BS, Lehigh University MS, Massachusetts Institute of Technology PhD, University of California, Berkeley Editor, Biochemical Engineering Journal Fellow, American Association for the Advancement of Science Presidential Young Investigator Award, National Science Foundation Additional awards and honors Cell and tissue culture applications in biotechnology and medicine

Master of Biotechnology Program Website

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.

Recent Publications

Chen, Yong; Ott, Christopher J.; Townsend, Kay; Subbaiah, Papasani; Aiyar, Ashok; Miller, William M. "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., in press (2009).

Dellatore, Shara M.; Garcia, A. Sofia; Miller, William M. "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).

Fuhrken, Peter G.; Apostolidis, Pani A.;  Lindsey, Stephan; Miller, William M.; Papoutsakis, Eleftherios T. "Tumor Suppressor Protein p53 Regulates Megakaryocytic Endomitosis and Apoptosis," J. Biol. Chem., 283: 15589-15600 (2008).

Fuhrken, Peter G.; Chen, Chi; Apostolidis, Pani A.; Wang, Min; Miller, William M.; Papoutsakis, Eleftherios T. "Gene-Ontology Driven Transcriptional Analysis of CD34+-Cell Initiated Megakaryocytic Cultures Identifies New Transcriptional Regulators of Megakaryopoiesis," Physiol. Genomics, 33: 159-169  (2008).

Chen, Chi; Fuhrken, Peter G.; Huang, Li T.; Apostolidis, Pani A.; Wang, Min; Paredes, Carlos J.; Miller, William M.; Papoutsakis, Eleftherios T. "A Systems-Biology Analysis of Isogenic Megakaryocytic and Granulocytic Cultures Identifies New Molecular Components of Megakaryocytic Apoptosis," BMC Genomics, 8: 384 (2007).

Lee, Haeshin; Dellatore, Shara M.; Miller, William M.; Messersmith, Phillip B. "Mussel-Inspired Surface Chemistry for Multifunctional Coatings." Science, 318: 426-430 (2007).

Gunawan, Rico C.; King, James A.; Lee, Bruce P.; Messersmith, Philiip B.; Miller, William M. "Surface Presentation of Bioactive Ligands in a Nonadhesive Background using DOPA-Tethered Biotinylated Poly(Ethylene Glycol)." Langmuir, 23: 10635-10643 (2007).

King, James A.; Miller, William M. "Bioreactor Development for Stem Cell Expansion and Controlled Differentiation." Curr. Opin. Chem. Biol., 11: 394-398 (2007).

Huang, Li-Ting; Paredes, Carlos J.; Papoutsakis, Eleftherios T.; Miller, William M. "Gene-Expression Analysis Illuminates the Transcriptional Programs Underlying the Functional Activity of Ex-Vivo-Expanded Granulocytes." Physiol. Genomics, 31: 114-125 (2007).

Pascoe, Deborah E.;  Arnott, David; Papoutsakis, Eleftherios T.; Miller, William M.; Andersen, Dana C. "Proteome Analysis of Antibody-Producing CHO Cell Lines with Different Metabolic Profiles." Biotechnol. Bioeng., 98: 391-410 (2007).

Fuhrken, Peter G.; Chen, C.; Miller, William M.; Papoutsakis, Eleftherios T. "Comparative, Genome-Scale Transcriptional Analysis of CHRF-288-11 and Primary Human Megakaryocytic Cell Cultures Provides Novel Insights into Lineage-Specific Differentiation." Exp. Hematol., 35: 476-489 (2007).

Giammona, Lisa M.; Fuhrken, Peter G.; Papoutsakis, Eleftherios T.; Miller, William M. "Nicotinamide (Vitamin B3) Increases the Polyploidization and Proplatelet Formation of Cultured Primary Human Megakaryocytes." Br. J. Haematol., 135: 554-566 (2006).

Awards and Honors

• Editor, Biochemical Engineering Journal
• Fellow, American Association for the Advancement of Science
  
• Presidential Young Investigator Award, National Science Foundation
• Fellow, American Association for the Advancement of Science
• Fellow, American Institute of Medical and Biological Engineers
• Lilly Biochemistry Grantee
• Dow Chemical Engineering Teaching Award
• Former Chair, AIChE Food, Pharmaceutical, and Bioengineering Division
• Area 15c speaker for the AIChE Food, Pharmaceutical and Bioengineering Plenary Session
• AIChE Food, Pharmaceutical and Bioengineering Division Service Award

Prof. William M. Miller
Department of Chemical and Biological Engineering
Northwestern University
2145 Sheridan Road
Evanston, IL 60208-3120

tel: 847/491-4828
fax: 847/491-3728
E-mail Professor Miller