revealed an increase in the colony forming cells with Cib1 deletion compared to WT (p Cib1 −/− mice, cultured with Tpo for 24 hours, produced more highly polyploid MKs than WT BM (p Y925 phosphorylation in Cib1 −/− BM-derived MKs treated with Tpo. Consequently, Akt and ERK1/2 activation downstream of Tpo was enhanced. These results suggested that Cib1 inhibits Tpo signaling by augmenting FAK activation. Interestingly, platelet recovery in Cib1 −/− mice following platelet depletion by experimental immunothrombocytopenia was attenuated compared to WT (p Cib1 −/− MKs compared to WT (p Cib1 −/− MKs formed fewer proplatelets compared to WT (p Disclosures: No relevant conflicts of interest to declare.
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dual role for cib1 in Thrombopoiesis cib1 suppresses megakaryocyte quantities but supports adhesion migration and proplatelet formation
Blood, 2011Co-Authors: John C. Kostyak, Ulhas P NaikAbstract:Abstract 2384 Megakaryocytes (MKs) are large polyploid cells that produce platelets through a process known as Thrombopoiesis. Thrombopoietin (Tpo) is the major cytokine that regulates a variety of steps in this process, including hematopoietic stem cell (HSC) differentiation to MKs, proplatelet formation, and platelet release into the circulation. However, the molecular mechanism of Thrombopoiesis is poorly understood. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in Thrombopoiesis, we utilized a Cib1 −/− mouse model. We observed that Cib1 −/− mice have a slightly elevated number of platelets and bone marrow (BM)-derived MKs than wild-type (WT) controls (p Cib1 −/− and WT mice, suggesting that the defective clearance is not the cause of the observed elevated platelet number. In order to determine if the HSC differentiation is dysregulated by the ablation of Cib1, we analyzed MK-colony forming unit production, which revealed an increase in the colony forming cells with Cib1 deletion compared to WT (p Cib1 −/− mice, cultured with Tpo for 24 hours, produced more highly polyploid MKs than WT BM (p Y925 phosphorylation in Cib1 −/− BM-derived MKs treated with Tpo. Consequently, Akt and ERK1/2 activation downstream of Tpo was enhanced. These results suggested that Cib1 inhibits Tpo signaling by augmenting FAK activation. Interestingly, platelet recovery in Cib1 −/− mice following platelet depletion by experimental immunothrombocytopenia was attenuated compared to WT (p Cib1 −/− MKs compared to WT (p Cib1 −/− MKs formed fewer proplatelets compared to WT (p Disclosures: No relevant conflicts of interest to declare.
Claudia Lobato Da Silva - One of the best experts on this subject based on the ideXlab platform.
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developing a co culture system for effective megakaryo Thrombopoiesis from umbilical cord blood hematopoietic stem progenitor cells
Cytotherapy, 2015Co-Authors: Javad Hatami, Pedro Z Andrade, A Alves P De Matos, Dusan Djokovic, Carla Lilaia, Frederico Castelo Ferreira, Joaquim M S Cabral, Claudia Lobato Da SilvaAbstract:Background aims. Platelet transfusion can be a life-saving procedure in different medical settings. Thus, there is an increasing demand for platelets, of which shelf-life is only 5 days. The efficient ex vivo biomanufacturing of platelets would allow overcoming the shortages of donated platelets. Methods. We exploited a two-stage culture protocol aiming to study the effect of different parameters on the megakaryo/Thrombopoiesis ex vivo. In the expansion stage, human umbilical cord blood (UCB)-derived CD34 þ -enriched cells were expanded in co-culture with human bone marrow mesenchymal stromal cells (BM-MSCs). The megakaryocytic commitment and platelet generation were studied, considering the impact of exogenous addition of thrombopoietin (TPO) in the expansion stage and a cytokine cocktail (Cyt) including TPO and interleukin-3 in the differentiation stage, with the use of different culture medium formulations, and in the presence/absence of BM-MSCs (direct versus non-direct cell-cell contact). Results. Our results suggest that an early megakaryocytic commitment, driven by TPO addition during the expansion stage, further enhanced megakaryopoiesis. Importantly, the results suggest that coculture with BM-MSCs under serum-free conditions combined with Cyt addition, in the differentiation stage, significantly improved the efficiency yield of megakaryo/Thrombopoiesis as well as increasing %CD41, %CD42b and polyploid content; in particular, direct contact of expanded cells with BM-MSCs, in the differentiation stage, enhanced the efficiency yield of megakaryo/Thrombopoiesis, despite inhibiting their maturation. Conclusions. The present study established an in vitro model for the hematopoietic niche that combines different biological factors, namely, the presence of stromal/accessory cells and biochemical cues, which mimics the BM niche and enhances an efficient megakaryo/Thrombopoiesis process ex vivo.
Kenneth Kaushansky - One of the best experts on this subject based on the ideXlab platform.
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Thrombopoiesis.
Seminars in hematology, 2014Co-Authors: Kenneth KaushanskyAbstract:The production of platelets is a complex process that involves hematopoietic stem cells (HSCs), their differentiated progeny, the marrow microenvironment and hematopoietic cytokines. Much has been learned in the 110 years since James Homer Wright postulated that marrow megakaryocytes were responsible for blood platelet production, at a time when platelets were termed the "dust of the blood". In the 1980s a number of in vitro culture systems were developed that could produce megakaryocytes, followed by the identification of several cytokines that could stimulate the process in vitro. However, none of these cytokines produced a substantial thrombocytosis when injected into animals or people, nor were blood levels inversely related to platelet count, the sine qua non of a physiological regulator. A major milestone in our understanding of Thrombopoiesis occurred in 1994 when thrombopoietin, the primary regulator of platelet production was cloned and initially characterized. Since that time many of the molecular mechanisms of Thrombopoiesis have been identified, including the effects of thrombopoietin on the survival, proliferation, and differentiation of hematopoietic stem and progenitor cells, the development of polyploidy and proplatelet formation, the final fragmentation of megakaryocyte cytoplasm to yield blood platelets, and the regulation of this process. While much progress has been made, several outstanding questions remain, such as the nature of the signals for final platelet formation, the molecular nature of the regulation of marrow stromal thrombopoietin production, and the role of these physiological processes in malignant hematopoiesis.
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Historical review: megakaryopoiesis and Thrombopoiesis.
Blood, 2008Co-Authors: Kenneth KaushanskyAbstract:The study of Thrombopoiesis has evolved greatly since an era when platelets were termed “the dust of the blood,” only about 100 years ago. During this time megakaryocytes were identified as the origin of blood platelets; marrow-derived megakaryocytic progenitor cells were functionally defined and then purified; and the primary regulator of the process, thrombopoietin, was cloned and characterized and therapeutic thrombopoietic agents developed. During this journey we continue to learn that the physiologic mechanisms that drive proplatelet formation can be recapitulated in cell-free systems and their biochemistry evaluated; the molecular underpinnings of endomitosis are being increasingly understood; the intracellular signals sent by engagement of a large number of megakaryocyte surface receptors have been defined; and many of the transcription factors that drive megakaryocytic fate determination have been identified and experimentally manipulated. While some of these biologic processes mimic those seen in other cell types, megakaryocytes and platelets possess enough unique developmental features that we are virtually assured that continued study of Thrombopoiesis will yield innumerable clinical and scientific insights for many decades to come.
Simon Panzer - One of the best experts on this subject based on the ideXlab platform.
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High levels of reticulated platelets and thrombopoietin characterize fetal Thrombopoiesis
British journal of haematology, 2001Co-Authors: Petra Jilma-stohlawetz, Claudia C. Folman, Albert E. G. Kr. Von Dem Borne, Bernd Jilma, Monika Homoncik, Gerhard Bernaschek, Josef Deutinger, Barbara Ulm, W. Eppel, Simon PanzerAbstract:To characterize fetal Thrombopoiesis, we determined plasma thrombopoietin (TPO) and glycocalicin levels, platelet counts and reticulated platelets (RP) of fetuses and compared them with the respective values of their mothers. Percutaneous umbilical vein sampling in abnormal pregnancies revealed twofold higher thrombopoietin levels and 20-fold higher reticulated platelet counts, but lower levels of glycocalicin in fetuses compared with their mothers (P < 0.05). Neither the expression of platelet glycoprotein Ib and IIb on platelets nor the platelet counts were different between mothers and their fetuses. These data indicate enhanced Thrombopoiesis and/or increased platelet turnover in fetuses.
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Effects of Endotoxemia on Thrombopoiesis in Men
Thrombosis and Haemostasis, 1999Co-Authors: Petra Stohlawetz, Claudia C. Folman, Albert E. G. Kr. Von Dem Borne, Thomas Pernerstorfer, Hans-georg Eichler, Simon Panzer, Bernd JilmaAbstract:Background. Febrile conditions are often associated with increased platelet turnover and refractoriness to platelet transfusions, although several pyrogenic cytokines enhance Thrombopoiesis. This study aimed to characterize the effects of experimental human endotoxemia on platelet turnover and Thrombopoiesis. Methods. Endotoxin (4 ng/kg) was infused into 30 healthy men to study the regulation of Thrombopoiesis in systemic human inflammation. Platelet counts, plasma thrombopoietin (TPO) and glycocalicin levels, and reticulated platelets (RP) were measured to evaluate the effect of acute endotoxemia on Thrombopoiesis. Ten subjects received pretreatment with 1000 mg aspirin po. to evaluate possible effects of aspirin on platelet turnover, and ten subjects received paracetamol to control for effects of antipyresis. Results. Platelet counts dropped by about 15% (p
