Journal articles: 'Megakaryopoiesis'

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Geddis, Amy E. "Megakaryopoiesis." Seminars in Hematology 47, no. 3 (July 2010): 212–19. http://dx.doi.org/10.1053/j.seminhematol.2010.03.001.

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Tozawa, Keiichi, Yukako Ono-Uruga, and Yumiko Matsubara. "Megakaryopoiesis." Clinical & Experimental Thrombosis and Hemostasis 1, no. 2 (November 10, 2014): 54–58. http://dx.doi.org/10.14345/ceth.14014.

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Jeanpierre, Sandrine, Franck Emmanuel Nicolini, Bastien Kaniewski, Charles Dumontet, Ruth Rimokh, Alain Puisieux, and Véronique Maguer-Satta. "BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling." Blood 112, no. 8 (October 15, 2008): 3154–63. http://dx.doi.org/10.1182/blood-2008-03-145326.

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Abstract Activin A, BMP2, and BMP4, 3 members of the transforming growth factor-β family, are involved in the regulation of hematopoiesis. Here, we explored the role of these molecules in human megakaryopoiesis using an in vitro serum-free assay. Our results highlight for the first time that, in the absence of thrombopoietin, BMP4 is able to induce CD34+ progenitor differentiation into megakaryocytes through all stages. Although we have previously shown that activin A and BMP2 are involved in erythropoietic commitment, these molecules have no effect on human megakaryopoietic engagement and differentiation. Using signaling pathway-specific inhibitors, we show that BMP4, like thrombopoietin, exerts its effects on human megakaryopoiesis through the JAK/STAT and mTor pathways. Inhibition of the BMP signaling pathway with blocking antibodies, natural soluble inhibitors (FLRG or follistatin), or soluble BMP receptors reveals that thrombopoietin uses the BMP4 pathway to induce megakaryopoiesis, whereas the inverse is not occurring. Finally, we show that thrombopoietin up-regulates the BMP4 autocrine loop in megakaryocytic progenitors by inducing their production of BMP4 and up-regulating BMP receptor expression. In summary, this work indicates that BMP4 plays an important role in the control of human megakaryopoiesis.

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Blobel, Gerd A. "Krüppeling megakaryopoiesis." Blood 110, no. 12 (December 1, 2007): 3823–24. http://dx.doi.org/10.1182/blood-2007-09-110999.

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KOZUMA, Yukinori. "Megakaryopoiesis and apoptosis." Japanese Journal of Thrombosis and Hemostasis 23, no. 6 (2012): 552–58. http://dx.doi.org/10.2491/jjsth.23.552.

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Jubinsky, Paul T. "Megakaryopoiesis and thrombocytosis." Pediatric Blood & Cancer 44, no. 1 (2004): 45–46. http://dx.doi.org/10.1002/pbc.20243.

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Feng, Gege, Wen Cui, Wenyu Cai, Tiejun Qin, Yue Zhang, Zefeng Xu, Liwei Fang, et al. "Impact of Megakaryocyte Morphology on Prognosis of Persons with Myelodysplastic Syndromes." Blood 126, no. 23 (December 3, 2015): 2876. http://dx.doi.org/10.1182/blood.v126.23.2876.2876.

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Abstract Purpose: To describe the morphological evolution of megakaryocytic dysplasia by developing a systematic classification and evaluate the impact of our classification of dys-megakaryopoiesis on prognosis of persons with MDS. Patients and methods: 423 consecutive patients who had received no prior therapy with MDS diagnosed from January 2000 to April 2014 were enrolled. Follow-up data were available for 371 subjects (88%). Date of last follow-up was December 15, 2014 or date of last contact. Median follow-up was 22 months (range, 1¨C180 months). Subjects with lower-risk MDS fall into Revised International Prognostic scoring systems (IPSS-R) categories of very low-, low-, and intermediate-risk groups and those with higher-risk category into the high- and very high-risk groups. We performed CD41 immune staining and proposed a systematic classification of dys-megakaryopoiesis on bone marrow films: (1) micro-megakaryocytes (<12 µm); (2) micro-megakaryocytes (12-40 µm) with 1 nucleus; (3) micro-megakaryocytes (12-40 µm) with 2 nuclei; (4) micro-megakaryocytes (12-40 um) with multiple nuclei; (5) dys-morphic megakaryocytes (¡Ý40µm) with 1 nucleus; (6) dys-morphic megakaryocytes (¡Ý40 µm) with 2 nuclei; and (7) dys-morphic megakaryocytes (¡Ý40 µm) with multiple nuclei. To evaluate the prognostic impact of dys-megakaryopoiesis based on cell size we divided the seven subtypes into dys-megakaryopoiesis with and without micro-megakaryocytes. Samples were also divided based on numbers of nuclei: (1) mono-nucleated dys-morphic megakaryocytes; (2) bi-nucleated dys-morphic megakaryocytes; and (3) multinucleated dys-morphic megakaryocytes. The best discriminator cutoff point of each group was determined by the minimal P-value approach. The best discriminators were micro-megakaryocytes ¡Ý25%, dys-megakaryopoiesis except micro-megakaryocytes ¡Ý5%, mono-nucleated dys-megakaryopoiesis ¡Ý30% and bi-nucleated dys-megakaryopoiesis ¡Ý1%. In multi-nucleated megakaryopoiesis category, differences in survival at the optimal discriminator were not statistically significant (P=0.10). Results: Subjects in low- and high-risk cohorts were different with platelets (micro-megakaryocytes; P<0.001; dys-megakaryopoiesis except micro-megakaryocytes; P<0.001; mono-nucleated dys-megakaryopoiesis; P<0.001; bi-nucleated dys-megakaryopoiesis; P=0.028), bone marrow blasts (micro-megakaryocytes; P<0.001; dys-megakaryopoiesis except micro-megakaryocytes; P<0.001; mono-nucleated dys-megakaryopoiesis except micro-megakaryocytes; P<0.001; bi-nucleated dys-megakaryopoiesis; P<0.001), WHO 2008 subtypes (dys-megakaryopoiesis; P=0.001; dys-megakaryopoiesis except micro-megakaryocytes; P<0.001; mono-nucleated dys-megakaryopoiesis P<0.001; bi-nucleated dys-megakaryopoiesis; P=0.014) and IPSS-R risk cohorts (micro-megakaryocytes; P<0.001; dys-megakaryopoiesis except micro-megakaryocytes; P<0.001; mono-nucleated dys-megakaryopoiesis; P<0.001; bi-nucleated dys-megakaryopoiesis; P=0.001). There was no significant difference in age, gender, hemoglobin concentration and blood neutrophils levels at diagnosis between low- and high-risk cohorts. In addition, levels of micro-megakaryocytes and mono-nucleated megakaryocytes were significantly associated with IPSS-R cytogenetic category (P=0.002 and P=0.001). A significant association with IPSS-R cytogenetic category was not found for subjects with dys-megakaryopoiesis except micro-megakaryocytes and bi-nucleated megakaryopoiesis (P=0.187 and P=0.654).In multivariate analyses, micro-megakaryocytes ¡Ý25% and mono-nucleated dys-morphic megakaryocytes ¡Ý30% were independent adverse prognostic factors (hazard ratio [HR]=1.56 [95% confidence interval [CI], 1.10, 2.20]; P=0.012 and 1.49 [1.05, 2.10]; P =0.024). These effects were greater than those for other boundaries except micro-megakaryocytes ¡Ý5% and bi-nucleated dys-morphic megakaryocytes ¡Ý1% (P=0.288 and P =0.133). Conclusion: Our data suggest integration of micro-megakaryocytes and mono-nuclear dysmorphic megakaryocytes improves the predictive accuracy of the International Prognostic Scoring System-Revised (IPSS-R) scoring system. Disclosures No relevant conflicts of interest to declare.

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Liu, Zhi-Jian, and Martha Sola-Visner. "Neonatal and adult megakaryopoiesis." Current Opinion in Hematology 18, no. 5 (September 2011): 330–37. http://dx.doi.org/10.1097/moh.0b013e3283497ed5.

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9

Behrens, Kira, and Warren S. Alexander. "Cytokine control of megakaryopoiesis." Growth Factors 36, no. 3-4 (July 4, 2018): 89–103. http://dx.doi.org/10.1080/08977194.2018.1498487.

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10

Szalai, G., A. C. LaRue, and D. K. Watson. "Molecular mechanisms of megakaryopoiesis." Cellular and Molecular Life Sciences 63, no. 21 (August 11, 2006): 2460–76. http://dx.doi.org/10.1007/s00018-006-6190-8.

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11

Nicolini, Franck E., Sandrine Jeanpierre, Bastien Kaniewski, Charles Dumontet, Ruth Rimokh, Alain Puisieux, and Véronique Maguer-Satta. "The Bone Morphogenetic Protein (BMP)-4 Is Involved in the Regulation of Human Megakaryocytic Differentiation during Thrombopoietin Signaling." Blood 112, no. 11 (November 16, 2008): 1339. http://dx.doi.org/10.1182/blood.v112.11.1339.1339.

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Abstract It has been shown in the past that Activin A, BMP-2 and BMP-4, three members of the TGF-β family, are involved in the regulation of hematopoiesis and particularly erythropoiesis, in humans. In this study, we explored the role of these molecules in human megakaryopoiesis using an in vitro serum-free assay initiated with purified normal CD34+ human bone marrow (BM) cells (from allogeneic BM donors), that allows the analysis of the impact of such molecules on all stages of megakaryocytic differentiation. We could demonstrate for the first time, that in the absence of thrombopoietin (TPO), BMP-4 is able to induce CD34+ progenitor commitment and differentiation into megakaryocytes throughout all stages through means of cytology, flow cytometry, CFU and LTC-IC and ploidy assays, as well as in vitro platelet production. We analyzed as well the expression of megakaryocytic specific factors such as FOG-2, Fli-1 and PF4 by RQ-PCR, and PF4, BMP-4 secretion in culture supernatants. While we have previously shown that Activin A and BMP-2 are involved in the erythropoietic commitment even in the absence of erythropoietin, we were not able to demonstrate any effect of these molecules on megakaryopoietic commitment and differentiation. Using signaling pathways specific inhibitors such as AG490 (JAK-2 pathway inhibitor), PD98059 (ERK pathway inhibitor), LY294002 (PI3-K inhibitor) and Rapamycin (mTOR pathway inhibitor), we could show that BMP-4, as TPO, exerts its effects on human megakaryopoiesis involving specifically the JAK/STAT and mTOR signaling pathways. In addition, the specific inhibition of the BMP signaling pathway with blocking antibodies (CD34+ BM cells cultured in the presence of anti-TPO-R and mouse anti-BMP-4 Antibody), natural soluble inhibitors [such as FLRG (Follistatin related gene) protein or Follistatin], or soluble BMP-receptors (sBMPR-Ia, sBMPR-Ib) has revealed that TPO uses the BMP-4 pathway to induce the megakaryopoietic commitment of human BM CD34+ progenitors. Finally, we could demonstrate that TPO up-regulates a BMP-4 autocrine loop in megakaryocytic progenitors, by inducing their own production of BMP-4 associated to an up-regulation of BMP-receptor expression. In conclusion, this study illustrates that BMP-4 represents an important actor in the regulation of human megakaryopoiesis.

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Zhao, Hong-Yan, Qi Wen, Zhong-Shi Lyu, Shu-Qian Tang, Yuan-Yuan Zhang, Meng Lyu, Yu Wang, et al. "M2 Macrophages, but Not M1 Macrophages, Support Megakaryopoiesis Via up-Regulating PI3K-AKT Pathway." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-136562.

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Background Megakaryopoiesis and platelets production intensely depend on bone marrow(BM) microenvironment. Our previous studies found that impaired BM microenvironment and dysfunctional megakaryopoiesis are responsible for the occurrence of prolonged isolated thrombocytopenia (PT), which is defined as the engraftment of all peripheral blood cell lines other than a platelet count less than 20×109/L or a dependence on platelet transfusions for more than 60 days following allo-HSCT(BBMT 2014; BBMT 2017; Brit J Haematol 2018; Am J Hematol 2018). As an important component of the BM microenvironment, macrophages (MՓs) are heterogeneous and polarized into classically activated (M1) MՓs and alternatively activated (M2) MՓs with distinct phenotypes and function. Although inconsistent effect of BM MՓs was reported on megakaryopoiesis, the functional role of M1 and M2 MՓs and related pathway in regulating megakaryopoiesis and its effect on PT patients post-allotransplant remain to be elucidated. Aims To address the roles of M1 MФs and M2 MФs in regulating megakaryopoiesis as well as PI3K-AKT pathway in the process. Moreover, polarization status and the function of BM MФs in regulating megakaryopoiesis were evaluated in PT patients. Methods This prospective nested case-control study enrolled 12 patients with PT, 24 matched patients with good graft function (GGF), defined as persistent successful engraftment after allotransplant, and 12 healthy donors (HD). BM standard monocyte subsets and M1/M2 MՓs polarization state were analyzed by flow cytometry. To generate M1 and M2 MՓs, both primary BM MՓs and THP1 cell lines were treated with LPS and IFN-γ or with IL-4 and IL-13. The functions of BM MՓs were evaluated by migration, phagocytosis and cytokine secretion assay. The sorted CD34+ cells from HD were co-cultured with BM MՓs from PT and GGF patients or M1 and M2 MՓs respectively for megakaryopoiesis. The quantification of the megakaryocytes(MKs), MKs apoptosis, MKs polyploidy distribution, colony-forming unit MK(CFU-MK) efficiency, and platelet production were analyzed in the coculture system. To understand the underlying mechanism of MՓs polarization in regulating MKs, RNA-seq analyses were performed in BM MՓs from PT and GGF patients. In addition, M1 and M2 MՓs were treated with the chemical inhibitors and lentivirus for PI3K-AKT pathway. Results Elevated intermediate and non-classical monocyte subsets were found in PT patients when compared with those in GGF patients. Moreover, PT patients displayed increased M1 and reduced M2 MՓs, resulting an unbalanced M1/M2 polarization, compared with GGF and HD. BM MՓs from PT patients, with high TNF-α levels and low TGF-β levels, showed decreased megakaryopoiesis-supporting ability. No significant differences in migration and phagocytosis function of MՓs among the three groups. RNA sequencing of BM MՓs showed down-regulated PI3K-AKT pathway in MՓs of PT patients compared with GGF. Consistently, the phosphorylation levels of AKT decreased significantly in MՓs of PT patients, suggesting that PI3K-AKT pathway may functionally regulate megakaryopoiesis-supporting ability of MՓs. Subsequently, BM-M2 and THP1-M2 showed superior effect on megakaryopoiesis-supporting ability compared with BM-M1 and THP1-M1. Specifically, the BM CD34+ cells cocultured with M2 MՓs demonstrated significant increased percentages of MKs and MK polyploidy, CFU-MK efficiency, and platelet count compared with those cocultured with M1 MՓs. Preventing PI3K-AKT pathway by PI3K inhibitor or Akt inhibitor significantly reduced the megakaryopoiesis-supporting ability of M2 MՓs. Moreover, knockdown of AKT1 induced the impairment of megakaryopoiesis-supporting ability via suppressing M2 MՓs polarization, which could be attenuated by AKT1 overexpression complementarily. Summary/Conclusion The current study demonstrated the polarization status of MՓs modulates their ability to support megakaryopoiesis. M2 MՓs, but not M1 MՓs, support megakaryopoiesis via up-regulating PI3K-AKT pathway. Defective M2 MՓs polarization via down-regulating PI3K-AKT pathway may be responsible for the pathogenesis of PT post-allotransplant, which provides a promising therapeutic target for PT patients. Disclosures No relevant conflicts of interest to declare.

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YUZURIHA, Akinori, and Koji ETO. "Hematopoietic stem cells to megakaryopoiesis." Japanese Journal of Thrombosis and Hemostasis 27, no. 5 (2016): 519–25. http://dx.doi.org/10.2491/jjsth.27.519.

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Kostyak, John C., and Satya P. Kunapuli. "PKCθ is dispensable for megakaryopoiesis." Platelets 26, no. 6 (June 23, 2014): 610–11. http://dx.doi.org/10.3109/09537104.2014.926474.

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15

Tsuji, Kohichiro, Kenji Muraoka, and Tatsutoshi Nakahata. "Interferon-γ and Human Megakaryopoiesis." Leukemia & Lymphoma 31, no. 1-2 (January 1998): 107–13. http://dx.doi.org/10.3109/10428199809057590.

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Viklicky, Vladimir, Antonin Hradilek, and Jan Neuwirt. "ABNORMAL MEGAKARYOPOIESIS IN ACUTE LEUKAEMIA." British Journal of Haematology 68, no. 3 (March 1988): 393. http://dx.doi.org/10.1111/j.1365-2141.1988.tb04222.x.

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Hoyle, C., and F. G. J. Hayhoe. "ABNORMAL MEGAKARYOPOIESIS IN ACUTE LEUKAEMIA." British Journal of Haematology 68, no. 3 (March 1988): 393a—394. http://dx.doi.org/10.1111/j.1365-2141.1988.tb04223.x.

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Bluteau, O., T. Langlois, P. Rivera-Munoz, F. Favale, P. Rameau, G. Meurice, P. Dessen, et al. "Developmental changes in human megakaryopoiesis." Journal of Thrombosis and Haemostasis 11, no. 9 (September 2013): 1730–41. http://dx.doi.org/10.1111/jth.12326.

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Kaushansky, Kenneth. "Historical review: megakaryopoiesis and thrombopoiesis." Blood 111, no. 3 (February 1, 2008): 981–86. http://dx.doi.org/10.1182/blood-2007-05-088500.

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Abstract 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.

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20

Dupont, H., M. A. Dupont, J. Larrue, M. R. Boisseau, and H. Bricaud. "Megakaryopoiesis disturbances in atherosclerotic rabbits." Atherosclerosis 63, no. 1 (January 1987): 15–26. http://dx.doi.org/10.1016/0021-9150(87)90077-3.

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21

Johnson, Andrew D. "Pairing megakaryopoiesis methylation with PEAR1." Blood 128, no. 7 (August 18, 2016): 890–92. http://dx.doi.org/10.1182/blood-2016-06-723940.

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Liu, Zhi-Jian, James B. Bussel, Madhavi Lakkaraja, Francisca Ferrer-Marin, Cedric Ghevaert, Henry A. Feldman, Janice G. McFarland, Chaitanya Chavda, and Martha Sola-Visner. "Suppression of in vitro megakaryopoiesis by maternal sera containing anti-HPA-1a antibodies." Blood 126, no. 10 (September 3, 2015): 1234–36. http://dx.doi.org/10.1182/blood-2014-11-611020.

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Key Points Maternal sera containing anti-HPA-1a antibodies suppress in vitro megakaryopoiesis through induction of cell death. The degree of suppression of megakaryopoiesis is variable and is one of the factors determining the severity of neonatal thrombocytopenia.

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Kong, Xianguo, Lin Ma, Edward Chen, Chad Shaw, and Leonard Edelstein. "Identification of the Regulatory Elements and Target Genes of Megakaryopoietic Transcription Factor MEF2C." Thrombosis and Haemostasis 119, no. 05 (February 7, 2019): 716–25. http://dx.doi.org/10.1055/s-0039-1678694.

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AbstractMegakaryopoiesis produces specialized haematopoietic stem cells in the bone marrow that give rise to megakaryocytes which ultimately produce platelets. Defects in megakaryopoiesis can result in altered platelet counts and physiology, leading to dysfunctional haemostasis and thrombosis. Additionally, dysregulated megakaryopoiesis is also associated with myeloid pathologies. Transcription factors play critical roles in cell differentiation by regulating the temporal and spatial patterns of gene expression which ultimately decide cell fate. Several transcription factors have been described as regulating megakaryopoiesis including myocyte enhancer factor 2C (MEF2C); however, the genes regulated by MEF2C that influence megakaryopoiesis have not been reported. Using chromatin immunoprecipitation-sequencing and Gene Ontology data we identified five candidate genes that are bound by MEF2C and regulate megakaryopoiesis: MOV10, AGO3, HDAC1, RBBP5 and WASF2. To study expression of these genes, we silenced MEF2C gene expression in the Meg01 megakaryocytic cell line and in induced pluripotent stem cells by CRISPR/Cas9 editing. We also knocked down MEF2C expression in cord blood-derived haematopoietic stem cells by siRNA. We found that absent or reduced MEF2C expression resulted in defects in megakaryocytic differentiation and reduced levels of the candidate target genes. Luciferase assays confirmed that genomic sequences within the target genes are regulated by MEF2C levels. Finally, we demonstrate that small deletions linked to a platelet count-associated single nucleotide polymorphism alter transcriptional activity, suggesting a mechanism by which genetic variation in MEF2C alters platelet production. These data help elucidate the mechanism behind MEF2C regulation of megakaryopoiesis and genetic variation driving platelet production.

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Lambert, Michele P., Yuhuan Wang, Khalil H. Bdeir, Yvonne Nguyen, M. Anna Kowalska, and Mortimer Poncz. "Platelet factor 4 regulates megakaryopoiesis through low-density lipoprotein receptor–related protein 1 (LRP1) on megakaryocytes." Blood 114, no. 11 (September 10, 2009): 2290–98. http://dx.doi.org/10.1182/blood-2009-04-216473.

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Abstract Platelet factor 4 (PF4) is a negative regulator of megakaryopoiesis, but its mechanism of action had not been addressed. Low-density lipoprotein (LDL) receptor–related protein-1 (LRP1) has been shown to mediate endothelial cell responses to PF4 and so we tested this receptor's importance in PF4's role in megakaryopoiesis. We found that LRP1 is absent from megakaryocyte-erythrocyte progenitor cells, is maximally present on large, polyploidy megakaryocytes, and near absent on platelets. Blocking LRP1 with either receptor-associated protein (RAP), an antagonist of LDL family member receptors, or specific anti-LRP1 antibodies reversed the inhibition of megakaryocyte colony growth by PF4. In addition, using shRNA to reduce LRP1 expression was able to restore megakaryocyte colony formation in bone marrow isolated from human PF4-overexpressing mice (hPF4High). Further, shRNA knockdown of LRP1 expression was able to limit the effects of PF4 on megakaryopoiesis. Finally, infusion of RAP into hPF4High mice was able to increase baseline platelet counts without affecting other lineages, suggesting that this mechanism is important in vivo. These studies extend our understanding of PF4's negative paracrine effect in megakaryopoiesis and its potential clinical implications as well as provide insights into the biology of LRP1, which is transiently expressed during megakaryopoiesis.

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Marziali, Giovanna, Valentina Lulli, Simona Coppola, Paolo Romania, Laura Fontana, Francesca Liuzzi, Mauro Biffoni, et al. "MicroRNAs 155, -221 and -222 Control Megakaryopoiesis at Progenitor and Precursor Level through Ets-1 Multitargeting." Blood 108, no. 11 (November 16, 2006): 1187. http://dx.doi.org/10.1182/blood.v108.11.1187.1187.

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Abstract It is generally accepted that microRNAs (miRs) control basic biological functions, such as cell proliferation and differentiation. However, only few targets of the ~ 300 known mammalian miRs have been validated so far, thus hampering delineation of miR-based control circuitries. Particularly, little is known on miR function in mammalian hematopoiesis. We have investigated by microarray and Northern blot evalutation miR expression profiles in human megakarypoiesis, as evaluated in cord blood hematopoietic progenitor cell (HPC) unilineage culture through the megakaryopoietic (MK) differentiation-maturation pathway. These studies indicated that miR-155, -221 and -222 are abundant in HPCs, but sharply decline during megakaryopoiesis. The decline may favour megakaryopoiesis by unblocking translation of key functional target protein(s). Bioinformatic analysis predicted that miR-155, -221 and -222 target Ets-1, a transcription factor up-regulated in Mk differentiation, which transactivates relevant Mk genes (e.g., TPO receptor, PF4, CD42 and von Willebrand factor). Consistently, in megakaryocytic cells the increase of Ets-1 protein expression coincides with the miR-155, -221 and -222 decrease. To find out whether Ets-1 mRNA is a possible target of miR-155, -221 and -222, we cloned segments of the 3′UTR of the Ets-1 gene downstream of a firefly luciferase ORF. Luciferase assay confirmed a direct interaction between each of these miRs and the 3′UTR of Ets-1. Functional studies showed that enhanced expression of these three miRs impairs proliferation, differentiation and maturation of MK cells, at least in part via enhanced degradation of Ets1 mRNA and down-modulation of Ets-1 protein. Similar results were obtained by RNA interference against Ets-1. Finally, HPCs transfected with miR-155, -221, and -222 showed a significant reduction of their Mk clonogenic capacity, suggesting that down-modulation of these miRs favours MK progenitor recruitment and commitment. Altogether, these studies indicate that a novel regulatory circuitry, based on miR-155, -221, -222 multitargeting Ets-1 mRNA leading in turn to transactivation of Mk-specific genes, plays a key role in the control of megakaryopoiesis at both progenitor and precursor level.

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FUJITA, Rie, Hozumi MOTOHASHI, and Masayuki YAMAMOTO. "Transcriptional regulation of megakaryopoiesis and thrombopoiesis." Japanese Journal of Thrombosis and Hemostasis 23, no. 6 (2012): 539–43. http://dx.doi.org/10.2491/jjsth.23.539.

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Kostyak, John, C. "Megakaryopoiesis: Transcriptional Insights into Megakaryocyte Maturation." Frontiers in Bioscience 12, no. 1 (2007): 2050. http://dx.doi.org/10.2741/2210.

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Wijgaerts, Anouck, and Kathleen Freson. "Megakaryopoiesis under normal and pathological conditions." Hématologie 20, no. 6 (November 2014): 319–28. http://dx.doi.org/10.1684/hma.2014.0970.

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Freson, Kathleen, Chantal Thys, Christine Wittevrongel, Rita De Vos, Jos Vermylen, Marc F. Hoylaerts, and Chris Van Geet. "VPAC1 Receptor-Mediated Regulation of Megakaryopoiesis." Blood 104, no. 11 (November 16, 2004): 735. http://dx.doi.org/10.1182/blood.v104.11.735.735.

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Abstract Identification of the regulatory pathways that direct megakaryopoiesis and platelet production is essential for the development of novel strategies to treat life threatening bleeding complications in bone marrow suppressed patients. We demonstrated that megakaryocytes and platelets express the Gs-coupled VPAC1 receptor, for which both PACAP and VIP are specific agonists. We have further identified a bleeding tendency and found three copies of the PACAP gene in two related patients with severe mental retardation, responsible for elevated PACAP plasma levels and associated increased platelet cAMP concentrations, resulting in strongly reduced platelet aggregation (JCI, 2004, 113, 905). In this study, we have further demonstrated a fundamental role for the VPAC1 signalling pathway during megakaryocyte maturation and platelet formation. Patients with PACAP overexpression have mild thrombocytopenia, a normal platelet survival and relatively small platelets with an MPV of 8.2 fL (normal MPV 9-13 fL). FACS analysis of the patients’ platelets showed reduced expression of GPIX and GPIIIa. Electron microscopy of bone marrow of patients and of mice, specifically overexpressing PACAP in megakaryocytes revealed the presence of early megakaryocyte progenitors but almost not of mature megakaryocytes. Immature megakaryoblasts seemed to have reduced levels of rough endoplasmic reticulum cisternae and free ribosomes. To further study the modulating role of VPAC1 in thrombopoiesis, control mice were therefore subcutaneously injected with neutralizing polyclonal or monoclonal anti-PACAP, anti-VIP or anti-VPAC1 antibodies. Injection of these antibodies in all cases led to increased platelet counts, compared to control antibodies (monoclonal anti-PACAP antibody: 1194 ± 237 x 109 plt/L; control antibody: 722 ± 178 x 109 plt/L; p=0.01, unpaired t-test at day 7 after injection). This strategy was also capable of reducing the drop in platelet count in busulfan treated mice (polyclonal anti-PACAP antibody: 561 ± 121 x 109 plt/L; control antibody: 349 ± 65 x 109 plt/L; p=0.033, unpaired t-test at day 29 or day 18 after respectively antibody and busulfan injection). In addition, bone marrow examination of mice injected with monoclonal anti-PACAP or anti-VPAC1 antibodies revealed an increase in megakaryocyte numbers and showed a marked expansion and mobilization of megakaryocyte progenitor cells. Mice injected with a monoclonal anti-VPAC1 antibody showed an increase of about 50% in bone marrow CFU-MK. In conclusion, we provide evidence that the VPAC1 pathway modulates normal megakaryopoiesis. Further studies are needed to evaluate whether this pathway can be safely manipulated in man in the treatment of thrombocytopenia.

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Raslova, H., W. Vainchenker, and I. Plo. "Eltrombopag, a potent stimulator of megakaryopoiesis." Haematologica 101, no. 12 (November 30, 2016): 1443–45. http://dx.doi.org/10.3324/haematol.2016.153668.

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Suraneni, P. K., and J. D. Crispino. "The Hippo-p53 pathway in megakaryopoiesis." Haematologica 101, no. 12 (November 30, 2016): 1446–48. http://dx.doi.org/10.3324/haematol.2016.156125.

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Bender, Markus, Silvia Giannini, Terese Jönsson, Renata Grozovsky, Hilary Christensen, Fred G. Pluthero, Walter H. Kahr, Karin M. Hoffmeister, and Hervé Falet. "Dynamin 2-Dependent Endocytosis Regulates Megakaryopoiesis." Blood 124, no. 21 (December 6, 2014): 339. http://dx.doi.org/10.1182/blood.v124.21.339.339.

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Abstract Dynamins are large and highly conserved GTPases involved in endocytosis and vesicle trafficking. Mutations K562E/del in the ubiquitous dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in megakaryopoiesis we generated Dnm2fl/fl Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2fl/fl Pf4-Cre mice were viable, but had severe macrothrombocytopenia with moderately accelerated platelet clearance and prolonged bleeding due to poorly functional platelets. Dnm2-null bone marrow MKs had altered demarcation membrane system, appearing at times as a compact, narrow twisting membrane system of clathrin-coated vesicles. Fetal liver cell derived Dnm2-null MKs formed proplatelets poorly in vitro, showing that DNM2 plays a major role in MK membrane formation and thrombopoiesis. Both endogenous DNM2 and overexpressed DNM2 WT, but not DNM2 K562E/del mutants localized with the early endosome in bone marrow MKs. The endocytic pathway was disrupted in Dnm2-null MKs, as evidenced by severely reduced early endosome EEA1 and APPL1 staining and weak LysoTracker internalization. Endocytosis of the thrombopoietin (TPO) receptor Mpl was impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating TPO levels. MK-specific DNM2 deletion severely disrupted bone marrow homeostasis, as reflected by massive MK hyperplasia and myelofibrosis, and consequent extramedullary hematopoiesis and splenomegaly. However, additional Mpl genetic deletion failed to rescue the severe splenomegaly of Dnm2fl/fl Pf4-Cre mice, and Mpl-/- Dnm2fl/fl Pf4-Cre mice instead died at 4-5 weeks of age. Taken together, our data demonstrates that unrestrained MK growth and proliferation results in rapid myelofibrosis independently of Mpl expression and other bone marrow cell types, and establishes a previously unrecognized role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis and bone marrow homeostasis. Disclosures No relevant conflicts of interest to declare.

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Goldfarb, Adam. "A Mad(2) modification modulating megakaryopoiesis." Journal of Experimental Medicine 211, no. 12 (November 17, 2014): 2326–27. http://dx.doi.org/10.1084/jem.21112insight2.

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Nagasawa, Toshiro, Yuichi Hasegawa, Masaharu Kamoshita, Kouji Ohtani, Takuya Komeno, Takayoshi Itoh, Atsushi Shinagawa, Hiroshi Kojima, Haruhiko Ninomiya, and Tsukasa Abe. "Megakaryopoiesis in patients with cyclic thrombocytopenia." British Journal of Haematology 91, no. 1 (September 1995): 185–90. http://dx.doi.org/10.1111/j.1365-2141.1995.tb05267.x.

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Bernard, Jamie J., Kathryn E. Seweryniak, Anne D. Koniski, Sherry L. Spinelli, Neil Blumberg, Charles W. Francis, Mark B. Taubman, James Palis, and Richard P. Phipps. "Foxp3 Regulates Megakaryopoiesis and Platelet Function." Arteriosclerosis, Thrombosis, and Vascular Biology 29, no. 11 (November 2009): 1874–82. http://dx.doi.org/10.1161/atvbaha.109.193805.

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Wang, Q. "BUBR1 deficiency results in abnormal megakaryopoiesis." Blood 103, no. 4 (October 23, 2003): 1278–85. http://dx.doi.org/10.1182/blood-2003-06-2158.

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Matsumura, Itaru, and Yuzuru Kanakura. "Molecular Control of Megakaryopoiesis and Thrombopoiesis." International Journal of Hematology 75, no. 5 (June 2002): 473–83. http://dx.doi.org/10.1007/bf02982109.

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Kim, Minjung, Tami J. Kingsbury, and Curt I. Civin. "RAB14 Regulates Human Erythropoiesis and Megakaryopoiesis." Blood 128, no. 22 (December 2, 2016): 2661. http://dx.doi.org/10.1182/blood.v128.22.2661.2661.

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We recently reported that RAB GTPase 14 (RAB14) knockdown (KD) increased the frequency and total numbers of erythroid cells generated in vitro in response to erythropoietin (EPO) from either the TF1 human leukemia erythropoietic model cell line or from primary human CD34+ hematopoietic stem-progenitor cells (HSPCs). RAB14 overexpression (OE) had the opposite effect. Thus, RAB14 functions as an endogenous inhibitor of human erythropoiesis (Kim et al., Br. J. Haematol., 2015). In contrast to the greater cell numbers generated in the presence of EPO, RAB14 KD TF1 cells grown in standard culture media containing granulocyte-macrophage colony-stimulating factor (GM-CSF; as the only cytokine) generated fewer total cells, compared to empty vector-transduced control TF1 cells. Furthermore, RAB14 KD TF1 cells cultured in GM-CSF media generated greater numbers of erythroid (CD34-/CD71+/CD235a+) cells, as compared to control TF1 cells, suggesting that RAB14 KD stimulated erythropoiesis even in the absence of EPO. Cells generated from RAB14 KD TF1 cells had higher GATA1 and lower GATA2 transcription factor expression, as compared to controls, demonstrating the cells had undergone the "GATA1/2 switch," a hallmark of erythropoiesis. Consistent with higher GATA1 levels, RAB14 KD TF1 cells generated cells with higher levels of b- and g-hemoglobins. Similarly, RAB14 KD in primary human CD34+ HSPCs generated greater numbers of erythroid cells, with or without exogenous EPO. RAB14 KD CD34+ HSPCs cultured in GM-CSF media generated fewer monocytic/granulocytic (CD13+/CD33+) cells, as compared to control CD34+ HSPCs. Interestingly, RAB14 OE CD34+ HSPCs cultured in thrombopoietin (TPO)-containing media generated higher numbers of megakaryocytic (CD34-/CD41a+/CD42b+) cells, as compared to control CD34+ HSPCs. In summary, (1) RAB14 KD in TF1 cells or primary human CD34+ HSPCs increased erythropoiesis in the presence or absence of EPO, but reduced myeloid cell differentiation, probably via the GATA1/2 switch; and (2) RAB14 OE in CD34+ HSPCs increased megakaryopoiesis in the presence of TPO. Thus, RAB14 normally serves as an endogenous hematopoietic decision-maker, physiologically inhibiting erythropoiesis and stimulating megakaryopoiesis (and possibly, to a lesser extent, mono-granulopoiesis). Disclosures No relevant conflicts of interest to declare.

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Jin, Q., Y. Ren, M. Wang, P. K. Suraneni, D. Li, J. D. Crispino, J. Fan, and Z. Huang. "Novel function of FAXDC2 in megakaryopoiesis." Blood Cancer Journal 6, no. 9 (September 2016): e478-e478. http://dx.doi.org/10.1038/bcj.2016.87.

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Kono, Tomoko, Harumi Mukai, Yukinori Kozuma, Hiroshi Kojima, and Haruhiko Ninomiya. "Functional Analysis of CD9 during Megakaryopoiesis." Blood 112, no. 11 (November 16, 2008): 891. http://dx.doi.org/10.1182/blood.v112.11.891.891.

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Abstract CD9 is a four transmembrane protein belonging to a tetraspanin family and regulates cell motility and adhesion. Several reports have indicated that CD9 form complexes with integrin including platelet fibrinogen receptor integrin aIIb-b III and involve in platelet function. We have previously reported that the c-myb knock down (KD) mice exhibited anemia and thrombocytopenia, and the expression level of CD9 mRNA was markdly increased in the c-myb KD mice. Reverse correlation of c-Myb expression with the CD9 gene expression was verified and agonistic antibody of CD9 stimulated megakaryocytic colony formation. These observations suggested that the CD9 expression was downregulated by c-myb. In our current study, we investigated the role of CD9 during megakaryopoiesis and platelet function by using CD9-null mice. Numbers of megakaryocytes and platelets, CFU-Meg, and ploidy were not different between wild-type and CD9-null mice. However, proplatelet formation (PPF) was significantly impaired in CD9-null megakaryocytes, and the size of proplatelets was smaller than those generated by wild-type megakaryocytes. Furthermore, after the bone marrow suppression with 5-fluorouracil (5-Fu), the recovery phase of platelet counts were delayed in the CD9-null mice. To clarify the reason of this platelet- recover delay, the number of bone marrow megakaryocyte was investigated using anti-vWF antibody staining, but the serial measurement of megakaryocyte number in CD9-null mice was not changed compared with wild-type mice. And also megakaryocyte ploidy was not changed in CD9-null mice compared with wild-type mice. Previous reports revealed that the cytoskeleton reorganization has a key role for the PPF formation, and Rac1-PAK1 signaling is important for actin restructure and aggregation prior to the cytoskeleton reorganization. The PPF formation was suppressed by Rac1 inhibitor. Although the mRNA expression levels of Rac1 in CD9-null mice were almost same as that in wild-type mice, PAK1 activation, major target of Rac1, was delayed in CD9-null mice compared with wild-type mice using thrombin-stimulating platelets. These results suggested that the delay of PAK1 activation cause the suppression of PPF formation in CD9-null mice. Our previous and current studies demonstrate that c-Myb suppresses the CD9 expression in a steady-state condition, while in the stress megakaryocytosis, CD9 is upregulated and acts to induce megakaryopoiesis and platelets production through Rac1-PAK1 signaling pathway. Elucidation of c-Myb-CD9 regulatory function seems to be important to understand the stress megakaryopoiesis.

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Mosoyan, Goar, Kevin Eng, Craig Parker, Ronald Hoffman, and Camelia Iancu-Rubin. "Inhibition of telomerase impairs normal megakaryopoiesis." Experimental Hematology 42, no. 8 (August 2014): S39. http://dx.doi.org/10.1016/j.exphem.2014.07.144.

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Gao, Ai, Yuemin Gong, Fang Dong, Shihui Ma, Hui Cheng, Sha Hao, and Tao Cheng. "Defective megakaryopoiesis in acute myeloid leukemia." Experimental Hematology 53 (September 2017): S117. http://dx.doi.org/10.1016/j.exphem.2017.06.292.

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Oh, Doyeun, Seongmin Yoon, Seonyang Park, and Jeehyeon Bae. "Differential Regulations and Roles of Mcl-1 and Bcl-Xl during Megakaryopoiesis." Blood 112, no. 11 (November 16, 2008): 4727. http://dx.doi.org/10.1182/blood.v112.11.4727.4727.

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Abstract Backgrounds: Platelet plays an essential role in thrombosis and hemostasis and is produced from hematopoietic stem cells through a serious of differentiation and maturation processes called megakaryopoiesis. The major factor known to control platelet formation is thrombopoietin (TPO), but recently more proteins including apoptosis regulators have been reported to involve in megakaryopoiesis. Evolutionally conserved Bcl-2 family proteins are central regulators of apoptosis. Antiapoptotic Bcl-2 subfamily comprised of Bcl-xL, Mcl-1, Bcl-2, Bcl-w, and Bfl-1 plays a pivotal role in controlling cell death and survival under various conditions. According a recent study, Bcl-xL is a key molecular clock that determines the life span of platelets, but the role and regulation of Bcl-2 members in megakaryopoiesis are largely unknown. Methods and Results: We have established an in vitro system of megakaryopoiesis and performed the profiling of Bcl-2 family genes during megakaryocytosis. We found that Bcl-xL and Mcl-1 were predominant molecules among other members of the pro-survival proteins as determined by quantitative RT-PCR. TPO differentially regulates Bcl-xL and Mcl-1 in Meg-01 cells, in which Bcl-xL protein was significantly up-regulated while the level of Mcl-1 was attenuated. Furthermore, the roles of Bcl-xL and Mcl-1 during megakaryopoiesis were determined by modulating the expression levels of two proteins. Overexpression of Mcl-1 prominently enhanced the viability of the cells, whereas the knockdown of Mcl-1 promoted apoptosis of the cells. In contrast, forced expression of Bcl-xL did not affect the cell survival but rather significantly stimulated differentiation of megakarycytes. Conclusion: Bcl-xL and Mcl-1 are likely essential molecules during megakaryopoiesis. Moreover, the present study implies that although both Bcl-xL and Mcl-1 are members of antiapoptotic Bcl-2 family that promote the survival of different cells, these two proteins have distinctive and non-redundant functions in megakaryocytes.

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Opalinska, Joanna B., Alexey Bersenev, Zhe Zhang, Alec A. Schmaier, John Choi, Yu Yao, Janine D'Souza, Wei Tong, and Mitchell J. Weiss. "MicroRNA expression in maturing murine megakaryocytes." Blood 116, no. 23 (December 2, 2010): e128-e138. http://dx.doi.org/10.1182/blood-2010-06-292920.

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Abstract MicroRNAs are small noncoding RNAs that regulate cellular development by interfering with mRNA stability and translation. We examined global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were up-regulated and 81 were down-regulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were up-regulated most strongly in murine megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly up-regulated during mouse and human megakaryopoiesis but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously.

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Hitchcock, Ian S., Norma E. Fox, Nicolas Prévost, Katherine Sear, Sanford J. Shattil, and Kenneth Kaushansky. "Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function: studies using a megakaryocyte lineage–specific FAK knockout." Blood 111, no. 2 (January 15, 2008): 596–604. http://dx.doi.org/10.1182/blood-2007-05-089680.

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Focal adhesion kinase (FAK) plays a key role in mediating signaling downstream of integrins and growth factor receptors. In this study, we determined the roles of FAK in vivo by generating a megakaryocyte lineage–specific FAK-null mouse (Pf4-Cre/FAK-floxed). Megakaryocyte and platelet FAK expression was ablated in Pf4-Cre/FAK-floxed mice without affecting expression of the FAK homologue PYK2, although PYK2 phosphorylation was increased in FAK−/− megakaryocytes in response to fibrinogen. Megakaryopoiesis is greatly enhanced in Pf4-Cre/FAK-floxed mice, with significant increases in megakaryocytic progenitors (CFU-MK), mature megakaryocytes, megakaryocyte ploidy, and moderate increases in resting platelet number and platelet recovery following a thrombocytopenic stress. Thrombopoietin (Tpo)–mediated activation of Lyn kinase, a negative regulator of megakaryopoiesis, is severely attenuated in FAK-null megakaryocytes compared with wild-type controls. In contrast, Tpo-mediated activation of positive megakaryopoiesis regulators such as ERK1/2 and AKT is increased in FAK-null megakaryocytes, providing a plausible explanation for the observed increases in megakaryopoiesis in these mice. In Pf4-Cre/FAK-floxed mice, rebleeding times are significantly increased, and FAK-null platelets exhibit diminished spreading on immobilized fibrinogen. These studies establish clear roles for FAK in megakaryocyte growth and platelet function, setting the stage for manipulation of this component of the Tpo signaling apparatus for therapeutic benefit.

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Wang, Jialing, Xiaodan Liu, Haixia Wang, Lili Qin, Anhua Feng, Daoxin Qi, Haihua Wang, et al. "JMJD1C Regulates Megakaryopoiesis in In Vitro Models through the Actin Network." Cells 11, no. 22 (November 18, 2022): 3660. http://dx.doi.org/10.3390/cells11223660.

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The histone demethylase JMJD1C is associated with human platelet counts. The JMJD1C knockout in zebrafish and mice leads to the ablation of megakaryocyte–erythroid lineage anemia. However, the specific expression, function, and mechanism of JMJD1C in megakaryopoiesis remain unknown. Here, we used cell line models, cord blood cells, and thrombocytopenia samples, to detect the JMJD1C expression. ShRNA of JMJD1C and a specific peptide agonist of JMJD1C, SAH-JZ3, were used to explore the JMJD1C function in the cell line models. The actin ratio in megakaryopoiesis for the JMJDC modulation was also measured. Mass spectrometry was used to identify the JMJD1C-interacting proteins. We first show the JMJD1C expression difference in the PMA-induced cell line models, the thrombopoietin (TPO)-induced megakaryocyte differentiation of the cord blood cells, and also the thrombocytopenia patients, compared to the normal controls. The ShRNA of JMJD1C and SAH-JZ3 showed different effects, which were consistent with the expression of JMJD1C in the cell line models. The effort to find the underlying mechanism of JMJD1C in megakaryopoiesis, led to the discovery that SAH-JZ3 decreases F-actin in K562 cells and increases F-actin in MEG-01 cells. We further performed mass spectrometry to identify the potential JMJD1C-interacting proteins and found that the important Ran GTPase interacts with JMJD1C. To sum up, JMJD1C probably regulates megakaryopoiesis by influencing the actin network.

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Chen, Hui, Min Zhou, Huiying Shu, Weiqing Su, Liuming Yang, Liang Li, Beng H. Chong, and Mo Yang. "Tanshinone Iia Inhibits Megakaryopoiesis in Immune Vasculitis." Blood 138, Supplement 1 (November 5, 2021): 4288. http://dx.doi.org/10.1182/blood-2021-152162.

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Abstract Introduction Tanshinone IIA, an active component of Danshen (Salvia miltiorrhiza), has been used for centuries to treat hypercoagulation-related diseases, which attributed to its anti-platelet and anti-inflammatory effects. However, the role of Tanshinone IIA in megakaryocytes, the precursor of platelet within the bone marrow, remains unclear. Therefore, the present study established a rabbit model with immune vasculitis to examine the effect of Tanshinone IIA on megakaryopoiesis and to identify the underlying mechanism(s). Methods Immune vasculitis was established in rabbits (3-4 weeks old) by two intravenous injection of 10% bovine serum albumin (2.5 ml/kg) at two-week interval. Those rabbits were randomly treated with Tanshinone IIA (5 mg/kg/d, 7 d, iv) or aspirin (100 mg/kg/d, 7 d, ig). Megakaryocyte count and CFU-MK formation were measured by Wright's and AChE staining, respectively. Human megakaryotic cell lines Meg-01 and CHRF-288-11 were used to examine the effect of Tanshinone IIA on apoptosis by Annexin V-FITC/PI, mitochondrial membrane potential/JC-1 and Caspase-3 activity assays using flow cytometry. ResultsIn rabbits with immune vasculitis, the platelet count, platelet aggregation and the serum levels of inflammatory cytokines IL-1β, TNF-α and IL-6 were significantly increased when compared to their healthy controls. After 7 days of Tanshinone IIA treatment, all these parameters were significantly reduced, with the inhibitions comparable to those caused by aspirin. In addition, the number of megakaryocytes and the formation of CFU-MK were also statistically increased in rabbits with immune vasculitis, which could be significantly reduced by Tanshinone IIA. In vitro, Tanshinone IIA (1, 3, 10 and 30 μg/ml) also significantly inhibited the formation of CFU-MK of bone marrow cells of BALB/c mice (6-10 weeks) in a dose-dependent manner. In human megakaryocytic cell line Meg-01, Tanshinone ⅡA (10 μg/ml, 72 h) induced apoptosis; both early and late apoptotic rates were significantly increased. In another human megakaryocytic cell line CHRF-288-11, Tanshinone ⅡA (10 μg/ml, 72 h) statistically increased the proportion of depolarized cells, from 9.70% to 14.13%, according to mitochondrial membrane potential using JC-1 assay. The expression of active Caspase-3 in CHRF-288-11 was also significantly increased by Tanshinone ⅡA (10 μg/ml, 72 h) from 5.25% to 15.86%. Conclusion The present study shows that Tanshinone IIA ameliorates immune vasculitis by inhibiting megakaryopoiesis and inducing apoptosis of megakaryocytes, which might explain the anti-platelet and anti-inflammatory effects of Tanshinone IIA. Disclosures No relevant conflicts of interest to declare.

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Wagner, Thomas, Gerhard Bernaschek, and Klaus Geissler. "Inhibition of Megakaryopoiesis by Kell-Related Antibodies." New England Journal of Medicine 343, no. 1 (July 6, 2000): 72. http://dx.doi.org/10.1056/nejm200007063430120.

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Engelfriet, C. P., T. Wagner, G. Bernaschek, and K. Geissler. "Inhibition of Megakaryopoiesis by Kell-Related Antibodies." Vox Sanguinis 79, no. 4 (December 2000): 266. http://dx.doi.org/10.1046/j.1423-0410.2000.79402654.x.

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Tan, Ying-Xia, Hao Cui, Lu-Ming Wan, Feng Gong, Xiao Zhang, Israel Vlodavsky, and Jin-Ping Li. "Overexpression of heparanase in mice promoted megakaryopoiesis." Glycobiology 28, no. 5 (February 19, 2018): 269–75. http://dx.doi.org/10.1093/glycob/cwy011.

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Journal articles on the topic 'Megakaryopoiesis'

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