William M. Miller
Professor of Chemical and Biological Engineering
2145 Sheridan Road
Evanston, IL 60208-3109
Ph.D. Chemical Engineering, University of California, Berkeley, CA
S.M. Chemical Engineering, MIT, Cambridge, MA
B.S. Chemical Engineering (Hons), Lehigh University, Bethlehem, PA
Controlled differentiation of hematopoietic (blood) cells
Our aim is to understand the regulation of hematopoietic stem cell (HSC) self-renewal (division with no loss in stem cell potential) and lineage-specific commitment and maturation. Applications include HSC expansion for transplantation or gene therapy, the selective production of granulocytic and megakaryocytic progenitor and mature cells to eliminate the nadirs in neutrophil and platelet counts after bone marrow transplants, the treatment of hematological disorders, and the production of culture-derived platelets for transfusions. To do this we are (1) evaluating the effects of pO2, pH, and growth factor combinations on HSC expansion and differentiation; (2) using RNA interference (RNAi) to modulate megakaryocytic commitment and differentiation; (3) using a mouse model of myelodysplastic syndromes; and (4) investigating the mechanisms responsible for megakaryocytic maturation.
Cell membrane-mimetic culture surfaces for stem cell expansion
Hematopoietic stem cell self-renewal occurs throughout life in the body, but is very difficult to achieve in culture. The ability to expand HSC numbers would greatly facilitate applications in cell and gene therapies, as well as in bone marrow transplantation. We are attempting to enhance the prospects for HSC renewal in culture by mimicking the stem cell "niche" in the bone marrow, which includes stem cell association with stromal (accessory) cells. We are mimicking the niche by developing lipid-based and polymer-based surfaces for the presentation of multiple cell adhesion molecule (CAM) ligands and bound growth factors that are normally presented by stromal cells and/or the stromal cell extracellular matrix. This project is a collaboration with Prof. Messersmith in biomedical engineering, and combines aspects of materials science (surface preparation and characterization) and stem cell biology (evaluation of HSC responses).
Therapeutic protein and viral vector production
The culture environment affects cell growth and protein production. We have examined inhibition of cell growth by the metabolic by-product CO2, and have evaluated genetic and biochemical approaches to mitigate this inhibition. Also, together with Prof. Aiyar of LSU Health Sciences Center, we have examined parameters (pH, cholesterol supplements, and vector stoichiometry) that affect the production and transduction efficiency of retroviral vectors for gene therapy applications.
"Mussel-Inspired Surface Chemistry for Multifunctional Coatings," H. Lee, S.M. Dellatore, W.M. Miller, and P.B. Messersmith, Science, 318: 426-430 (2007). PMID: 17947576. PMCID: PMC2601629
"Gene-Ontology Driven Transcriptional Analysis of CD34+-Cell Initiated Megakaryocytic Cultures Identifies New Transcriptional Regulators of Megakaryopoiesis," P.G. Fuhrken, C. Chen, P.A. Apostolidis, M. Wang, W.M. Miller, and E.T. Papoutsakis, Physiological Genomics, 33: 159-169 (2008). PMID: 18252802.
"Tumor Suppressor Protein p53 Regulates Megakaryocytic Endomitosis and Apoptosis," P.G. Fuhrken, P.A. Apostolidis, S. Lindsey, W.M. Miller, and E.T. Papoutsakis, J. Biol. Chem., 283: 15589-15600 (2008). PMID: 18397889. PMCID: PMC2414295.
"Mimicking Stem Cell Niches to Increase Stem Cell Expansion," S.M. Dellatore, A.S. Garcia, and W.M. Miller, Curr. Opin. Biotechnol., 19: 534-540 (2008). PMID: 2585613, NIHMSID: 74769. PMCID: PMC2585613.
"Effects of Supported Lipid Monolayer Fluidity on the Adhesion of Hematopoietic Progenitor Cell Lines to Fibronectin-Derived Peptide Ligands for a5b1 and a4b1 Integrins," A.S. Garcia, S.M. Dellatore, P.B. Messersmith, and W.M. Miller, Langmuir, 25: 2994-3002 (2009). PMID: 19183010. NIHMSID: 92497. PMCID: PMC2784606.
"Cholesterol Supplementation During Production Increases the Infectivity of Retroviral and Lentiviral Vectors Pseudotyped with the Vesicular Stomatitis Virus Glycoprotein (VSV-G), " Y. Chen, C.J. Ott, K. Townsend, P. Subbaiah, A. Aiyar, and W.M. Miller, Biochem. Eng. J., 44: 199-207 (2009). PMID: 20160854. PMCID: PMC2663912.
"Energy Sprawl or Energy Efficiency: Climate Policy Impacts on Natural Habitat for the United States of America," R.I. McDonald, J. Fargione, J. Kiesecker, W.M. Miller, and J. Powell, PLoS ONE, 4: e6802 (11 pages) (2009). PMID: 19707570. PMCID: PMC2728545.
"Mechanistic Studies on the Effects of Nicotinamide on Megakaryocytic Polyploidization and the roles of NAD+ levels and SIRT inhibition," L.M. Giammona*, S. Panuganti*, J.M. Kemper, P.A. Apostolidis, S. Lindsey, E.T. Papoutsakis, and W.M. Miller, Exp. Hematol., 37: 13401352 (2009). NIHMSID: 141764. PMID: 19715739. PMCID: PMC2763937.
"Bone Marrow Niche-Inspired, Multi-Phase Expansion of Megakaryocytic Progenitors with High Polyploidization Potential," S. Panuganti, E.T. Papoutsakis, and W.M. Miller, Cytotherapy, 12: 767-782 (2010). PMCID: PMC3077558. NIHMSID: NIHMS256466"Role of Tumor Suppressor P53 in Megakaryopoiesis and Platelet Function," P.A. Apostolidis, D.S. Woulfe, M. Chavez, W.M. Miller, and E.T. Papoutsakis, Exp. Hematol., doi: 10.1016/j.exphem.2011.10.006 (2011).