Lurie Cancer Center Member
William M Miller, PhD
Professor, Chemical and Biological Engineering; Robert R. McCormick School of Engineering and Applied Science
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Dr. Miller's laboratory is examining the regulation of hematopoietic stem cell (HSC) self-renewal, lineage commitment, and differentiation, with an emphasis on megakaryopoiesis. HSC expansion has the potential to produce stem cells for gene therapies, including the introduction of drug resistance genes into normal HSCs to minimize damage to blood cells during chemotherapy. HSC expansion is also required to produce culture-derived blood cells and platelets for transfusions. Chemotherapy typically results in low platelet counts (thrombocytopenia), so cancer patients often receive frequent transfusions of donor platelets. However, there are concerns including platelet rejection, platelet shortages, the risk of blood-borne pathogens, and decreased platelet efficacy with extended storage. Production of platelets in culture by megakaryocytic (Mk) cells derived from autologous or matched HSCs would increase the supply and decrease adverse consequences. However, platelet production in culture is very inefficient. Generating multiple units of 500 billion platelets will require advances in HSC expansion, Mk cell production and maturation, and platelet release and recovery. Platelet production has received less attention than HSC expansion or Mk production. Several groups have produced small quantities of functional platelets, but yields are often less than one platelet per Mk, vs. several thousand platelets in vivo. The Mk bone marrow niche – from which proplatelets are extended between endothelial cells into the sinusoids – is comprised of soft tissue, so compliant surfaces are likely to increase proplatelet formation (PPF). Shear from blood flow is important for PPF and platelet release. Inspired by the Mk bone marrow sinusoid niche, Dr. Miller’s lab is investigating the effects of adhesive ligands, substrate compliance, and shear on PPF and platelet biogenesis in static and bioreactor cultures. The lab is also investigating the mechanisms that underlie Mk maturation, including the effects of reversible protein lysine deacetylation, and makes extensive use of the flow cytometry core facility.