Platelets play a central role in the formation of blood clots, and they also contribute to atherosclerosis, inflammation, tumor metastasis, angiogenesis and other medically important processes. Platelet transfusions have been lifesaving for thousands of individuals, and modern cancer medicine would be impossible without the reliable availability of platelets. The fundamental and long range goals of this laboratory are to increase understanding of the mechanisms underlying platelet formation. Platelets are normally produced in the bone marrow by the highly regulated fragmentation of their parent cell, the megakaryocyte. One unanswered question in platelet production is how the megakaryocyte coordinates the synthesis and delivery of the myriad proteins present in each of the thousands of platelets it releases. To answer this question we are investigating the mechanisms of protein processing and trafficking in megakaryocytes, using the highly expressed platelet protein, aIIbb3, as a model system. We are using a multidisciplinary, collaborative approach to integrate data from expression studies using cDNA, inhibitory RNA and site-directed mutagenesis, with functional and morphological cell biology assays, culture and differentiation of megakaryocytes from human stem cells, and with proteomics and bioinformatics in order to increase our understanding platelet formation, with the goal of exploiting this knowledge to benefit human health.
Stem cells, which can be differentiated into any of the body's tissues, are a resource that offers the possibility of generating human platelets ex vivo for therapeutic use. However, current technology can produce only limited numbers of platelets in the laboratory. Accordingly, we are applying our research findings to exploring the means for increasing the yield of platelets from cultured stem cells. We hope that clearer understanding of key events in megakaryocyte development and platelet formation may open the door to increased platelet yield from cultured stem cells.