Towards Large-Scale Platelet Production from Adult Hematopoietic Stem and Progenitor Cells

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This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).0853603W. MillerIntellectual merit Although several research groups have demonstrated the capability to produce small quantities of functional platelets from megakaryocytic cells (Mks) in culture, producing the 3-6 x 10-11 platelets required for a single transfusion dose using current technology would require 250 million CD34+ hematopoietic (blood) stem and progenitor cells. Since an umbilical cord blood harvest typically contains less than 5 million CD34+ cells and peripheral blood harvested from donors treated (or mobilized) with cytokines such as G-CSF (mPB) contains up to 200 million CD34+ cells, the platelet yield must be increased by several orders of magnitude to be practical, The objective of this project is to enable the production of one platelet transfusion dose from one million mPB CD34+ cells - or 500,000 platelets per input CD34+ cell.Broader impacts Platelet transfusions are routinely used for a wide range of thrombotic deficiencies, and several million units are transfused each year in the USA and Europe. However, collecting enough platelets for a single transfusion requires either expensive apheresis equipment or the pooling of platelets from 4 to 8 different donors. There are also concerns with bacterial contamination, blood-borne pathogens, and alloimmunization of recipients. Production of autologous or fully matched platelets from Mks in culture using Good Manufacturing Practices has the potential to alleviate all of these problems, but many challenges remain to be addressed. Successful completion of the proposed research would bring the large-scale production of culture-derived platelets closer to fruition. This project will also contribute to the training of highly qualified individuals. Graduate students and undergraduates working on this project will be trained in an interdisciplinary environment that includes having life science faculty members on graduate student thesis committees and collaboration with faculty and graduate students in the medical school. Graduate students will actively participate, together with students from other engineering and life science departments, and present their work in the seminars and journal club of Northwestern University's predoctoral Biotechnology Training Program, which also provides interactions with scientists and engineers from industry. Each graduate student will attend at least one scientific meeting per year and will present their results and interact with other attendees at engineering, hematology, and interdisciplinary meetings. The PIs will make a concerted effort to recruit underrepresented minority and women graduate students for the Department of Chemical and Biological Engineering and this project, and has supervised a large fraction of female and minority students. The PI?s former doctoral students are employed by diverse pharmaceutical, biotechnology, and engineering companies.