Megakaryocyte

Lethal toxin (LT) is the critical virulence factor of Bacillus anthracis , the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression...

(1) Background: Radiation-induced thrombocytopenia (RIT) often occurs in cancer patients undergoing radiation therapy, which can result in morbidity and even death. However, a notable deficiency exists in the availability of specific drugs designed for the treatment of RIT. (2) Methods: In our pursuit of new drugs for RIT treatment, we employed three deep learning (DL) algorithms: convolutional neural network (CNN), deep neural network (DNN), and a hybrid neural network that combines the computational characteristics of the two...

BACKGROUND: Megakaryocytes (MKs) are polyploid cells responsible for producing ∼1011 platelets daily in humans. Unraveling the mechanisms regulating megakaryopoiesis holds the promise for the production of clinical-grade platelets from stem cells, overcoming significant current limitations in platelet transfusion medicine. Previous work identified that loss of the epigenetic regulator SETD2 was associated with an increased platelet count in mice. However, the role of SETD2 in megakaryopoiesis remains unknown...

Mechanosensation is a fundamental function through which cells sense mechanical stimuli by initiating intracellular ion currents. Ion channels play a pivotal role in this process by orchestrating a cascade of events leading to the activation of downstream signaling pathways in response to particular stimuli. Piezo1 is a cation channel that reacts with Ca2+ influx in response to pressure sensation evoked by tension on the cell lipid membrane, originating from cell-cell, cell-matrix, or hydrostatic pressure forces, such as laminar flow and shear stress...

Five pathogenic variants in the gene encoding cytochrome c (CYCS) associated with mild autosomal dominant thrombocytopenia have been reported. Previous studies of peripheral blood CD34+ or CD45+ cells from subjects with the G42S CYCS variant showed an acceleration in megakaryopoiesis compared to wild-type (WT) cells. To determine whether this result reflects a common feature of the CYCS variants, the c.145T>C mutation (Y49H variant) was introduced into the endogenous CYCS locus in K-562 cells, which undergo megakaryocytic maturation in response to treatment with a phorbol ester...

A State of the Art lecture titled "Immune Attack on Megakaryocytes in ITP: The Role of Megakaryocyte Impairment" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Immune thrombocytopenia (ITP) is an acquired autoimmune disorder caused by autoantibodies against platelet surface glycoproteins that provoke increased clearance of circulating platelets, leading to reduced platelet number. However, there is also evidence of a direct effect of antiplatelet autoantibodies on bone marrow megakaryocytes...

Background: Previous studies have reported that genes highly expressed in leukemic stem cells (LSC) may dictate the survival probability of patients and expression-based cellular deconvolution may be informative in forecasting prognosis. However, whether the prognosis of acute myeloid leukemia (AML) can be predicted using gene expression and deconvoluted cellular abundances is debatable. Methods: Nine different cell-type abundances of a training set composed of the AML samples of 422 patients, were used to build a model for predicting prognosis by least absolute shrinkage and selection operator Cox regression...

Megakaryocytes, integral to platelet production, predominantly reside in the bone marrow and undergo regulated fragmentation within sinusoid vessels to release platelets into the bloodstream. Inflammatory states and infections influence megakaryocyte transcription, potentially affecting platelet functionality. Notably, COVID-19 has been associated with altered platelet transcriptomes. In this study, we investigated the hypothesis that SARS-CoV-2 infection could impact the transcriptome of bone marrow megakaryocytes...

Epidemiological studies show that cardiovascular events related to platelet hyperactivity remain the leading causes of death among multiple sclerosis (MS) patients. Quantitative or structural changes of platelet cytoskeleton alter their morphology and function. Here, we demonstrated, for the first time, the structural changes in MS platelets that may be related to their hyperactivity. MS platelets were found to form large aggregates compared to control platelets. In contrast to the control, the images of overactivated, irregularly shaped MS platelets show changes in the cytoskeleton architecture, fragmented microtubule rings...

INTRODUCTION: Thrombocytopenia is among the most common complications following hematopoietic stem cell transplantation and is associated with increased mortality and morbidity with no standard treatment yet. In this multicenter and retrospective study, we aim to present our multi-center experience of Eltrombopag treatment in patients with isolated thrombocytopenia following HSCT. MATERIAL-METHOD: A total of 73 patients from 5 centers who underwent autologous or allogeneic stem cell transplantation, had no primary disease relapse, all of whom had neutrophil engraftment, complete chimerism, and who were diagnosed with Prolonged Isolated Thrombocytopenia (PIT) or Secondary Failure Of Platelet Recovery (SFPR) were included in the study...

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...

OBJECTIVE: X-linked chronic granulomatous disease (X-CGD) is a rare primary immunodeficiency disease characterized by phagocyte dysfunction. It is caused by genetic mutations in the CYBB gene, predominantly affecting males. However, a small number of female carriers can also present with the disease due to biased X chromosome inactivation.1 This study aims to enhance the understanding of X-CGD in a rare case of an infant and young woman and provide insights into its diagnosis and treatment...

GATA transcriptional factors are zinc finger DNA binding proteins that regulate transcription during development and cell differentiation. The 3 important GATA transcription factors GATA1, GATA2 and GATA3 play essential role in the development and maintenance of hematopoietic systems. GATA1 is required for the erythroid and Megakaryocytic commitment during hematopoiesis. GATA2 is crucial for the proliferation and survival of early hematopoietic cells, and is also involved in lineage specific transcriptional regulation as the dynamic partner of GATA1...

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are used in several advanced malignancies and may cause various immune-related adverse events (irAEs). Among them, hematological irAEs are less described. Acquired amegakaryocytic thrombocytopenia (AAT) is a rare immune hematologic disorder characterized by severe thrombocytopenia and complete absence of megakaryocytes in bone marrow. CASE PRESENTATION: Herein, we present the case of a patient in their 40s with metastatic melanoma who developed an AAT after 12 cycles of nivolumab (anti-PD1)...

Hematopoietic stem and progenitor cells (HSPCs) continuously generate platelets throughout one's life. Inherited Platelet Disorders affect ≈ 3 million individuals worldwide and are characterized by defects in platelet formation or function. A critical challenge in the identification of these diseases lies in the absence of models that facilitate the study of hematopoiesis ex vivo. Here, a silk fibroin-based bioink is developed and designed for 3D bioprinting. This bioink replicates a soft and biomimetic environment, enabling the controlled differentiation of HSPCs into platelets...

This study aimed to identify key proteomic analytes correlated with response to splenectomy in primary immune thrombocytopenia (ITP). Thirty-four patients were retrospectively collected in the training cohort and 26 were prospectively enrolled as validation cohort. Bone marrow biopsy samples of all participants were collected prior to the splenectomy. A total of 12 modules of proteins were identified by weighted gene co-expression network analysis (WGCNA) method in the developed cohort. The tan module positively correlated with megakaryocyte counts before splenectomy (r = 0...

The transcription factor RUNX1 is a master regulator of hematopoiesis and is frequently mutated in myeloid malignancies. Mutations in its runt homology domain (RHD) frequently disrupt DNA binding and result in loss of RUNX1 function. However, it is not clearly understood how other RUNX1 mutations contribute to disease development. Here, we characterize RUNX1 mutations outside of the RHD. Our analysis of patient datasets revealed that mutations within the C-terminus frequently occur in hematopoietic disorders...

Sitosterolemia is a rare autosomal-recessive genetic disorder in which patients develop hypercholesterolemia, and may exhibit abnormal hematologic and/or liver test results. In this disease, dysfunction of either ABCG5 or ABCG8 results in intestinal hyperabsorption of all sterols, including cholesterol and more specifically plant sterols or xenosterols, as well as in the impaired ability to excrete xenosterols into the bile. It remains unknown how and why some patients develop hematologic abnormalities. Only a few unrelated patients with hematologic abnormalities at the time of diagnosis have been reported...

The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes...

Maintenance of hematopoietic stem cell (HSC) function is an orchestrated event between multiple cell types, and crosstalk between these cell types is an essential part of HSC regulation. Among the cell groups of the niche involved in this process are a group of bone-resident macrophages known as osteomacs (OM). Previously, it was demonstrated that OM and osteoblasts contained within neonatal calvarial cells are critical to maintain hematopoietic function. Additionally, interactions between neonatal calvarial cells and megakaryocytes further enhance this hematopoietic activity...