Explore the vast range of titles available.

In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts. Megakaryocyte maturation is thought to occur as the cells migrate from a vessel-distant (endosteal) niche to the vessel within the bone. Here, the authors show that megakaryocytes represent largely sessile cells in close contact with the vasculature and homogeneously distributed in the bone marrow.

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. β4GalT1 deficiency increases the number of fully differentiated MKs. However, the resulting lack of glycosylation enhances β1 integrin signaling leading to dysplastic MKs with severely impaired demarcation system formation and thrombopoiesis. Platelets lacking β4GalT1 adhere avidly to β1 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, β1 integrin deletion, specifically in MKs, restores thrombopoiesis. TPO and CXCL12 regulate β4GalT1 in the MK lineage. Thus, our findings establish a non-redundant role for β4GalT1 in the regulation of β1 integrin function and signaling during thrombopoiesis. Defective thrombopoiesis and lack of β4GalT1 further affect HSC homeostasis. Mutations affecting sialylation and galactosylation affect megakaryocyte function and thrombopoiesis. Here the authors show that the enzyme β4GalT1 regulates thrombopoiesis and hematopoietic stem cell homeostasis by controlling beta-1 integrin function.

AMG 531 is a novel dipeptide linked to the Fc fragment of IgG. It is structurally unrelated to thrombopoietin but can stimulate the thrombopoietin receptor. In this phase 1–2 study of AMG 531 in patients with chronic immune thrombocytopenia, there were no major adverse events that could be attributed to the protein. AMG 531 elevated platelet counts in about half the patients, but platelet counts returned to previous low levels after discontinuation of the treatment. AMG 531 increased platelet counts in about half the patients, but platelet counts returned to previous low levels after discontinuation of the treatment. AMG 531 is a novel dipeptide linked to the Fc fragment of IgG. Immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which antiplatelet autoantibodies cause platelet destruction. 1 – 6 The annual incidence of ITP in the United States is estimated to be approximately 16,000 cases. 1 , 4 The initial treatment for ITP, usually corticosteroids, intravenous immune globulin, or Rh 0 (D) immune globulin acts primarily by interfering with platelet destruction. 7 Other immunomodulatory agents suppress the production of antiplatelet antibodies, but relapse is common when these agents are discontinued. Splenectomy, by contrast, can have lasting effects and even cures the disease in some patients. There is evidence that platelet production is suboptimal in a substantial . . .

Thrombocytopenia is a major complication in a subset of patients with multiple myeloma (MM). However, little is known about its development and significance during MM. Here, we show thrombocytopenia is linked to poor prognosis in MM. In addition, we identify serine, which is released from MM cells into the bone marrow microenvironment, as a key metabolic factor that suppresses megakaryopoiesis and thrombopoiesis. The impact of excessive serine on thrombocytopenia is mainly mediated through the suppression of megakaryocyte (MK) differentiation. Extrinsic serine is transported into MKs through SLC38A1 and downregulates SVIL via SAM-mediated tri-methylation of H3K9, ultimately leading to the impairment of megakaryopoiesis. Inhibition of serine utilization or treatment with TPO enhances megakaryopoiesis and thrombopoiesis and suppresses MM progression. Together, we identify serine as a key metabolic regulator of thrombocytopenia, unveil molecular mechanisms governing MM progression, and provide potential therapeutic strategies for treating MM patients by targeting thrombocytopenia. The molecular mechanisms underlying the development of thrombocytopenia in multiple myeloma (MM) remain to be explored. Here, the authors show an association of thrombocytopenia with poor prognosis in MM and identify serine as a key metabolic regulator of thrombocytopenia.

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B ( RALB ) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population. The authors pioneered the iPSC-derived platelet transfusion in human. Here they employ miRNA switches, identifying RALB as a determinant of immune megakaryocytes and a marker for quality control, advancing standardization of iPSC-platelet production.

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.

Infantile (fetal and neonatal) megakaryocytes (Mks) have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived Mks. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with the potential to affect MKL1 function and found that DYRK1A inhibition dramatically enhanced Mk morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal Mks. Mks derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss-of-function studies confirmed MKL1 involvement in this morphogenetic pathway. Expression of Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile Mks.

Estrogen is reported to be involved in thrombopoiesis and the disruption of its signaling may cause myeloproliferative disease, yet the underlying mechanisms remain largely unknown. GATA-binding factor 1 (GATA1) is a key regulator of megakaryocyte (MK) differentiation and its deficiency will lead to megakaryoblastic leukemia. Here we show that estrogen can dose-dependently promote MK polyploidization and maturation via activation of estrogen receptor beta (ERβ), accompanied by a significant upregulation of GATA1. Chromatin immunoprecipitation and a dual luciferase assay demonstrate that ERβ can directly bind the promoter region of GATA1 and activate its transcription. Steroid receptor coactivator 3 (SRC3) is involved in ERβ-mediated GATA1 transcription. The deficiency of ERβ or SRC3 , similar to the inhibition of GATA1 , leads to the impediment of estrogen-induced MK polyploidization and platelet production. Further investigations reveal that signal transducer and activator of transcription 1 signaling pathway downstream of GATA1 has a crucial role in estrogen-induced MK polyploidization, and ERβ-mediated GATA1 upregulation subsequently enhances nuclear factor erythroid-derived 2 expression, thereby promoting proplatelet formation and platelet release. Our study provides a deep insight into the molecular mechanisms of estrogen signaling in regulating thrombopoiesis and the pathogenesis of ER deficiency-related leukemia.

The development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigate whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion of Nlrp3 within the hematopoietic compartment completely prevents increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promotes excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promotes expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhances bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease leads to regression of thrombocytosis, splenomegaly and bone marrow fibrosis. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients. In JAK2V617F mutant myeloproliferative neoplasms (MPN), inflammation impacts clinical outcomes. This study uncovers that the NLRP3 inflammasome drives thrombocytosis, granulocytosis, HSPC expansion, splenomegaly, and bone marrow fibrosis in MPN

Chronic myeloproliferative neoplasms are characterized by clonal myeloid expansion driven by activating mutations in the JAK2 pathway and chronic inflammation. The aim was to investigate the contribution of circulating inflammatory mediators to the abnormalities in the megakaryocytic lineage characteristic of MF and ET. Plasma samples from 30 MF and 28 ET patients were incubated with normal cord-blood CD34 + progenitors and megakaryo/thrombopoiesis was evaluated. MF plasma increased megakaryocyte output, which was attenuated in sequential samples from ruxolitinib-treated patients. JAK1/2, MAPK and NF-kB inhibitors reverted this effect, revealing the concomitant involvement of all three pathways. Elevated levels of circulating IL-1β and IL-6 correlated with megakaryocyte output, which was reverted by blocking antibodies, indicating this phenotype is partly driven by these inflammatory cytokines. Instead, ET plasma promoted enhanced proplatelet formation, which was coupled with increased NFE2 and Bcl-xL expression. Elevated levels of circulating RANTES correlated with ET plasma-induced proplatelet formation, which was partially reverted by RANTES receptor CCR5 antagonist Maraviroc, indicating RANTES is involved in this process. These findings indicate that, in addition to clonal mutations, extrinsic inflammatory mediators play a direct role in MF and ET megakaryocyte abnormalities. The distinct cytokine profile could potentially be useful for the development of targeted therapies.