1,721,115 research outputs found
Megakaryocyte Cytoskeletal Proteins in Platelet Biogenesis and Diseases
No full textThrombopoiesis governs the formation of blood platelets in bone marrow by converting megakaryocytes into long, branched proplatelets on which individual platelets are assembled. The megakaryocyte cytoskeleton responds to multiple microenvironmental cues, including chemical and mechanical stimuli, sustaining the platelet shedding. During the megakaryocyte's life cycle, cytoskeletal networks organize cell shape and content, connect them physically and biochemically to the bone marrow vascular niche, and enable the release of platelets into the bloodstream. While the basic building blocks of the cytoskeleton have been studied extensively, new sets of cytoskeleton regulators have emerged as critical components of the dynamic protein network that supports platelet production. Understanding how the interaction of individual molecules of the cytoskeleton governs megakaryocyte behavior is essential to improve knowledge of platelet biogenesis and develop new therapeutic strategies for inherited thrombocytopenias caused by alterations in the cytoskeletal genes
A human factor-dependent cell line stimulates cobblestone formation under human bone marrow stromal cells in vitro
No full textHigh doses of romiplostim induce proliferation and reduce proplatelet formation by human megakaryocytes.
Full text linkRomiplostim (AMG531) is a Thrombopoietin (TPO) receptor agonist with no homology with the endogenous TPO that has been used to treat patients affected by immune thrombocytopenia (ITP). Despite the use of TPO mimetics in the clinical practice, the mechanisms underlying their impact on megakaryocyte function is still unknown.In this project we took advantage of an in vitro human model, that we have established in our laboratory for long time to study megakaryocyte development from human cord blood-derived progenitor cells, and we demonstrated that increasing doses of AMG531 (100 to 2000 ng/mL) determine a progressive increase of megakaryocyte proliferation with a parallel decrease in megakaryocyte ploidy and capacity of extending proplatelets. Most importantly, these differences in megakaryocyte function seemed to be correlated to modulation of AKT phosphorylation.Overall our results shed new light on the mechanisms and on the relevance of dosage related to AMG531 impact on megakaryocyte function
Silk fibroin engineered 3D system for the study of megakaryocytes and functional platelet production
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Translational approaches to functional platelet production ex vivo
No full textPlatelets, which are released by megakaryocytes, play key roles in haemostasis, angiogenesis, immunity, tissue regeneration and wound healing. The scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells
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