Interactions between platelets and hematopoietic cells
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- PhD theses (HV) 
OriginalversjonInteractions between platelets and hematopoietic cells by Daniel Limi Cacic, Stavanger : University of Stavanger, 2022 (PhD thesis UiS, no. 638)
In addition to their primary role in hemostasis, platelets are increasingly recognized as important participants in numerous biological processes. Their ability to adhere to and communicate with different immune cells, endothelial cells, and cancer cells makes them a natural nexus that participates in development of different diseases, including cancer. Thus, one could also surmise interactions between platelets and hematopoietic stem and progenitor cells. Previous studies have shown that bone marrow function recovers more quickly after transplantation with mobilized peripheral blood stem cells than with bone marrow-derived hematopoietic stem cells. A major difference between the two techniques is that mobilized peripheral blood stem cells are exposed to activated platelets during harvesting. As platelets communicate with a myriad of blood cells and carry cargoes of hundreds of proteins and other biologically active compounds, I wanted to investigate potential interactions between platelets and hematopoietic progenitor cells, including leukemic cells from acute myelogenous leukemia (AML). Using flow cytometric analysis and colony forming unit (CFU) assessment, our group show that platelet releasate inhibits proliferation, conserves erythroid phenotype, and increases levels of erythroid progenitors in cultivated mobilized peripheral blood stem and progenitor cells. Expression of CD14 antigen and monocyte-associated mRNAs also increased, suggesting that platelet releasate induced monocytopoiesis. Upon activation, platelets degranulate and release the content of their alpha granules, dense granules, and lysosomes. Activated platelets also shed platelet microparticles (PMP), membranous vesicles that contain platelet cargo. These microparticles are internalized by many different cells, including cancer cells, and are known to alter their biological behavior. Using flow cytometry and fluorescence microscopy, we show that these microparticles are internalized by AML cells, with a subsequent transfer of miR-125a and miR-125b and a downregulation of the pro-apoptotic protein PUMA. This microRNA transfer could explain the anti-apoptotic properties of PMPs that we also observed following treatment with several apoptosis inductors, where daunorubicin is of particular interest, as it is a mainstay in the treatment of AML. Thus, multiple potential interactions between platelets and hematopoietic progenitor cells and leukemic cells are identified. The results must be confirmed by more advanced in vitro and translational models before their clinical relevance can be fully appreciated, but the findings may benefit ex vivo production of monocytes and erythrocytes and support the use of therapeutic platelet inhibition in AML patients.
Består avPaper 1: Cacic, D.; Nordgård, O.; Meyer, P.; Hervig, T. Platelet Releasate Augments in vitro Monocytopoiesis and Erythropoiesis. Manuscript.
Paper 2: Cacic, D.; Reikvam, H.; Nordgård, O.; Meyer, P.; Hervig, T. Platelet Microparticles Protect Acute Myelogenous Leukemia Cells against Daunorubicin-Induced Apoptosis. Cancers 2021, 13, 1870. https://doi.org/10.3390/cancers13081870
Paper 3: Cacic, D.; Nordgård, O.; Meyer, P.; Hervig, T. Platelet Microparticles Decrease Daunorubicin-Induced DNA Damage and Modulate Intrinsic Apoptosis in THP-1 Cells. Int. J. Mol. Sci. 2021, 22, 7264. https://doi.org/10.3390/ijms22147264
UtgiverUniversity of Stavanger, Norway
SeriePhD thesis UiS;