Platelets are made by megakaryocytes, large bone marrow cells that fragment into thousands of tiny, clot-forming discs. The UK needs 300,000 platelet transfusions each year, all currently donated by volunteers. This project aims to decode the calcium signals that tell a megakaryocyte when and how to break apart into platelets. Without these signals, platelets can become too sticky (causing clots) or too sluggish (causing bleeding), contributing to heart disease, cancer complications, and post-viral syndromes like long COVID. The researcher has bred a special mouse line whose megakaryocytes glow when calcium levels change, allowing real-time filming inside living bone marrow. If the calcium code is cracked, labs could one day grow platelets in a dish, ending reliance on blood donors. Even if that application remains distant, understanding how a single cell orchestrates a controlled explosion of thousands of fragments is fundamental cell biology—the kind of knowledge that has, in the past, unexpectedly unlocked new ways to treat bleeding disorders and design artificial blood products.
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Megakaryocytes (MKs) produce platelets by undergoing a process of controlled fragmentation called thrombopoiesis. If researchers can understand and harness this process, we may be able to generate enough platelets in vitro to provide the 300,000 transfusions required annually in the UK without the use of blood products. If researchers could understand and alter ways in which MKs sense and respond to their environment, we could prevent them from generating hyperreactive or hyporeactive platelets that contribute to bleeding, thrombotic, and other pathologies associated with cardiovascular disease, cancer, and post-viral syndromes such as long COVID. My previous research demonstrated that MK behaviour, such as the development of polarity, can be closely regulated by information encoded by the spatiotemporal dynamics of intracellular Ca2+ signals. Thrombopoiesis involves a complex sequence of events including the projection of cellular protrusions into the bloodstream, development of anchor points, fusion of the internal membrane system with the extracellular membrane, and major reorganization of the cytoskeleton. I have generated a mouse line expressing a genetically encoded Ca2+ sensor in the MK and platelet lineage, “MKPLT_Salsa6f,” which will enable the study of Ca2+ signalling during this process in vivo by intravital microscopy (IVM) imaging of calvarium bone marrow. My preliminary data suggest that unique Ca2+ signalling processes occur during thrombopoiesis. This funding will allow the calvarium IVM imaging technique to be established within my lab, providing novel insights into the signalling processes that underpin thrombopoiesis and aberrant MK behaviour that contribute to disease pathology in post-viral, cardiovascular, and haematological diseases.
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